Secondary Logo

Journal Logo

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Knezevic, Nebojsa Nick MD, PhD*†‡; Yekkirala, Ajay PhD§‖; Yaksh, Tony L. PhD¶#

doi: 10.1213/ANE.0000000000002442
Chronic Pain Medicine

Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management has limitations, and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of reinforcing activity in the absence of a pain state. The present work provides a nonexclusive overview of current drug targets and potential future directions of research and development. We discuss channel activators and blockers, including sodium channel blockers, potassium channel activators, and calcium channel blockers; glutamate receptor–targeted agents, including N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and metabotropic receptors. Furthermore, we discuss therapeutics targeted at γ-aminobutyric acid, α2-adrenergic, and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors and agonists/antagonists of adenosine, purine receptors, and cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies, which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of druggable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising preclinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans’ targets, which should assist in developing nonaddictive analgesics.

From the *Department of Anesthesiology, Advocate Illinois Masonic Medical Center Chicago, Illinois; Departments of Anesthesiology and Surgery, University of Illinois, Chicago, Illinois; §Department of Neurobiology, Harvard Medical School, and Boston Children’s Hospital, Boston, Massachusetts; Blue Therapeutics, Harvard Innovation Launch Lab, Allston, Massachusetts; and Departments of Anesthesiology and #Pharmacology, University of California, San Diego, La Jolla, California.

Accepted for publication July 31, 2017.

Funding: The authors acknowledge generous funding support from the following National Institutes of Health grants: A.Y.: DA041912 (NIDA), T.L.Y.: DA15353; NS 099338.

Conflicts of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Tony L. Yaksh, PhD, Departments of Anesthesiology and Pharmacology, University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr, La Jolla, CA 92093. Address e-mail to

The management of pain is a clinical imperative. Aside from humanistic concerns, failure to adequately control pain has negative consequences in terms of system biology. Opioids, through their potent modulatory effect mediated via canonical receptors on pain processing, have been, and remain, an essential component of pain management. Nevertheless, reliance on this therapeutic approach has limitations and deleterious consequences to the patient and society. Opioid misuse is an expanding crisis with over 36,000 deaths due to opioid overdose in 2015 alone.1,2 Pharmaceutical companies have pursued abuse-deterrent opioid formulations.3,4 While these formulations reduce the possibility of the content of the pills being extracted, the underlying properties of the pharmaceutical agent (ie, opioids) remain the same and extraction-deterrent systems are subject to being overcome.5–8

Our understanding of systems that mediate and regulate nociceptive processing has yet to produce a recognized alternative to opioids. Advances in pain biology have, however, yielded remarkable insights and opportunities. We will provide an overview of salient areas of research that focus on current advances in pharmacological targets. Meaningful advances in drug therapy must consider not only (i) analgesic efficacy, but also (ii) therapeutic ratio (separation of pain relief from side effects); (iii) constancy of response over extended use (eg, tolerance); (iv) lack of positive reinforcing properties in the absence of a pain state. Due to space restriction, this review must be considered a nonexclusive overview of advances in terms of analgesic targets.

Back to Top | Article Outline


Pain is an aversive state that reflects the perceptual covariates of events that arise from stimuli of sufficient intensity to induce tissue damage or which otherwise mimic the activity induced by such stimuli, as in nerve injury. It is heuristically useful to think of mechanisms generating the aversive condition associated with afferent stimulation as having 4 elements.

  • i. Acute nociception in which an acute, noninjuring, high-intensity stimulus activates small unmyelinated and myelinated afferents, driving intensity-linked excitation of second-order dorsal horn projection neurons, leading to a stimulus-linked pain report/escape.
  • ii. After tissue injury and inflammation, hyperalgesia occurs at the injury site, causing an enhanced response to moderate stimuli, and an enlarging receptive field, including areas not injured, resulting in a second hyperalgesia/allodynia. This phenotype reflects a peripheral sensitization (development of ongoing activity and a left shift in the intensity response relationship at the terminal) and a central/spinal sensitization (heightened excitability of the primary afferent terminal and second-order neurons causing an enhanced discharge to a given afferent input).
  • iii. Injury to the peripheral nerve resulting in ongoing dysesthesias and enhanced sensitivity to light touch and modest changes in temperatures (allodynia), associated with reactive changes in the afferent axon, dorsal root ganglia (DRG) and dorsal horn (typically reflecting a loss of inhibitory regulation).
  • iv. After persistent inflammation and tissue injury, the evolving pain state displays characteristics, suggesting the development of a nerve injury phenotype, for example, an acute to chronic pain transition.

The biology of these above states has been reviewed in detail elsewhere.9–11 These comments importantly emphasize that a pain condition may represent multiple mechanistic phenotypes. Accordingly, the regulation of the encoding and trafficking of the nociceptive stimulus to higher centers may reflect a role for engaging multiple targets.

Back to Top | Article Outline


Demonstration of Target Analgesic Efficacy

Development of analgesic drugs with known targets and mechanisms of action can use models of target engagement, such as in silico and in vitro modeling (eg, opioids and cyclooxygenase [COX] inhibitors), which can move a drug with some predictability into a behavioral assessment. Novel targets often arise based on association of the target with specific systems, but their efficacy in regulating the pain state requires a sense of what role that target plays in mediating the behaviorally defined pain construct. Preclinical behavioral models provide such insights. Detailed reviews of preclinical models that focus on events secondary to inflammation (acute and chronic) and nerve injury (mono- and polyneuropathies) with their strengths and shortcomings have been provided elsewhere.12,13 While instances of failure of the predictive models have been discussed (as is true for virtually every translational system in biology), mechanistic studies have made a number of valid predictions of clinical efficacy ranging from COX inhibitors to antimigraine drugs.9 Several issues regarding preclinical models are noted.

  • i. Each behavioral model has mechanistic components particular to that system. Convergent results from multiple models and comparable dose-effect relationships increase the likelihood of assessing mechanisms relevant to the human state.
  • ii. Preclinical models have long examined a single sex, for several reasons including economy and the belief there is little difference between the sexes. Numerous instances at the behavioral and mechanistic level can now be cited to dispute this assertion.14,15
  • iii. Many models employ threshold measurements. Alternative models use “spontaneous behaviors,” including general activity, rearing, weight bearing, and gait as markers of an aversive condition.16 There is also an understanding that if there is an aversive condition generated by an injury, a drug that has no intrinsic rewarding property but which serves to diminish that pain state will in fact acquire a positive reinforcing property in the presence of the pain state. Such “conditioned place preference” models have an important place in current drug evaluations.16,17
  • iv. While preclinical analgesic drug evaluation has been largely successful in rodents, characterization of issues of analgesic efficacy and tolerability may also be achieved through naturally occurring pathologies in companion animals, notably dogs. The incidence of canine osteoarthritis and osteosarcoma provides an important way station in defining efficacy in controlled trials using validated inventories and neurological assessments.18 While safety-toxicology studies in such animals are routinely part of an investigational new drug package during drug development, there may be an advantage to pursuing efficacy studies as well. Such information is pivotal in the development of veterinary analgesic products and their approval by the US Food and Drug Administration (FDA) veterinary division to manage the pain states in this patient population. The predicted spending on analgesics for pets alone was predicted to be ~$335 million in 2011, so there is a secondary market that can incentivize additional testing in the veterinary patient.19
  • v. Human experimental models initiating a local injury (eg, ultraviolet B irradiation, thermode burn) or afferent stimulation (capsaicin) are increasingly used to determine efficacy of both new and existing analgesics. Their apparent ability to demonstrate efficacy with known analgesics provides some validation of their sensitivity20 and to define a drug effect and corresponding side effects at the effective dose.
  • vi. The following commentary considers a variety of targets and comments on systemic and neuraxial routes of delivery, reflecting the fact that drug effects upon pain processing frequently reflect an action at the first-order synapse. It must be stressed that these discussions do not raise issues of safety. This commentary is particularly relevant for neuraxial drugs where appropriate assessment of neuraxial safety must be undertaken before such drug implementation.21
  • vii. Finally, it is challenging to find a drug target that can alter a pain state with a favorable therapeutic ratio (eg, little or no effects upon mentation, arousal, or motor function). An important concern we must now consider is that the drug target is not a mediator of positive reinforcement.
Back to Top | Article Outline

Assessment of Abuse Liability

An important issue in developing novel analgesics is to overcome the potential for abuse. If the drug acts on components of systems associated with positive reinforcement or possessive of stimulant and/or sedative effects, suspicion of its potential for abuse must be elevated. Such examples, at present, include drugs interacting with opioid receptors, central nervous system (CNS) depressants (γ-aminobutyric acid-A [GABAA] receptors); CNS stimulants (increased dopamine release/block reuptake; nicotine), hallucinogens, glutamate antagonists (ketamine), and cannabinoids.22,23 It seems reasonable that a molecule lacking CNS bioavailability would show a reduced likelihood of having a reinforcing property (eg, loperamide24), but now even large molecules are considered not to be excluded as having potential liability.25 To this end, locomotor, reinforcing, and dependence-producing effects of the agent must be routinely assessed. A variety of strategies are considered relevant and have been effective in predicting human-drug behavior including self-administration, drug discrimination, and conditioned place preference paradigms.26–28

Back to Top | Article Outline






In the following sections, we will consider several current drug targets and potential future directions of research and development. The Figure summarizes these targets as they reflect upon actions at the level of the peripheral terminal and central sites. The Table summarizes those agents that moved into clinical trials.

Back to Top | Article Outline

Sodium Channel Blockers/Potassium Channel Activators

Axon excitability depends directly on voltage-gated sodium channel, while activation of potassium channels produces hyperpolarization reducing membrane excitability. These represent potential peripheral targets for altering afferent transmission.

Back to Top | Article Outline

Sodium Channels.

Voltage-gated sodium channels (Nav) are the target of all clinical “local anesthetics.”29 Nine Nav isoforms with distinct activation properties and tissue distributions have been identified: Nav1.1 and Nav1 (large DRG/axons), Nav1.4 and Nav1.5 (skeletal and cardiac muscle), and Nav1.7, -1. (small sensory DRGs/afferents).30 After inflammation and nerve injury, increases in small afferent Nav (Nav1.3, 1.7, 1.8, and 1.9) expression are believed to underlie ectopic afferent traffic and increased responsiveness.30–32

Specific confirmation of the role of Nav 1.7 in human pain processing is based on the phenotype of naturally occurring gain and loss of function mutations in Nav1.7 channels, wherein those expressing these mutations, respectively, show pronounced increased and decreased pain states.33,34

While local anesthetics given perineurally and neuraxially produce conduction block anesthesia, systemic anesthetics such as intravenous lidocaine have surprisingly selective antihyperpathic effects in a variety of preclinical models and human pain states at concentrations that do not produce a general conduction block, suggesting a differential sensitivity of systems related to facilitated states after tissue and nerve injury.35,36

Future development of the sodium channel–blocking drugs focuses on the role of selective blockers of channels expressed on nociceptive linkages. Clinically used local anesthetics (amide and ester) do not selectively block these channels,37 although several isoforms are sensitive to puffer fish toxin, tetrodotoxin (TTX) (Nav1.1–7), with the remainder resistant to TTX.37,38 Toxin-based sodium channel blockers, neosaxitoxin and TTX, demonstrated long-lasting nerve blocks after perineural and intrathecal delivery and, surprisingly, after systemic delivery in human and animal models38–41 (Table). In regard to selective channel antagonists, intrathecally delivered, toxin-based Nav1.742 and 1.843 inhibitors have shown preclinical efficacy in models of inflammation and nerve injury, with a favorable therapeutic ratio. Development of systemically bioavailable, small-molecule, channel-selective antagonists as analgesics have faced challenges.44,45 Clinical work with oral-targeted, sodium channel–selective blockade was negative,46 although promising results from multicenter studies in postherpetic neuralgia and primary erythromelalgia have been reported.47 Loss of response to local anesthetics (eg, tolerance or tachyphylaxis) has been reported after neural blocks, but the phenomenon does not appear to be robust.48

An interesting application of the specific association of transient receptor potential vanilloid 1 (TRPV1) with pain afferents has been the use of protonated local anesthetics such as QX314, which are able to enter the otherwise impermeant axon membrane through TRPV1 channels upon their activation by capsaicin, and result in function block of the sodium channel in the TRPV1 (+) afferent axon.49 It is now understood that lidocaine by itself is a TRPV1 agonist and can promote passage of the protonated form,50 allowing quaternary lidocaine (QX314) to enter the TRPV1-bearing axon and selectively block the Nav channel, resulting in specific block of TRPV1 (+) primary afferents.50

Back to Top | Article Outline

Potassium Channels.

There are 4 major families of K channels (voltage-gated [Kv], calcium-activated [K Ca], inwardly rectifying [Kir], 2 P domain [K2P] potassium channels), which when activated lead to membrane hyperpolarization through increased potassium conductance. Genetic analyses illustrate that variations in several K+ channel genes are relevant to the risk for persistent pain after injury (KCNS1-Kv9.1, GIRKs-Gir, TRESK-K2P18.1), increased pain sensitivity (KCNS1, GIRKs), and analgesic efficacy of G-protein–coupled receptors (GPCRs; GIRK2).51 Inwardly rectifying, ATP-sensitive potassium (K-ATP) channels are widely expressed in numerous cell types including neurons and are linked to antiallodynic and antihyperalgesic activity. ATP-sensitive potassium channel agonist–mediated antinociceptive effects are reversed with pretreatment with ATP-sensitive K+ channel blockers.52,53

Interestingly, autoantibodies targeting Kv channels can lead to neuronal hyperexcitability and a pain state.54 Increasing potassium channel expression and potassium conductance via receptor channel agonists assists in hyperpolarizing (normalizing) otherwise enhanced axon, DRG, and terminal excitability, resulting in antihyperalgesic actions.55,56

Back to Top | Article Outline

Calcium Channel Blockers

Movement of calcium into the cell represents a significant source of charge leading to membrane depolarization, while increased intracellular calcium leads to activation of a variety of kinases that phosphorylate: enzymes, channels (lower threshold for activation and increasing ion permeability), and receptors, resulting in hyperalgesic states.57–60 One source of this intracellular calcium is a variety of high and low voltage-gated calcium channels (VGCCs): high VGCCs include L-(CaV1.1–4), P/Q-(CaV2.1), N-(CaV2.2), and R-(CaV2.3) type channels; low VGCCs include T-type (CaV3.1–3).61,62 These are transmembrane channels composed of multiple subunits endowing members of each family with distinguishing properties of voltage gating and antagonist pharmacologies. They are located on primary afferents and postsynaptic membranes in spinal dorsal horn.63

Back to Top | Article Outline

N-Type Channel (Cav2.2).

The N-type calcium channel is present on presynaptic nerve terminals in the superficial dorsal horn and dorsal root ganglia. Upregulation occurs after peripheral nerve injury.64 Ziconotide, is an N-type VGCC blocker,65 possessing potent antihyperpathic properties in rodents and humans when administered intrathecally as a bolus or an infusion66,67 and is without tachyphylaxis (tolerance).68 Although ziconotide remains the only approved N-type channel blocker, there are efforts to develop new peptides and small molecules65,69 and to alter nociceptive properties of N-type VGCC function by hindering its membrane trafficking.70,71 In humans, a systematically active N-type calcium channel blocker (Z160) failed in phase 2 clinical trials in treatment of postherpetic neuralgia and lumbosacral radiculopathy72 (Table).

Back to Top | Article Outline

L-Type Channel (Cav1).

Channels are largely present postsynaptically and are considered to play a possible role in maintaining facilitated states. Intrathecal delivery preclinically of channel blockers (nifedipine, verapamil, and benzothiazepines) has shown efficiency in altering injury-induced hyperpathia.73

Back to Top | Article Outline

T-Type Channel (Cav3.2).

T-type calcium channels are present in the dorsal horn and channel blockers, such as ethosuximide and mibefradil, have antihyperalgesic effects in rodents.74

Back to Top | Article Outline

Glutamate Receptor–Targeted Agents

Glutamate released from primary afferents, interneurons, and sequestrated stores in astrocytes may interact with a variety of receptor-gated ionophores and receptors with G-protein coupling.

Back to Top | Article Outline

NMDA Receptor.

The N-methyl-d-aspartate receptor (NMDA-R) is a calcium ionophore composed of 3 subunits (NR1, NR2, and NR3), each with multiple combinations of subunits.75 This channel is expressed on primary afferents in the dorsal horn, on second-order neurons, and on nonneuronal cells (oligodendroglia and astrocytes). Glutamate is released from afferents and interneurons and binds to the NMDA-R. At the spinal dorsal horn, high-frequency C-fiber stimulation leads to postsynaptic depolarization, removal of an Mg2+ ion blocking the pore, and, if the allosterically coupled channel-binding sites for glycine and polyamines are occupied,76 there is a channel influx of sodium and calcium,76 leading to a cascade known as windup.77 NMDA-R blockade inhibits this phenomenon.

Block of NMDA-R function is achieved by competitive glutamate-binding site blockers, noncompetitive channel blockers, and agents blocking associated allosteric binding sites.78 While NMDA-R function may be prevented by blocking any of these sites, the side effect profile (learning, memory, excitability) for these different agents varies considerably and impacts clinical tolerability.79

Preclinical work has demonstrated the antihyperpathic effects in inflammatory and nerve injury models of a variety of intrathecally and/or systemically administered competitive glutamate blockers (2-amino-5-phosphonovalorate), noncompetitive NMDA channel blockers (ketamine, MK-801 and memantine, conantokin-G; agmatine), and glycine site blocker (7-chlorokynurenic acid, ifenprodil).80–82 Ifenprodil administered into the rostral cingulate cortex alleviated bone cancer pain in rats.83 While there are surprisingly few high-quality clinical trials, ketamine has a long clinical history of use alone and in combination with opioids in diverse pain states characterized by hyperalgesia and allodynia, including neuropathic pain, surgery, and fibromyalgia.84–88 Ifenprodil, an inhibitor of the NMDA glycine-binding site, is currently being tested for the treatment of posttraumatic stress disorder in phase 1/2 study (Table).

The abuse potential of NMDA antagonists is controversial and complex.89 Channel blockers such as ketamine have identified abuse potential. This effect may be mediated by channels associated with specific subunit constituents.90 The role of other antagonism motifs in contributing to abuse potential is not known.

Back to Top | Article Outline

AMPA Receptor.

The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor is a glutamate-activated sodium-selective ionophore composed of 4 subunits (GluR1 to GluR4), which plays a pivotal role in acute dorsal horn evoked excitation.91 In preclinical studies, tezampanel (LY-293558, NGX-424) displayed efficacy in postoperative pain and spasticity.92,93 In humans, oral administration showed efficacy upon capsaicin-evoked hyperalgesia94 and in postoperative pain.95

With peripheral injury, the AMPA subunit composition changes, leading to a calcium-permeable channel. Joro spider toxin, selective for calcium-permeable AMPA site, decreases secondary mechanical allodynia development evoked in tissue injury models.96 The abuse potential of these agents is not known.

Back to Top | Article Outline

Metabotropic Receptors.

Eight mGluRs (mGluR1–8) have been identified and are divided into 3 groups97: group I (mGluR1 and mGluR5) stimulates phospholipase C (PLC); group II (mGluR2 and mGluR3) and group III (mGluR4 to mGluR8) inhibit adenylate cyclase.97,98 mGluRs have been localized on the primary afferents, neurons, and glia within the brain and spinal cord.99,100 Group I resides postsynaptically, and group II and group III are dominantly located on presynaptic terminal.101

Activation of group I mGluRs is linked to central sensitization and persistent nociception, while the activation of group II mGluRs suppresses facilitated states.102 Group I mGluR antagonists have an analgesic action by an effect on peripheral terminal, spinal, and supraspinal sites.103 Group II mGluR agonists regulate neurotransmitter release and depress pain transmission by acting at different levels of pain neuraxis, including nociceptors, dorsal horn, and supraspinal regions such as the amygdala and periaqueductal gray.104 Group III mGluR agonists are also involved in the control of hyperalgesia after inflammation. As with the other metabotropic receptors, agonist injections into a peripherally inflamed site or into the spinal dorsal horn regulate glutamatergic transmission in inflammatory and neuropathic pain.103 Group I mGluRs antagonists and group II and III mGluRs agonists exhibited analgesic properties in neuropathic or inflammatory pain states105–112 and may serve as a basis to develop future spinally targeted agents.113,114 Importantly, antagonists affecting group I mGluRs have minimal impact on fast synaptic transmission and minimal cognitive effects as compared to ionotropic glutamate antagonists.115

Blocking a glutamate transporter (excitatory amino acid transporter [EAAT-3]) reduces intracellular glutamate, attenuates pain, and decreases cellular activation. In addition to their cytoplasmic location, mGluR5s are nuclear and may mediate these effects of intracellular glutamate. Accordingly, cell-permeable mGluR5 antagonists may show increased efficacy in attenuating neuropathic pain.116

Regarding abuse potential, central group I mGluRs appear to be substrates for stimulants.115 Importantly, antagonists at group I mGluRs reduce self-administration with no alteration in motor function or the reward value of natural rewards, while agonists at group II mGluRs prevent reinstatement of drug seeking after abstinence.117

Back to Top | Article Outline

GABA Receptors

GABA, a principal inhibitor transmitter, is expressed in neurons throughout brain and spinal cord. GABAergic spinal interneurons presynaptically regulate large mechanosensitive afferents and postsynaptic excitation input by a potential interaction with 2 GABA receptors: the GABA-A ionophore and the GABA-B metabotropic receptor.118,119

Back to Top | Article Outline

γ-Aminobutyric Acid-A.

The GABA-A receptor is a GABA-gated chloride ionophore and is composed of 5 subunits, each with 4 transmembrane-spanning domains. The specific subunits define the binding of a number of molecules at the ionophore. Drugs can activate the channel (GABA, Muscimol), while others (benzodiazepines, neurosteroids, alcohol, many anesthetics) act as positive allosteric modulators at channels having specific subunit composition, stabilizing an open conformation in the presence of the agonist and at greater concentrations to directly activate the chloride channel.120 Studies show dense and variable staining for GABA-A subunits in brain121 and spinal dorsal horn and on primary afferent terminals,118,122 regulating their excitability.123,124 Nonspinal GABA-A ionophore activation leads to sedative, anxiolytic, and amnestic effects, whereas at the spinal level increased GABA-A activity alters motor function.125 The high degree of GABA-A receptor structure/subtype heterogeneity raises expectations for determining specific structures to target these subtypes.126–129 Subtype specificity may exhibit different effects upon neuronal inhibition in various systems.130

GABA-A agonists, such as muscimol or isoguvacine, display preclinical efficacy in neuropathic pain models.131–135 Intrathecal benzodiazepines depressed nociceptive reflexes in dogs,136 while bolus intrathecal midazolam has displayed efficacy in postoperative, low back, and labor pain in humans.137–140 At allosteric binding sites, neurosteroids, such as allopregnanolone, have shown efficacy in preclinical models of tissue and nerve injury.141 Of note, etifoxine promotes production of 3alpha-reduced neurosteroids and has efficacy in reducing mechanical and thermal pain symptoms in vincristine-induced neuropathic pain.142 Further, etifoxine, by binding to GABA-A receptor subunits, has shown to be effective in different pain disorders followed by anxiety.143 Etifoxine was clinically tested in combination with lorazepam for cognitive improvement in elderly patients (Table).

The abuse potential of GABA-A-targeted drugs is clearly suggested by role of the GABA-A receptor in reward circuitry. It is clear, however, that the potential abuse for any GABA-A-targeted drug must be interpreted in terms of the subunits with which the drug interacts and the systems with which the subunits are associated.144

Back to Top | Article Outline

γ-Aminobutyric Acid-B.

Two GABA-B receptors have been cloned and are metabotropic receptors serving to block the opening of voltage-gated Ca channel and activate inwardly rectifying K channels. These receptors are expressed peripherally and centrally, including thalamus, brainstem nuclei, and spinal cord. While positive antinociceptive actions have been reported, they tend to be minimal. An important element is the potent effect on motor neuron excitability leading to a clinically useful effect on elevated motor tone underlying spasticity occurring with neuraxial injury.119 Lioresal, typically used by oral or intrathecal delivery in spasticity, is not a controlled agent, but significant withdrawal can be seen with drug termination.

Back to Top | Article Outline

Opioid Receptor–Targeted Drugs

Mu-opioid receptor–targeted agonists represent the gold standard for modifying acute nociceptive processing. This action reflects the association of these receptors (i) with small afferent input that encode nociceptive processing at the spinal dorsal horn and, (ii) at supraspinal levels, regulating spinal processing through descending pathways, altering perceptual processing, and initiating reinforcing/reward circuit function.145 Apart from their analgesic efficacy, the classic opioids display tolerance, physical dependence, respiratory depression, and a high propensity for abuse.

Back to Top | Article Outline

Receptor Targeting.

There are 3 identified gene products that yield 3 families of opioid receptors (μ/MOR, δ/DOR, and κ/KOR)146 that, when activated, alter pain processing in a naloxone-reversible fashion. More recently, identification of a receptor for the neuropeptide nociceptin has led to designation of a fourth receptor family (NOP), which is typically naloxone insensitive. While subtypes have been proposed, it appears likely that differences in pharmacology within a class may reflect on properties endowed by receptor organization and posttranslational processing versus a distinctive receptor protein. These receptors are widely distributed in the brain and spinal cord and are characterized by comparable transmembrane-spanning motifs and intracellular GPCR signaling. At the membrane level, opioid receptors have typically been shown to be coupled, so that there is a presynaptic action reducing terminal release through a block of calcium-mediated exocytosis and membrane hyperpolarization through an increased potassium conductance.147 At the spinal level, the distribution of opioid receptors on C-fiber terminals and second-order neurons is consistent with the analgesic actions being mediated by a block of excitatory transmitter release from C-fibers and inhibition of second-order neuron excitability.145 A peripheral opioid action manifested on sensitized afferent nerve terminals is observed reflecting in part the presence of opioid receptors on the peripheral terminals of the afferent.148 Supraspinal opioid actions have been identified, wherein the classic descending pathways are considered to be activated by the effects of the opioid receptor on GABA interneurons in the mesencephalon removing a tonic modulation of downstream descending projections.149 Higher order action on forebrain structures have additionally been identified145 and likely reflect upon the effects of opioids on distress.150 Recent work has suggested possible efficacy of κ-opioid antagonists as a migraine therapeutic.151 Preclinical actions of opioids and their effects mediated through the several opioid receptors on pain behavior after systemic and spinal delivery have been reviewed extensively.145,152–154

As noted, the common opioid target for the clinically used agents is typically the µ-receptor. The possibility that among these receptors there may be subtypes appears likely to reflect other aspects of signaling, including ligand bias and the role of heteromers (see below). δ-Opioid receptors clearly exert a regulatory role.153 Intrathecal δ-preferring agonist such as DADL has analgesic efficacy in humans after intrathecal delivery.155 Two nonpeptide molecules ADL5747 and ADL5859 were 2 orally bioavailable compounds156 tested for acute (NCT00993863) and chronic (NCT00979953) pain management in phase 2 clinical trials but were not more effective than placebo in osteoarthritic patients.

κ-Opioid agonists that are peripherally restricted have shown minimum abuse potential and efficacy in inflammatory and visceral pain. This along with the potential of a reduced side effect profile and lower abuse potential suggests such agonists as promising candidates for treating pain.157,158

Interestingly, while there is a typical aim to seek selective agonists, some have argued that effective improvements in efficacy side effect profiles may be achieved through ligands targeting multiple opioid receptors.159,160

Back to Top | Article Outline

Biased Ligands.

One of the major strategies that is gaining interest is that GPCRs can associate with multiple second messengers (such as G α proteins, β-arrestin) and ligands can modulate GPCR response via one of those functional pathways, thereby exhibiting “biased agonism.”161,162 Such biased agonists at the μ-opioid receptors produce analgesia with limited side effects.163 Currently, a biased ligand (TRV130) shows analgesia with reduced respiratory depression in phase 2 clinical trials164 (Table). Recently, an in silico screening approach has identified PZM21, as a μ-opioid-biased agonist that shows promising analgesic data with reduced side effects.165

Back to Top | Article Outline

Heteromeric Receptors.

Many GPCRs couple to yield homo- and heteromers.166–168 Such oligomerized receptors serve as targets for developing novel analgesics. For instance, a bivalent ligand containing µ-agonist and δ-antagonist pharmacophores linked via a spacer (MDAN-21) effectively bridges µ-δ opioid receptor heteromers and exhibits enhanced efficacy and a reduced tendency for tolerance.169,170 Better understanding of µ- and δ-opioid receptor heteromers will help in understanding peripheral pain, as well as development of tolerance, as it has been shown that several clinically used opioids are also selective for these heteromers.171–173 A combination of µ-receptor agonists and cannabinoid receptor agonists in rhesus monkey models showed significant antinociception.174 µ-Opioid receptor and CB1 (cannabinoid) receptor heterodimers175 and µ-mGluR5176,177 heteromers with opioid and nonopioid binding sites expressed strong antinociceptive effects in a range of models. In addition, a small-molecule agonist for the μ-κ opioid receptor heteromer, N-naphthoyl-β-naltrexamine, is a potent antinociceptive agent with no propensity to display physical dependence or drug-seeking behavior.178

Back to Top | Article Outline

Tissue Target-Selective Opioids.

Inflamed tissues display an acidic environment as compared to a healthy tissue. NFEPP ([{±}-N-{3-fluoro-1-phenethylpiperidin-4-yl}-N-phenylpropionamide]) is a μ-opioid agonist that displays pH-sensitive binding and is thus limited in its activity to a peripheral action at injured/inflamed tissues inflammatory. It is reported to be absent CNS effects or display addiction potential.179

Abuse liability of the classical analgesic opioid agonists reflecting an effect on higher order neuraxial function is clear. To the degree that a pain state reflects on activity generated by a peripheral stimulus (eg, tissue injury, inflammation, neuroma), opioids with a peripherally restricted action acting upon systems outside the blood–brain barrier offer a potential way forward. As reviewed above, there is anticipation that NOP agonists or opioid agonists restricted to a peripheral action do not have intrinsic reinforcing effects.154 Additional work on the biased ligands and heterodimer systems is required.

Back to Top | Article Outline

α2 Adrenergic Receptor-Targeted Drugs

α2 Adrenergic agonists have a potent analgesic action that is accompanied by sedation. The analgesic effects are mediated in large part by spinal α2 receptors of which there are 3 subtypes (α2A, B, C).180 These are GPCRs that regulate dorsal horn excitation produced by small primary afferent input. Studies with mutations, antisense, and antagonists suggest an important role for the α2A subtype.181–183 α2 Agonists delivered systemically or intrathecally have significant effects upon acute, inflammatory, and nerve injury hyperpathias.184,185 In humans, neuraxial α2 agonist (clonidine) and systemic (clonidine, tizanidine, dexmedetomidine) have analgesic properties with sedation being a common sequelae of the actions of these agents. Dexmedetomidine is not a controlled substance. While the dependence potential of dexmedetomidine has not been studied in human, preclinical studies have shown, as with clonidine, withdrawal upon discontinuation.186

Back to Top | Article Outline


Cannabinoids can produce strong antinociceptive results in various animal models of acute, tissue injury, and nerve injury-induced nociception.187 Cannabinoid receptors (CB1 and CB2) are G-protein–bound receptors that negatively bind via Gi/o proteins.188 CB1 receptors are found in spinal neurons, particularly in the dorsal root ganglia,189 and its agonists decrease excitatory transmitter release, whereas CB2 receptors reside in spinal microglia and attenuate microglial activation.190,191 Cannabinoids mediate their psychotropic effects through CB1, not CB2.192,193 Ligands that interact with CB1 and CB2 demonstrated the ability to regulate nociceptive processing.194,195 Agents that block the metabolism of CB1 endogenous agonists consequentially increase its concentration and may be used to activate cannabinoid receptor function.196 CB1- and CB2-selective agents, when intrathecally delivered, decreased facilitated states such formalin model, hyperpathia in neuropathy models and in tumor bone pain in rodents.197–199 Cannabinoid role in pain processing is based on spinal and nociceptive neuron inhibition, although peripheral sites of action have also been identified. The use of spinal cord stimulation in a rodent neuropathic pain model revealed long-lasting and incremental reduction of hyperalgesia mediated by endocannabinoids. The effect was amplified by coadministration of LY2183240, an endocannabinoid reuptake/breakdown inhibitor, and inhibited by a CB1 receptor antagonist, AM251, but not by a CB2 receptor antagonist, AM630.200 CB2 receptor antagonists may be a potential target in treating chronic pain of several etiologies by modifying cytokine profile when blocking peripheral immune tissue receptors and by blocking receptors in neurons and glial cells.201

The antinociceptive effect of eslicarbazepine acetate (ESL), an antiepileptic drug derived from carbamazepine/oxcarbazepine, has been shown to be mediated by serotonergic 5-HT1B/1D and cannabinoid CB1/CB2 receptors. ESL showed beneficial effect in different neuropathic and visceral pain models.202 ESL has been tested clinically in different pain conditions (diabetic neuropathy, postherpetic neuralgia [PHN], fibromyalgia, etc; Table).

Abuse potential associated with CB1 receptor agonists has been well documented.203 The CB2 receptors has been shown to modulate ventral tegmental dopamine neuron activity, circuitry considered pivotal in the addictive process.204

Back to Top | Article Outline

Angiotensin 2 Receptor Antagonist

Angiotensin may reside in primary afferents and can activate facilitatory cascades mediated through AT1 and AT2 receptors.205,206 An AT2 antagonist, EMA401, has been tested in phase 2 clinical trials for the treatment of PHN, and preliminary data showed that it is well tolerated and it exhibited a primary analgesic efficacy end point.207 Two phase 2b studies with EMA401 for PHN and painful diabetic neuropathy were put on hold.208 However, recently, the new phase 2 study for PHN was registered at (Table).

Back to Top | Article Outline

Adenosine Agonists/Antagonists

In models of acute nociceptive processing,209 neuropathy209–213 and inflammatory pain214 administration of adenosine and related ligands yielded significant antihyperalgesic effects. Intrathecally administered adenosine lowered allodynia in experimental pain models215,216 and in patients experiencing neuropathic pain,217,218 although negative results have also been reported.219 Adenosine activates 4 G-protein–bound receptors: A1, A2A, A2B, A3.220 A1 receptors, which presynaptically inhibit neurotransmitter release and postsynaptically inhibit excitatory transmission,221,222 are found on dorsal horn neurons and on small- to medium-sized neurons of the DRG.221,223–226 A2A receptor agonists were reportedly able to cause long-term reversal of allodynia in mononeuropathies,227 while the possible explanation was the role of A2A agonists as potential glial inhibitors. In addition, A2A receptors may enhance glutamate release and A2A antagonists may behave protectively by reducing such excitatory effect.228 A2A receptor knockout mice showed a significant reduction of the mechanical allodynia and a suppression of thermal hyperalgesia and allodynia, as well as attenuated expression of microglia and astrocytes, confirming potential beneficial role of A2A receptor antagonists in the treatment of neuropathic pain.229 Activation of the A3 adenosine receptor (A3AR) blocked hyperalgesia in mono- and polyneuropathies.230 The abuse potential of agonists at these A1-3 receptors is not known.

Back to Top | Article Outline

Purine Agonist/Antagonists

Adenosine triphosphate, widely present in the CNS,231 reacts with P2 receptor family with several subtypes: the P2X ligand-gated ionotropic receptors (consisting of 7 subtypes) and P2Y\GPCRs (divided into 8 subtypes). P2Y receptors may signal either via Gq/G11 to initiate the phospholipase C/inositol triphosphate (InsP3) endoplasmic reticulum Ca2+-release pathway (the P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 receptors) or via Gi/o, blocking adenylate cyclase and modulating ion channel function.232 Both P2X and P2Y receptors reside in dorsal root ganglia, spinal neurons, and glia.233 These receptors serve to activate glia, leading to the spinal release of proinflammatory proteins and cytokines underlying a facilitated pain state.234–238 Transient reversal of hyperpathia after nerve injury was achieved via intrathecal administration of P2X and P2Y inhibitors.239–242 The P2X3 subtype is predominantly on C- and Aδ-fiber primary afferent neurons. P2X3 antagonists have shown efficacy in inflammatory and in mono- and polyneuropathic pain states.243 P2X4 subtype is important in spinal facilitation that originated from tissue and nerve injury.244 P2X4R antisense oligodeoxynucleotide intrathecal delivery prevented P2X4R protein expression and restrained mechanical allodynia development.239 P2X4R, by modulating neuroimmune interactions in the spinal cord and DRG, could have an important role in development of neuropathic pain, signifying potential therapeutic effects of P2X4 receptor antagonists.245 Electroacupuncture showed beneficial effect in neuropathic pain models by attenuating interferon-γ release and reduced expression of P2X4R in microglia.246 Furthermore, duloxetine, a serotonin and noradrenaline reuptake inhibitor, showed results in neuropathic pain models by inhibition of P2X4 receptors.247 AF-219, a P2X3 antagonist, is in clinical development as an antitussive. The abuse potential of purine receptor agonists and antagonists is unknown248 (Table).

Back to Top | Article Outline

Innate Immune Signaling

Toll-like receptors (TLRs), a key sensory component in innate immune function, are found on neuronal and nonneuronal cells in the spinal cord and function by recognizing injury-associated molecular structures, while being strongly associated with proalgesic/inflammatory cytokines (DRG).249,250 Intrathecal TLR4 antagonist administration resulted in improved effects within inflammatory and neuropathic pain states251 and was associated with opioid-induced hyperalgesia phenomenon.252 Another perspective on the role of TLR4 signaling was noted when it was found that the spinal delivery of a TLR4 antagonist (lipopolysaccharide-RS [LPS-RS]) would prevent the transition from an acute inflammatory state to chronic postinflammatory state with neuropathic pain phenotype,253 while a small-molecule TLR4 antagonist (TAK242) would prevent the onset of late-phase allodynia after intraplantar formalin.254 Repeated intrathecal administration of LPS-RS (TLR2 and TLR4 antagonist) and LPS-RS Ultrapure (TLR4 antagonist) attenuated allodynia and hyperalgesia and potentiated the effect of buprenorphine but not morphine.255 Effort has been put into developing new structures to block TLR activation by interacting with the TLR4 ligand or downstream signaling256–258 as shown by the antihyperpathic effects achieved by inhibition of MyD88 signaling.259

Back to Top | Article Outline

Lipid Mediators


The role of lipid mediators, such as the omega-6–derived prostaglandins, which produce a sensitized primary afferent and is centrally facilitated and mediated by eponymous receptors, has been long appreciated. Discovery of cyclooxygenase isoforms led to the rational development of prostanoid receptor antagonists and isoform-specific inhibitors, which were shown to have both a peripheral anti-inflammatory and a central action on spinal facilitatory processing.260 Nonselective and COX-2 inhibitors have been shown to have significant antihyperpathic effects in a variety of tissue injury pain states in animal models260 and in humans.261 Unfortunately, typical limiting issues involve target-related actions on cyclooxygenase (gastrointestinal, platelet function, and cardiovascular) side effects.262 An interesting parallel to the nonsteroidal anti-inflammatory drugs is the actions of acetaminophen.263 This molecule has been shown to be efficacious in a variety of preclinical models and in clinical pain states associated with inflammation and tissue injury and in mono- and polyneuropathies, with dose-dependent effects on hyperalgesia and allodynia.264–266 Available as an over the counter, this agent, in the United States for more than 100 years, has revealed no abuse liability. In spite of its utility, its mechanism of action is at best controversial.265

Back to Top | Article Outline

Soluble Epoxide Hydrolases.

The epoxidized metabolites obtained from omega-3 long-chain fatty acids show anti-inflammatory and an antihyperpathic effect in a variety of preclinical models. However, they are being rapidly metabolized by enzymatic hydrolysis by soluble epoxide hydrolases. Of interest, inhibitors of soluble epoxide hydrolase have been shown to have significant antihyperalgesic actions in a variety of preclinical models.267

Back to Top | Article Outline


Inflammatory cascades are typically self-limited leading to the healing phase of an injury. One of the mechanisms of this resolution has been a variety of lipid mediators referred to as proresolvins. These endogenous mediators include omega 3- (resolvins, protectins, and maresins) and omega 6-derived lipoxins. It is increasingly recognized that anti-inflammation and proresolution cascades represent distinct mechanisms for controlling the inflammatory response.268 Delivery of a variety of these proresolvin molecules has shown to have significant antihyperpathic actions in a variety of inflammatory, mono-, and polyneuropathic models.269,270 The abuse potential of these lipid mediators is not known.

Back to Top | Article Outline

Anti-inflammatory Cytokines

Upon activation of various glial signaling cascades, numerous cytokines (including activation of nuclear factor-κB) influence the proinflammatory mediators’ production (eg, tumor necrosis factor, interleukin [IL]-6, and IL-1β), which, in turn, activate proalgesic cascades.271 Additionally, such cascades can aid in the release of anti-inflammatory products (eg, IL-4, IL-6, IL-10, IL-11, IL-13, TGF-β) and soluble cytokine receptors,272 which control the inflammatory cascade.273

Back to Top | Article Outline


It has been shown that IL-10 is one of the most powerful endogenous anti-inflammatory cytokines in the nervous system.274 In animal models, IL-10 intrathecal delivery demonstrated therapeutic efficacy in various chronic pain models, primarily in treating different types of neuropathic pain.274 In different animal models, viral vector-mediated expression of IL-10 in DRGs prevented development of painful diabetic neuropathy275 and helped in treatment of HIV-induced neuropathy.276

Back to Top | Article Outline


Another anti-inflammatory cytokine IL-4 showed beneficial role in treating different types of neuropathic pain in different animal models.277–279 An interesting variation is the intrathecal transfection of an IL4/IL10 fusion protein leading to a potent and persistent antihyperalgesia.280

Back to Top | Article Outline


There is an increasing interest in the potential of producing long-term changes in neuraxial pain processing by the peripheral or spinal delivery of agents that target the functionality of systems processing pain information. Here the consideration is for the treatment of persisting pain states. The role of these therapeutic approaches is not clear at the present time. For those approaches leading to permanent loss of cells, such as the saporin conjugates or the TRPV1 agonists, it appears less likely that they would be used outside the terminal patient (as in cancer). Toxins that result in long-lasting but irreversible effects such as the botulinum toxins (BoNTs) might be a therapeutic approach for persistent pain states in a nonterminal patient.

Back to Top | Article Outline

TRPV1 Receptors.

TRPV1 channels are with few exceptions located on the central and peripheral terminals of high-threshold primary afferents. Topical281 and spinal delivery282 of TRPV1 agonists such as capsaicin or analogues such as resiniferatoxin desensitize the TRPV1 (+) afferent and destroy the DRG terminal283 by calcium cytotoxicity284 and analgesia. The effects after topical delivery have led to the approval of transdermal capsaicin.285 Neuraxial delivery of TRPV1 agonists has been shown to result in robust antinociception in dogs.286,287 Intrathecal resiniferatoxin showed potent and persistent antihyperalgesic effects refractory bone cancer pain in canines, without evidence of deafferentation sequelae.288 One clinical trial testing the use of intrathecal resiniferatoxin for intractable cancer pain was begun and is currently on hold (Table).

Back to Top | Article Outline

Saporin Conjugates.

GPCRs undergo internalization when occupied by their respective agonists.289 Appropriate linking of a G-protein–targeted agonist such as substance P (SP) and a toxin such as saporin (plant product from Saponaria officinalis which is not otherwise taken up by the cell) will result after agonist binding to the neurokinin 1 (NK1) receptor, internalization of the agonist, and toxin complex into the cell expressing that receptor.290 Saporin blocks ribosylation and protein synthesis, resulting in cell death. The NK1 receptor, a GPCR, found on postsynaptic second-order dorsal horn nociceptive neurons291 is taken up into the neuron and the neuron dies. Intrathecally administered sP-saporin, but not saporin, robustly destroys NK1(+) dorsal horn neurons and attenuates pain states in rodents and bone cancer pain in dogs.292–294 Intrathecal administration of sP-saporin is currently in phase 1 clinical trial for the treatment of intractable cancer pain (Table). Importantly, this functional coupling of a ligand to saporin is effective for any ligand for any GPCR that displays internalization.290

Back to Top | Article Outline

Botulinum Toxin.

These toxins are composed of a heavy chain and a light chain (LC). The heavy-chain portion enables the toxin to be taken into the cell. Once inside, the complex is cleaved, freeing LC, which serves as enzyme cleaving Soluble N-ethylmaleimide-sensitive fusion protein Attachment protein REceptors (SNARES).295,296 SNAREs mobilize vesicles for transmitter release and aid in the transport of GLUA1 AMPA receptor subunits to the membrane.297 In case of SNARE cleavage, transmitter release is blocked. Preclinically, intrathecally administered BoNTs produced antihyperalgesic effects in various inflammatory and neuropathic hyperpathia.298–301 The BoNT uptake is ubiquitous, and the potent effects on transmitter release may include inhibitory interneurons and motor neurons.151,302 Several BoNT serotypes have been shown after topical application to be taken up and to block both local (peripheral) release from a nociceptor and to be transported centrally to inhibit downstream nociceptive processing, with indications of a possible pre- and postsynaptic effect.303 Intravesical injections of onabotulinumtoxin-A (BoNT-A) showed significant pain reduction in patients with interstitial cystitis/bladder pain syndrome refractory to other treatments, suggesting a local effect upon the urothelium.304 Coupling of the LC of BoNT-A with substance P showed a beneficial role in treating chronic pain after intrathecal delivery.305

Back to Top | Article Outline

Transfection Targets

The use of viral transection at the spinal level represents an exciting approach to modify spinal function. Intrathecal delivery of various transfection systems has been used to increase the expression of cytokines,151,303 knock down of pivotal targets with shRNAs,304,305 expression of transcription factor decoy proteins,306 overexpression of micro-RNAs are among many spinal targets that have been successfully manipulated through transfection approaches. Technically, it is clear that, while intrathecal delivery of AAV may transfect ganglion neurons, parenchymal transfection may be limited, in part, by the diffusion barrier presented by the pia and transfection enhanced by subpial delivery.307 Intraganglionic injections have also been suggested as an efficient tool to alter afferent function.308 The ability to produce long-term, regulated changes in processing offers a potential to modify the pathological expression of pain by modifying system function.

Back to Top | Article Outline


The FDA has been mandated to address the national epidemic of opioid abuse with policies aimed at reversing the epidemic. One element of this plan, recognizing the pivotal role opioid receptors play in pain management, is to stimulate development of more effective pain medications with abuse-deterrent properties and abuse-deterrent formulations of opioids. The rational way forward is to develop analgesics that minimize abuse potential. To improve the translations, the FDA launched the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) that issued recommendations to improve the reproducibility of research pertaining to pain studies.306

In the past 3 decades, by virtue of funding from the national funding agencies and by pharma, we have obtained an increased understanding of pain mechanisms and, accordingly, an abundance of relevant targets for which we must develop druggable molecules. The development of novel targets and the implementation of approaches that can alter processing for extended periods (transfection and toxins) represent exciting advances in managing the chronic condition.

An important issue in analgesic drug discovery is that apparently promising preclinical candidates can fail during clinical trials. Several reasons for this may be entertained. It is straightforward to model human conditions for which the initiating mechanisms are likely known, as for example in chemotherapy-induced neuropathy. Conversely, it is difficult, if not impossible, to rationally define surrogate models for a pain state such as fibromyalgia, where the mechanisms of hyperpathia observed in the human conditions are not known.307 Thus, preclinical models may fail to recapitulate the human pain condition being studied. Research into mechanisms and the appreciation of the role played by innate and adaptive immunity are likely to shed light on these complex problems, revealing novel, mechanistically defined targets that lack congruence of the clinical and preclinical target, where minor species differences in a receptor sequence may yield a drug that does not engage the human target. Modern molecular techniques and target sequencing make this disconnect less likely. Further research into biological biomarkers (exosomes) and genetic characterization will provide an important link to define human and animal covariates.308,309

It is interesting to note, as outlined in the Figure, that a preponderance of the targets producing therapeutic efficacy as analgesics (versus anesthetics) displays a robust effect on primary afferent and dorsal horn processing that leads to surprisingly specific changes in pain behavior, denoting the role played by the content of the ascending message in characterizing components of the aversive nature of the stimulus event. This emphasis does not exclude the likelihood that many agents, notably opioids, can exert a potent effect on pain behavior after supraspinal action with such actions accounting for changes in the affective-motivational component of the pain state. While it appears likely that specific supraspinal systems may be found that possess a pharmacology specifically targeting the pain state, current research has provided little evidence that what affects pain processing/behavior at supraspinal sites does not also have pronounced effects upon behavior and perception, aspects of which are associated with positive reward and the addictive potential. These results suggesting the interdigitation of these affective components are in parallel with the early work involving surgical resection of limbic and forebrain structures. While such interventions were reported to lead to a loss of the affective components of the pain state, they also led to profound changes in personality and judgment.310

Finally, the translational development of analgesics for the clinic must increasingly consider the issues of drug abuse. The aim is to address the specific management of pain and suffering. Clearly, agents minimizing the psychological underpinnings of suffering may well display a positive reinforcing component in the absence of pain. This conflation emphasizes the complexity of the problem and the challenges to selectively modify one of the most basic cognitive elements, the pain experience.

Back to Top | Article Outline


Name: Nebojsa Nick Knezevic, MD, PhD.

Contribution: This author contributed to the writing and editing of the manuscript and approved the final version.

Conflicts of Interest: None.

Name: Ajay Yekkirala, PhD.

Contribution: This author contributed to the writing and editing of the manuscript and approved the final version.

Conflicts of Interest: Ajay Yekkirala holds a patent on an analgesic agent and is co-founder, Chief Scientific Officer, and shareholder of Blue Therapeutics, Inc, a biotechnology company developing novel analgesics.

Name: Tony L. Yaksh, PhD.

Contribution: This author contributed to the writing and editing of the manuscript and approved the final version.

Conflicts of Interest: Tony L. Yaksh has performed contract work with Sorrento on TRPV1 agonists, advanced targeting on substance P-Saporin, VistaGen with glycine site antagonism, Johnson and Johnson on Nav 1.7 antagonists, in particular, and others that were disclosed online.

This manuscript was handled by: Honorio T. Benzon, MD.

Back to Top | Article Outline


1. CDC. Opioid Overdose Deaths. 2015.Atlanta, GA: Centers for Disease Control and Prevention.
2. Volkow ND, McLellan AT. Opioid abuse in chronic pain—misconceptions and mitigation strategies. N Engl J Med. 2016;374:1253–1263.
3. Cassidy TA, DasMahapatra P, Black RA, Wieman MS, Butler SF. Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent opioid formulation. Pain Med. 2014;15:440–451.
4. Kunins HV. Abuse-deterrent opioid formulations: part of a public health strategy to reverse the opioid epidemic. JAMA Intern Med. 2015;175:987–988.
5. Chilcoat HD, Coplan PM, Harikrishnan V, Alexander L. Decreased diversion by doctor-shopping for a reformulated extended release oxycodone product (OxyContin). Drug Alcohol Depend. 2016;165:221–228.
6. Coplan PM, Chilcoat HD, Butler SF, et al. The effect of an abuse-deterrent opioid formulation (OxyContin) on opioid abuse-related outcomes in the postmarketing setting. Clin Pharmacol Ther. 2016;100:275–286.
7. Cicero TJ, Ellis MS, Kasper ZA. A tale of 2 ADFs: differences in the effectiveness of abuse-deterrent formulations of oxymorphone and oxycodone extended-release drugs. Pain. 2016;157:1232–1238.
8. Cicero TJ, Ellis MS, Surratt HL. Effect of abuse-deterrent formulation of OxyContin. N Engl J Med. 2012;367:187–189.
9. Yaksh TL, Woller SA, Ramachandran R, Sorkin LS. The search for novel analgesics: targets and mechanisms. F1000Prime Rep. 2015;7:56.
10. Ren K, Dubner R. Activity-triggered tetrapartite neuron-glial interactions following peripheral injury. Curr Opin Pharmacol. 2016;26:16–25.
11. Walker SM, Beggs S, Baccei ML. Persistent changes in peripheral and spinal nociceptive processing after early tissue injury. Exp Neurol. 2016;275(pt 2):253–260.
12. Chaplan S, Eckert W III, Carruthers N. Kruger L, Light AR. Drug discovery and development for pain. In: Translational Pain Research: From Mouse to Man Frontiers in Neuroscience. 2010:Boca Raton, FL: CRC Press/Taylor & Francis; 391–404.
13. Mogil JS, Davis KD, Derbyshire SW. The necessity of animal models in pain research. Pain. 2010;151:12–17.
14. Mogil JS. Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci. 2012;13:859–866.
15. Doyle HH, Murphy AZ. Sex differences in innate immunity and its impact on opioid pharmacology. J Neurosci Res. 2017;95:487–499.
16. Navratilova E, Xie JY, King T, Porreca F. Evaluation of reward from pain relief. Ann N Y Acad Sci. 2013;1282:1–11.
17. Roughan JV, Coulter CA, Flecknell PA, Thomas HD, Sufka KJ. The conditioned place preference test for assessing welfare consequences and potential refinements in a mouse bladder cancer model. PLoS One. 2014;9:e103362.
18. Brown DC, Bell M, Rhodes L. Power of treatment success definitions when the Canine Brief Pain Inventory is used to evaluate carprofen treatment for the control of pain and inflammation in dogs with osteoarthritis. Am J Vet Res. 2013;74:1467–1473.
19. FTC. Competition in the Pet Medications Industry. Federal Trade Commission Staff Report. 2015.Washinton, DC: Federal Trade Commission;
20. van Amerongen G, de Boer MW, Groeneveld GJ, Hay JL. A literature review on the pharmacological sensitivity of human evoked hyperalgesia pain models. Br J Clin Pharmacol. 2016;82:903–922.
21. Yaksh TL, Fisher CJ, Hockman TM, Wiese AJ. Current and future issues in the development of spinal agents for the management of pain. Curr Neuropharmacol. 2017;15:232–259.
22. Johnson KA, Lovinger DM. Presynaptic G protein-coupled receptors: gatekeepers of addiction? Front Cell Neurosci. 2016;10:264.
23. Chen W, Nong Z, Li Y, Huang J, Chen C, Huang L. Role of dopamine signaling in drug addiction. Curr Top Med Chem. 2017;17:2440–2455.
24. Jaffe JH, Kanzler M, Green J. Abuse potential of loperamide. Clin Pharmacol Ther. 1980;28:812–819.
25. Gauvin DV, Zimmermann ZJ, Baird TJ. Preclinical assessment of abuse liability of biologics: In defense of current regulatory control policies. Regul Toxicol Pharmacol. 2015;73:43–54.
26. Mansbach RS, Feltner DE, Gold LH, Schnoll SH. Incorporating the assessment of abuse liability into the drug discovery and development process. Drug Alcohol Depend. 2003;70:S73–S85.
27. Kallman MJ. Preclinical abuse potential assessment. Handb Exp Pharmacol. 2015;229:115–130.
28. Swedberg MD. Drug discrimination: a versatile tool for characterization of CNS safety pharmacology and potential for drug abuse. J Pharmacol Toxicol Methods. 2016;81:295–305.
29. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev. 2005;57:397–409.
30. Wang W, Gu J, Li YQ, Tao YX. Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain? Mol Pain. 2011;7:16.
31. Liu M, Wood JN. The roles of sodium channels in nociception: implications for mechanisms of neuropathic pain. Pain Med. 2011;12(suppl 3):S93–S99.
32. Kharatmal SB, Singh JN, Sharma SS. Voltage-gated sodium channels as therapeutic targets for treatment of painful diabetic neuropathy. Mini Rev Med Chem. 2015;15:1134–1147.
33. Waxman SG. Painful Na-channelopathies: an expanding universe. Trends Mol Med. 2013;19:406–409.
34. Brouwer BA, Merkies IS, Gerrits MM, Waxman SG, Hoeijmakers JG, Faber CG. Painful neuropathies: the emerging role of sodium channelopathies. J Peripher Nerv Syst. 2014;19:53–65.
35. Araujo MC, Sinnott CJ, Strichartz GR. Multiple phases of relief from experimental mechanical allodynia by systemic lidocaine: responses to early and late infusions. Pain. 2003;103:21–29.
36. Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev. 2005:CD003345.
37. Docherty RJ, Farmer CE. The pharmacology of voltage-gated sodium channels in sensory neurones. Handb Exp Pharmacol. 2009:519–561.
38. Nieto FR, Cobos EJ, Tejada MÁ, Sánchez-Fernández C, González-Cano R, Cendán CM. Tetrodotoxin (TTX) as a therapeutic agent for pain. Mar Drugs. 2012;10:281–305.
39. Iwamoto T, Takasugi Y, Higashino H, Ito H, Koga Y, Nakao S. Antinociceptive action of carbamazepine on thermal hypersensitive pain at spinal level in a rat model of adjuvant-induced chronic inflammation. J Anesth. 2011;25:78–86.
40. Kohane DS, Lu NT, Gökgöl-Kline AC, et al. The local anesthetic properties and toxicity of saxitonin homologues for rat sciatic nerve block in vivo. Reg Anesth Pain Med. 2000;25:52–59.
41. Rodríguez-Navarro AJ, Berde CB, Wiedmaier G, et al. Comparison of neosaxitoxin versus bupivacaine via port infiltration for postoperative analgesia following laparoscopic cholecystectomy: a randomized, double-blind trial. Reg Anesth Pain Med. 2011;36:103–109.
42. Schmalhofer WA, Calhoun J, Burrows R, et al. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol. 2008;74:1476–1484.
43. Moon JY, Song S, Yoon SY, et al. The differential effect of intrathecal Nav1.8 blockers on the induction and maintenance of capsaicin- and peripheral ischemia-induced mechanical allodynia and thermal hyperalgesia. Anesth Analg. 2012;114:215–223.
44. Vetter I, Deuis JR, Mueller A, et al. NaV1.7 as a pain target—from gene to pharmacology. Pharmacol Ther. 2017;172:73–100.
45. Deuis JR, Dekan Z, Wingerd JS, et al. Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a. Sci Rep. 2017;7:40883.
46. Wallace MS, Rowbotham M, Bennett GJ, Jensen TS, Pladna R, Quessy S. A multicenter, double-blind, randomized, placebo-controlled crossover evaluation of a short course of 4030W92 in patients with chronic neuropathic pain. J Pain. 2002;3:227–233.
47. Goldberg YP, Price N, Namdari R, et al. Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker. Pain. 2012;153:80–85.
48. Kongsgaard UE, Werner MU. Tachyphylaxis to local anaesthetics. What is the clinical evidence? A systematic review. Acta Anaesthesiol Scand. 2016;60:6–14.
49. Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature. 2007;449:607–610.
50. Roberson DP, Binshtok AM, Blasl F, Bean BP, Woolf CJ. Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review. Br J Pharmacol. 2011;164:48–58.
51. Tsantoulas C. Emerging potassium channel targets for the treatment of pain. Curr Opin Support Palliat Care. 2015;9:147–154.
52. Perimal EK, Akhtar MN, Mohamad AS, et al. Zerumbone-induced antinociception: involvement of the L-arginine-nitric oxide-cGMP-PKC-K+ ATP channel pathways. Basic Clin Pharmacol Toxicol. 2011;108:155–162.
53. Zulazmi NA, Gopalsamy B, Min JC, et al. Zerumbone alleviates neuropathic pain through the involvement of l-arginine-nitric oxide-cGMP-K(+) ATP channel pathways in chronic constriction injury in mice model. Molecules. 2017;22;pii: E555.
54. Klein CJ, Lennon VA, Aston PA, McKeon A, Pittock SJ. Chronic pain as a manifestation of potassium channel-complex autoimmunity. Neurology. 2012;79:1136–1144.
55. Du X, Gamper N. Potassium channels in peripheral pain pathways: expression, function and therapeutic potential. Curr Neuropharmacol. 2013;11:621–640.
56. Tsantoulas C, McMahon SB. Opening paths to novel analgesics: the role of potassium channels in chronic pain. Trends Neurosci. 2014;37:146–158.
57. Price TJ, Ghosh S. ZIPping to pain relief: the role (or not) of PKMζ in chronic pain. Mol Pain. 2013;9:6.
58. Edelmayer RM, Brederson JD, Jarvis MF, Bitner RS. Biochemical and pharmacological assessment of MAP-kinase signaling along pain pathways in experimental rodent models: a potential tool for the discovery of novel antinociceptive therapeutics. Biochem Pharmacol. 2014;87:390–398.
59. Chahine M, O’Leary ME. Regulation/modulation of sensory neuron sodium channels. Handb Exp Pharmacol. 2014;221:111–135.
60. Luo XQ, Cai QY, Chen Y, et al. Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord contributes to chronic visceral pain in rats. Brain Res. 2014;1542:167–175.
61. Yaksh TL. Calcium channels as therapeutic targets in neuropathic pain. J Pain. 2006;7:S13–S30.
62. Zamponi GW, Striessnig J, Koschak A, Dolphin AC. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev. 2015;67:821–870.
63. Park J, Luo ZD. Calcium channel functions in pain processing. Channels (Austin). 2010;4:510–517.
64. Schroeder CI, Doering CJ, Zamponi GW, Lewis RJ. N-type calcium channel blockers: novel therapeutics for the treatment of pain. Med Chem. 2006;2:535–543.
65. Adams DJ, Callaghan B, Berecki G. Analgesic conotoxins: block and G protein-coupled receptor modulation of N-type (Ca(V) 2.2) calcium channels. Br J Pharmacol. 2012;166:486–500.
66. Patel R, Montagut-Bordas C, Dickenson AH. Calcium channel modulation as a target in chronic pain control (published online ahead of print March 20 1027). Br J Pharmacol. doi: 10.1111/bph.13789.
67. Brookes ME, Eldabe S, Batterham A. Ziconotide monotherapy: a systematic review of randomised controlled trials. Curr Neuropharmacol. 2017;15:217–231.
68. Malmberg AB, Yaksh TL. Effect of continuous intrathecal infusion of omega-conopeptides, N-type calcium-channel blockers, on behavior and antinociception in the formalin and hot-plate tests in rats. Pain. 1995;60:83–90.
69. Chu YX, Zhang Y, Zhang YQ, Zhao ZQ. Involvement of microglial P2X7 receptors and downstream signaling pathways in long-term potentiation of spinal nociceptive responses. Brain Behav Immun. 2010;24:1176–1189.
70. Feldman P, Khanna R. Challenging the catechism of therapeutics for chronic neuropathic pain: targeting CaV2.2 interactions with CRMP2 peptides. Neurosci Lett. 2013;557(pt A):27–36.
71. Xie JY, Chew LA, Yang X, et al. Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential. Pain. 2016;157:2124–2140.
72. Sałat K, Kowalczyk P, Gryzło B, Jakubowska A, Kulig K. New investigational drugs for the treatment of neuropathic pain. Expert Opin Investig Drugs. 2014;23:1093–1104.
73. Roca-Lapirot O, Radwani H, Aby F, Nagy F, Landry M, Fossat P. Calcium signalling through L-type calcium channels: role in pathophysiology of spinal nociceptive transmission (published online ahead of print February 18, 2017). Br J Pharmacol. doi: 10.1111/bph.13747.
74. Snutch TP, Zamponi GW. Recent advances in the development of T-type calcium channel blockers for pain intervention (published online ahead of print June 13, 2107). Br J Pharmacol. doi: 10.1111/bph.13906.
75. Zhou HY, Chen SR, Pan HL. Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain. Expert Rev Clin Pharmacol. 2011;4:379–388.
76. Glasgow NG, Siegler Retchless B, Johnson JW. Molecular bases of NMDA receptor subtype-dependent properties. J Physiol. 2015;593:83–95.
77. Mendell LM. Physiological properties of unmyelinated fiber projection to the spinal cord. Exp Neurol. 1966;16:316–332.
78. Ogden KK, Traynelis SF. New advances in NMDA receptor pharmacology. Trends Pharmacol Sci. 2011;32:726–733.
79. Chen HS, Lipton SA. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem. 2006;97:1611–1626.
80. Yaksh TL, Schwarcz R, Snodgrass HR. Characterization of the effects of L-4-chlorokynurenine on nociception in rodents (published online ahead of print April 18, 2017). J Pain. doi: 10.1016/j.jpain.2017.03.014.
81. Chaplan SR, Malmberg AB, Yaksh TL. Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat. J Pharmacol Exp Ther. 1997;280:829–838.
82. Yamamoto T, Yaksh TL. Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve. Excitatory amino acid antagonists. Pain. 1992;49:121–128.
83. Feng H, Chen Z, Wang G, Zhao X, Liu Z. Effect of the ifenprodil administered into rostral anterior cingulate cortex on pain-related aversion in rats with bone cancer pain. BMC Anesthesiol. 2016;16:117.
84. Schwartzman RJ, Alexander GM, Grothusen JR. The use of ketamine in complex regional pain syndrome: possible mechanisms. Expert Rev Neurother. 2011;11:719–734.
85. Sheehy KA, Muller EA, Lippold C, Nouraie M, Finkel JC, Quezado ZM. Subanesthetic ketamine infusions for the treatment of children and adolescents with chronic pain: a longitudinal study. BMC Pediatr. 2015;15:198.
86. Iacobucci GJ, Visnjevac O, Pourafkari L, Nader ND. Ketamine: an update on cellular and subcellular mechanisms with implications for clinical practice. Pain Physician. 2017;20:E285–E301.
87. Littlejohn G, Guymer E. Modulation of NMDA receptor activity in fibromyalgia (published online ahead of print April 11, 2107). Biomedicines. doi: 10.3390/biomedicines5020015.
88. Bennett M, Bonanno L, Kuhn W. Effectiveness of ketamine as an adjuvant to opioid-based therapy in decreasing pain associated with opioid tolerance in adults undergoing orthopedic surgery: a systematic review protocol. JBI Database System Rev Implement Rep. 2016;14:22–28.
89. Hopf FW. Do specific NMDA receptor subunits act as gateways for addictive behaviors? Genes Brain Behav. 2017;16:118–138.
90. Bergeron S, Rompré PP. Blockade of ventral midbrain NMDA receptors enhances brain stimulation reward: a preferential role for GluN2A subunits. Eur Neuropsychopharmacol. 2013;23:1623–1635.
91. Tong CK, MacDermott AB. Both Ca2+-permeable and -impermeable AMPA receptors contribute to primary synaptic drive onto rat dorsal horn neurons. J Physiol. 2006;575:133–144.
92. Jin HC, Keller AJ, Jung JK, Subieta A, Brennan TJ. Epidural tezampanel, an AMPA/kainate receptor antagonist, produces postoperative analgesia in rats. Anesth Analg. 2007;105:1152–1159.
93. Oshiro M, Hefferan MP, Kakinohana O, et al. Suppression of stretch reflex activity after spinal or systemic treatment with AMPA receptor antagonist NGX424 in rats with developed baclofen tolerance. Br J Pharmacol. 2010;161:976–985.
94. Sang CN, Hostetter MP, Gracely RH, et al. AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans. Anesthesiology. 1998;89:1060–1067.
95. Gilron I, Max MB, Lee G, et al. Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain. Clin Pharmacol Ther. 2000;68:320–327.
96. Sorkin LS, Yaksh TL, Doom CM. Mechanical allodynia in rats is blocked by a Ca2+ permeable AMPA receptor antagonist. Neuroreport. 1999;10:3523–3526.
97. Ferraguti F, Shigemoto R. Metabotropic glutamate receptors. Cell Tissue Res. 2006;326:483–504.
98. Ritter SL, Hall RA. Fine-tuning of GPCR activity by receptor-interacting proteins. Nat Rev Mol Cell Biol. 2009;10:819–830.
99. Osikowicz M, Mika J, Przewlocka B. The glutamatergic system as a target for neuropathic pain relief. Exp Physiol. 2013;98:372–384.
100. Boye Larsen D, Ingemann Kristensen G, Panchalingam V, et al. Investigating the expression of metabotropic glutamate receptors in trigeminal ganglion neurons and satellite glial cells: implications for craniofacial pain. J Recept Signal Transduct Res. 2014;34:261–269.
101. Shigemoto R, Kinoshita A, Wada E, et al. Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J Neurosci. 1997;17:7503–7522.
102. Palazzo E, Marabese I, de Novellis V, Rossi F, Maione S. Supraspinal metabotropic glutamate receptors: a target for pain relief and beyond. Eur J Neurosci. 2014;39:444–454.
103. Chiechio S. Modulation of chronic pain by metabotropic glutamate receptors. Adv Pharmacol. 2016;75:63–89.
104. Chiechio S, Nicoletti F. Metabotropic glutamate receptors and the control of chronic pain. Curr Opin Pharmacol. 2012;12:28–34.
105. Mills CD, Johnson KM, Hulsebosch CE. Group I metabotropic glutamate receptors in spinal cord injury: roles in neuroprotection and the development of chronic central pain. J Neurotrauma. 2002;19:23–42.
106. Mills CD, Johnson KM, Hulsebosch CE. Role of group II and group III metabotropic glutamate receptors in spinal cord injury. Exp Neurol. 2002;173:153–167.
107. Osikowicz M, Mika J, Makuch W, Przewlocka B. Glutamate receptor ligands attenuate allodynia and hyperalgesia and potentiate morphine effects in a mouse model of neuropathic pain. Pain. 2008;139:117–126.
108. Fisher K, Coderre TJ. Comparison of nociceptive effects produced by intrathecal administration of mGluR agonists. Neuroreport. 1996;7:2743–2747.
109. Fisher K, Coderre TJ. The contribution of metabotropic glutamate receptors (mGluRs) to formalin-induced nociception. Pain. 1996;68:255–263.
110. Zeilhofer HU. Loss of glycinergic and GABAergic inhibition in chronic pain—contributions of inflammation and microglia. Int Immunopharmacol. 2008;8:182–187.
111. Goudet C, Chapuy E, Alloui A, Acher F, Pin JP, Eschalier A. Group III metabotropic glutamate receptors inhibit hyperalgesia in animal models of inflammation and neuropathic pain. Pain. 2008;137:112–124.
112. Ren BX, Gu XP, Zheng YG, et al. Intrathecal injection of metabotropic glutamate receptor subtype 3 and 5 agonist/antagonist attenuates bone cancer pain by inhibition of spinal astrocyte activation in a mouse model. Anesthesiology. 2012;116:122–132.
113. Acher F, Goudet C. Therapeutic potential of group III metabotropic glutamate receptor ligands in pain. Curr Opin Pharmacol. 2015;20:64–72.
114. Montana MC, Gereau RW. Metabotropic glutamate receptors as targets for analgesia: antagonism, activation, and allosteric modulation. Curr Pharm Biotechnol. 2011;12:1681–1688.
115. Olive MF. Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev. 2009;2:83–98.
116. Vincent K, Wang SF, Laferrière A, Kumar N, Coderre TJ. Spinal intracellular metabotropic glutamate receptor 5 (mGluR5) contributes to pain and c-fos expression in a rat model of inflammatory pain. Pain. 2017;158:705–716.
117. Markou A. The role of metabotropic glutamate receptors in drug reward, motivation and dependence. Drug News Perspect. 2007;20:103–108.
118. Enna SJ, McCarson KE. The role of GABA in the mediation and perception of pain. Adv Pharmacol. 2006;54:1–27.
119. Malcangio M. GABAB receptors and pain (published online ahead of print May 11, 2107). Neuropharmacology. doi: 10.1016/j.neuropharm.2017.05.012.
120. Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev. 2008;60:243–260.
121. Sieghart W, Sperk G. Subunit composition, distribution and function of GABA(A) receptor subtypes. Curr Top Med Chem. 2002;2:795–816.
122. Bohlhalter S, Weinmann O, Mohler H, Fritschy JM. Laminar compartmentalization of GABAA-receptor subtypes in the spinal cord: an immunohistochemical study. J Neurosci. 1996;16:283–297.
123. Labrakakis C, Tong CK, Weissman T, Torsney C, MacDermott AB. Localization and function of ATP and GABAA receptors expressed by nociceptors and other postnatal sensory neurons in rat. J Physiol. 2003;549:131–142.
124. Witschi R, Punnakkal P, Paul J, et al. Presynaptic alpha2-GABAA receptors in primary afferent depolarization and spinal pain control. J Neurosci. 2011;31:8134–8142.
125. Yaksh TL, Allen JW. The use of intrathecal midazolam in humans: a case study of process. Anesth Analg. 2004;98:1536–1545.
126. Krall J, Balle T, Krogsgaard-Larsen N, et al. GABAA receptor partial agonists and antagonists: structure, binding mode, and pharmacology. Adv Pharmacol. 2015;72:201–227.
127. Wafford KA, van Niel MB, Ma QP, et al. Novel compounds selectively enhance delta subunit containing GABA A receptors and increase tonic currents in thalamus. Neuropharmacology. 2009;56:182–189.
128. Ferando I, Mody I. Interneuronal GABAA receptors inside and outside of synapses. Curr Opin Neurobiol. 2014;26:57–63.
129. Petersen JG, Bergmann R, Krogsgaard-Larsen P, Balle T, Frølund B. Probing the orthosteric binding site of GABAA receptors with heterocyclic GABA carboxylic acid bioisosteres. Neurochem Res. 2014;39:1005–1015.
130. Hoestgaard-Jensen K, Dalby NO, Krall J, et al. Probing α4βδ GABAA receptor heterogeneity: differential regional effects of a functionally selective α4β1δ/α4β3δ receptor agonist on tonic and phasic inhibition in rat brain. J Neurosci. 2014;34:16256–16272.
131. Dirig DM, Yaksh TL. Intrathecal baclofen and muscimol, but not midazolam, are antinociceptive using the rat-formalin model. J Pharmacol Exp Ther. 1995;275:219–227.
132. Nadeson R, Guo Z, Porter V, Gent JP, Goodchild CS. gamma-Aminobutyric acid A receptors and spinally mediated antinociception in rats. J Pharmacol Exp Ther. 1996;278:620–626.
133. Hwang JH, Yaksh TL. The effect of spinal GABA receptor agonists on tactile allodynia in a surgically-induced neuropathic pain model in the rat. Pain. 1997;70:15–22.
134. Malan TP, Mata HP, Porreca F. Spinal GABA(A) and GABA(B) receptor pharmacology in a rat model of neuropathic pain. Anesthesiology. 2002;96:1161–1167.
135. Gwak YS, Tan HY, Nam TS, Paik KS, Hulsebosch CE, Leem JW. Activation of spinal GABA receptors attenuates chronic central neuropathic pain after spinal cord injury. J Neurotrauma. 2006;23:1111–1124.
136. Whitwam JG, Niv D, Loh L, Jack RD. Depression of nociceptive reflexes by intrathecal benzodiazepine in dogs. Lancet. 1982;2:1465.
137. Serrao JM, Marks RL, Morley SJ, Goodchild CS. Intrathecal midazolam for the treatment of chronic mechanical low back pain: a controlled comparison with epidural steroid in a pilot study. Pain. 1992;48:5–12.
138. Tucker AP, Lai C, Nadeson R, Goodchild CS. Intrathecal midazolam I: a cohort study investigating safety. Anesth Analg. 2004;98:1512–1520.
139. Tucker AP, Mezzatesta J, Nadeson R, Goodchild CS. Intrathecal midazolam II: combination with intrathecal fentanyl for labor pain. Anesth Analg. 2004;98:1521–1527.
140. Ho KM, Ismail H. Use of intrathecal midazolam to improve perioperative analgesia: a meta-analysis. Anaesth Intensive Care. 2008;36:365–373.
141. Coronel MF, Labombarda F, González SL. Neuroactive steroids, nociception and neuropathic pain: a flashback to go forward. Steroids. 2016;110:77–87.
142. Aouad M, Charlet A, Rodeau JL, Poisbeau P. Reduction and prevention of vincristine-induced neuropathic pain symptoms by the non-benzodiazepine anxiolytic etifoxine are mediated by 3alpha-reduced neurosteroids. Pain. 2009;147:54–59.
143. Choi YM, Kim KH. Etifoxine for pain patients with anxiety. Korean J Pain. 2015;28:4–10.
144. Stephens DN, King SL, Lambert JJ, Belelli D, Duka T. GABAA receptor subtype involvement in addictive behaviour. Genes Brain Behav. 2017;16:149–184.
145. Yaksh TL. Pharmacology and mechanisms of opioid analgesic activity. Acta Anaesthesiol Scand. 1997;41:94–111.
146. Cox BM, Christie MJ, Devi L, Toll L, Traynor JR. Challenges for opioid receptor nomenclature: IUPHAR Review 9. Br J Pharmacol. 2015;172:317–323.
147. Reisine T, Law SF, Blake A, Tallent M. Molecular mechanisms of opiate receptor coupling to G proteins and effector systems. Ann N Y Acad Sci. 1996;780:168–175.
148. Stein C, Baerwald C. Opioids for the treatment of arthritis pain. Expert Opin Pharmacother. 2014;15:193–202.
149. Ingram SL. Cellular and molecular mechanisms of opioid action. Prog Brain Res. 2000;129:483–492.
150. Kim J, Ham S, Hong H, Moon C, Im HI. Brain reward circuits in morphine addiction. Mol Cells. 2016;39:645–653.
151. Matak I, Lacković Z. Botulinum toxin A, brain and pain. Prog Neurobiol. 2014;119–120:39–59.
152. Chavkin C. The therapeutic potential of κ-opioids for treatment of pain and addiction. Neuropsychopharmacology. 2011;36:369–370.
153. Abdallah K, Gendron L. The delta opioid receptor in pain control (published online ahead of print May 17, 2017). Handb Exp Pharmacol. doi: 10.1007/164_2017_32.
154. Kiguchi N, Ding H, Ko MC. Central N/OFQ-NOP receptor system in pain modulation. Adv Pharmacol. 2016;75:217–243.
155. Onofrio BM, Yaksh TL. Intrathecal delta-receptor ligand produces analgesia in man. Lancet. 1983;1:1386–1387.
156. Le Bourdonnec B, Windh RT, Ajello CW, et al. Potent, orally bioavailable delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4’-piperidine]-4-yl)benzamide (ADL5859). J Med Chem. 2008;51:5893–5896.
157. Kivell B, Prisinzano TE. Kappa opioids and the modulation of pain. Psychopharmacology (Berl). 2010;210:109–119.
158. Jones MR, Kaye AD, Kaye AJ, Urman RD. The emerging therapeutic roles of κ-opioid agonists. J Opioid Manag. 2016;12:101–107.
159. Gunther T, Dasgupta P, Mann A, et al. Targeting multiple opioid receptors—improved analgesics with reduced side effects? (published online ahead of print April 5, 2017). Br J Pharmacol. doi: 10.1111/bph.13809.
160. Pasternak GW. Opioids and their receptors: are we there yet? Neuropharmacology. 2014;76(pt B):198–203.
161. Whalen EJ, Rajagopal S, Lefkowitz RJ. Therapeutic potential of β-arrestin- and G protein-biased agonists. Trends Mol Med. 2011;17:126–139.
162. Wisler JW, Xiao K, Thomsen AR, Lefkowitz RJ. Recent developments in biased agonism. Curr Opin Cell Biol. 2014;27:18–24.
163. Soergel DG, Subach RA, Burnham N, et al. Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. Pain. 2014;155:1829–1835.
164. Viscusi ER, Webster L, Kuss M, et al. A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain. Pain. 2016;157:264–272.
165. Manglik A, Lin H, Aryal DK, et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature. 2016;537:185–190.
166. Yekkirala AS. Two to tango: GPCR oligomers and GPCR-TRP channel interactions in nociception. Life Sci. 2013;92:438–445.
167. Ferré S, Casadó V, Devi LA, et al. G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev. 2014;66:413–434.
168. Alfaras-Melainis K, Gomes I, Rozenfeld R, Zachariou V, Devi L. Modulation of opioid receptor function by protein-protein interactions. Front Biosci (Landmark Ed). 2009;14:3594–3607.
169. Daniels DJ, Lenard NR, Etienne CL, Law PY, Roerig SC, Portoghese PS. Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc Natl Acad Sci U S A. 2005;102:19208–19213.
170. Yekkirala AS, Kalyuzhny AE, Portoghese PS. An immunocytochemical-derived correlate for evaluating the bridging of heteromeric mu-delta opioid protomers by bivalent ligands. ACS Chem Biol. 2013;8:1412–1416.
171. Costantino CM, Gomes I, Stockton SD, Lim MP, Devi LA. Opioid receptor heteromers in analgesia. Expert Rev Mol Med. 2012;14:e9.
172. Yekkirala AS, Kalyuzhny AE, Portoghese PS. Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin as selective μ-δ agonists. ACS Chem Neurosci. 2010;1:146–154.
173. Yekkirala AS, Banks ML, Lunzer MM, Negus SS, Rice KC, Portoghese PS. Clinically employed opioid analgesics produce antinociception via μ-δ opioid receptor heteromers in Rhesus monkeys. ACS Chem Neurosci. 2012;3:720–727.
174. Maguire DR, France CP. Impact of efficacy at the μ-opioid receptor on antinociceptive effects of combinations of μ-opioid receptor agonists and cannabinoid receptor agonists. J Pharmacol Exp Ther. 2014;351:383–389.
175. Le Naour M, Akgün E, Yekkirala A, et al. Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance. J Med Chem. 2013;56:5505–5513.
176. Smeester BA, Lunzer MM, Akgün E, Beitz AJ, Portoghese PS. Targeting putative mu opioid/metabotropic glutamate receptor-5 heteromers produces potent antinociception in a chronic murine bone cancer model. Eur J Pharmacol. 2014;743:48–52.
177. Akgün E, Javed MI, Lunzer MM, Smeester BA, Beitz AJ, Portoghese PS. Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception. Proc Natl Acad Sci U S A. 2013;110:11595–11599.
178. Yekkirala AS, Lunzer MM, McCurdy CR, et al. N-naphthoyl-beta-naltrexamine (NNTA), a highly selective and potent activator of μ/kappa-opioid heteromers. Proc Natl Acad Sci U S A. 2011;108:5098–5103.
179. Spahn V, Del Vecchio G, Labuz D, et al. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science. 2017;355:966–969.
180. Philipp M, Brede M, Hein L. Physiological significance of alpha(2)-adrenergic receptor subtype diversity: one receptor is not enough. Am J Physiol Regul Integr Comp Physiol. 2002;283:R287–R295.
181. Takano Y, Yaksh TL. Characterization of the pharmacology of intrathecally administered alpha-2 agonists and antagonists in rats. J Pharmacol Exp Ther. 1992;261:764–772.
182. Stone LS, MacMillan LB, Kitto KF, Limbird LE, Wilcox GL. The alpha2a adrenergic receptor subtype mediates spinal analgesia evoked by alpha2 agonists and is necessary for spinal adrenergic-opioid synergy. J Neurosci. 1997;17:7157–7165.
183. Mizobe T, Maghsoudi K, Sitwala K, Tianzhi G, Ou J, Maze M. Antisense technology reveals the alpha2A adrenoceptor to be the subtype mediating the hypnotic response to the highly selective agonist, dexmedetomidine, in the locus coeruleus of the rat. J Clin Invest. 1996;98:1076–1080.
184. Yaksh TL. Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol Biochem Behav. 1985;22:845–858.
185. Giovannoni MP, Ghelardini C, Vergelli C, Dal Piaz V. Alpha2-agonists as analgesic agents. Med Res Rev. 2009;29:339–368.
186. Nguyen V, Tiemann D, Park E, Salehi A. Alpha-2 agonists. Anesthesiol Clin. 2017;35:233–245.
187. Dhopeshwarkar A, Mackie K. CB2 Cannabinoid receptors as a therapeutic target-what does the future hold? Mol Pharmacol. 2014;86:430–437.
188. Vasileiou I, Fotopoulou G, Matzourani M, Patsouris E, Theocharis S. Evidence for the involvement of cannabinoid receptors’ polymorphisms in the pathophysiology of human diseases. Expert Opin Ther Targets. 2013;17:363–377.
189. Morisset V, Ahluwalia J, Nagy I, Urban L. Possible mechanisms of cannabinoid-induced antinociception in the spinal cord. Eur J Pharmacol. 2001;429:93–100.
190. Anand P, Whiteside G, Fowler CJ, Hohmann AG. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res Rev. 2009;60:255–266.
191. Starowicz K, Przewlocka B. Modulation of neuropathic-pain-related behaviour by the spinal endocannabinoid/endovanilloid system. Philos Trans R Soc Lond B Biol Sci. 2012;367:3286–3299.
192. Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014;370:2219–2227.
193. Deng L, Guindon J, Cornett BL, Makriyannis A, Mackie K, Hohmann AG. Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biol Psychiatry. 2015;77:475–487.
194. Guindon J, Hohmann AG. The endocannabinoid system and pain. CNS Neurol Disord Drug Targets. 2009;8:403–421.
195. Davis MP. Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands. Expert Opin Investig Drugs. 2014;23:1123–1140.
196. Piomelli D. More surprises lying ahead. The endocannabinoids keep us guessing. Neuropharmacology. 2014;76():228–234.
197. Cui JH, Kim WM, Lee HG, Kim YO, Kim CM, Yoon MH. Antinociceptive effect of intrathecal cannabinoid receptor agonist WIN 55,212-2 in a rat bone tumor pain model. Neurosci Lett. 2011;493:67–71.
198. Cui JH, Ju J, Yoon MH. Pharmacology of cannabinoid receptor agonists and a cyclooxygenase-2 inhibitor in rat bone tumor pain. Pharmacology. 2013;92:150–157.
199. Wilkerson JL, Gentry KR, Dengler EC, et al. Immunofluorescent spectral analysis reveals the intrathecal cannabinoid agonist, AM1241, produces spinal anti-inflammatory cytokine responses in neuropathic rats exhibiting relief from allodynia. Brain Behav. 2012;2:155–177.
200. Sun L, Tai L, Qiu Q, et al. Endocannabinoid activation of CB1 receptors contributes to long-lasting reversal of neuropathic pain by repetitive spinal cord stimulation. Eur J Pain. 2017;21:804–814.
201. Shang Y, Tang Y. The central cannabinoid receptor type-2 (CB2) and chronic pain. Int J Neurosci. 2016;127:812–823.
202. Tomić MA, Pecikoza UB, Micov AM, Stepanović-Petrović RM. The efficacy of eslicarbazepine acetate in models of trigeminal, neuropathic, and visceral pain: the involvement of 5-HT1B/1D serotonergic and CB1/CB2 cannabinoid receptors. Anesth Analg. 2015;121:1632–1639.
203. Panagis G, Mackey B, Vlachou S. Cannabinoid regulation of brain reward processing with an emphasis on the role of CB1 receptors: a step back into the future. Front Psychiatry. 2014;5:92.
204. Zhang HY, Gao M, Liu QR, et al. Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci U S A. 2014;111:E5007–E5015.
205. Smith MT, Woodruff TM, Wyse BD, Muralidharan A, Walther T. A small molecule angiotensin II type 2 receptor (AT2R) antagonist produces analgesia in a rat model of neuropathic pain by inhibition of p38 mitogen-activated protein kinase (MAPK) and p44/p42 MAPK activation in the dorsal root ganglia. Pain Med. 2013;14:1557–1568.
206. Smith MT, Wyse BD, Edwards SR. Small molecule angiotensin II type 2 receptor (AT2R) antagonists as novel analgesics for neuropathic pain: comparative pharmacokinetics, radioligand binding, and efficacy in rats. Pain Med. 2013;14:692–705.
207. Rice AS, Dworkin RH, McCarthy TD, et al.; EMA401-003 Study Group. EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet. 2014;383:1637–1647.
208. Keppel Hesselink JM, Schatman ME. EMA401: an old antagonist of the AT2R for a new indication in neuropathic pain. J Pain Res. 2017;10:439–443.
209. Sosnowski M, Stevens CW, Yaksh TL. Assessment of the role of A1/A2 adenosine receptors mediating the purine antinociception, motor and autonomic function in the rat spinal cord. J Pharmacol Exp Ther. 1989;250:915–922.
210. Lee YW, Yaksh TL. Pharmacology of the spinal adenosine receptor which mediates the antiallodynic action of intrathecal adenosine agonists. J Pharmacol Exp Ther. 1996;277:1642–1648.
211. Cui JG, Sollevi A, Linderoth B, Meyerson BA. Adenosine receptor activation suppresses tactile hypersensitivity and potentiates spinal cord stimulation in mononeuropathic rats. Neurosci Lett. 1997;223:173–176.
212. Yamaguchi D, Terayama R, Omura S, et al. Effect of adenosine A1 receptor agonist on the enhanced excitability of spinal dorsal horn neurons after peripheral nerve injury. Int J Neurosci. 2014;124:213–222.
213. Katz NK, Ryals JM, Wright DE. Central or peripheral delivery of an adenosine A1 receptor agonist improves mechanical allodynia in a mouse model of painful diabetic neuropathy. Neuroscience. 2015;285:312–323.
214. Zahn PK, Straub H, Wenk M, Pogatzki-Zahn EM. Adenosine A1 but not A2a receptor agonist reduces hyperalgesia caused by a surgical incision in rats: a pertussis toxin-sensitive G protein-dependent process. Anesthesiology. 2007;107:797–806.
215. Rane K, Karlsten R, Sollevi A, Gordh T Jr, Svensson BA. Spinal cord morphology after chronic intrathecal administration of adenosine in the rat. Acta Anaesthesiol Scand. 1999;43:1035–1040.
216. Eisenach JC, Curry R, Hood DD. Dose response of intrathecal adenosine in experimental pain and allodynia. Anesthesiology. 2002;97:938–942.
217. Belfrage M, Segerdahl M, Arnér S, Sollevi A. The safety and efficacy of intrathecal adenosine in patients with chronic neuropathic pain. Anesth Analg. 1999;89:136–142.
218. Eisenach JC, Rauck RL, Curry R. Intrathecal, but not intravenous adenosine reduces allodynia in patients with neuropathic pain. Pain. 2003;105:65–70.
219. Sharma M, Mohta M, Chawla R. Efficacy of intrathecal adenosine for postoperative pain relief. Eur J Anaesthesiol. 2006;23:449–453.
220. Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001;53:527–552.
221. Sawynok J. Adenosine receptor activation and nociception. Eur J Pharmacol. 1998;347:1–11.
222. Li J, Perl ER. Adenosine inhibition of synaptic transmission in the substantia gelatinosa. J Neurophysiol. 1994;72:1611–1621.
223. Choca JI, Green RD, Proudfit HK. Adenosine A1 and A2 receptors of the substantia gelatinosa are located predominantly on intrinsic neurons: an autoradiography study. J Pharmacol Exp Ther. 1988;247:757–764.
224. Sawynok J, Liu XJ. Adenosine in the spinal cord and periphery: release and regulation of pain. Prog Neurobiol. 2003;69:313–340.
225. Roberts JC, Grocholski BM, Kitto KF, Fairbanks CA. Pharmacodynamic and pharmacokinetic studies of agmatine after spinal administration in the mouse. J Pharmacol Exp Ther. 2005;314:1226–1233.
226. Schulte G, Robertson B, Fredholm BB, DeLander GE, Shortland P, Molander C. Distribution of antinociceptive adenosine A1 receptors in the spinal cord dorsal horn, and relationship to primary afferents and neuronal subpopulations. Neuroscience. 2003;121:907–916.
227. Loram LC, Harrison JA, Sloane EM, et al. Enduring reversal of neuropathic pain by a single intrathecal injection of adenosine 2A receptor agonists: a novel therapy for neuropathic pain. J Neurosci. 2009;29:14015–14025.
228. Dai SS, Zhou YG. Adenosine 2A receptor: a crucial neuromodulator with bidirectional effect in neuroinflammation and brain injury. Rev Neurosci. 2011;22:231–239.
229. Bura SA, Nadal X, Ledent C, Maldonado R, Valverde O. A 2A adenosine receptor regulates glia proliferation and pain after peripheral nerve injury. Pain. 2008;140:95–103.
230. Chen Z, Janes K, Chen C, et al. Controlling murine and rat chronic pain through A3 adenosine receptor activation. FASEB J. 2012;26:1855–1865.
231. Burnstock G. Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev. 2007;87:659–797.
232. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H. Purinergic signalling in the nervous system: an overview. Trends Neurosci. 2009;32:19–29.
233. Kobayashi K, Yamanaka H, Noguchi K. Expression of ATP receptors in the rat dorsal root ganglion and spinal cord. Anat Sci Int. 2013;88:10–16.
234. Bianco F, Fumagalli M, Pravettoni E, et al. Pathophysiological roles of extracellular nucleotides in glial cells: differential expression of purinergic receptors in resting and activated microglia. Brain Res Brain Res Rev. 2005;48:144–156.
235. Inoue K, Tsuda M. [The role of microglia and ATP receptors in a mechanism of neuropathic pain]. Nihon Yakurigaku Zasshi. 2006;127:14–17.
236. Jarvis MF. The neural-glial purinergic receptor ensemble in chronic pain states. Trends Neurosci. 2010;33:48–57.
237. Clark AK, Wodarski R, Guida F, Sasso O, Malcangio M. Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor. Glia. 2010;58:1710–1726.
238. Donnelly-Roberts D, McGaraughty S, Shieh CC, Honore P, Jarvis MF. Painful purinergic receptors. J Pharmacol Exp Ther. 2008;324:409–415.
239. Tsuda M, Shigemoto-Mogami Y, Koizumi S, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature. 2003;424:778–783.
240. Chessell IP, Hatcher JP, Bountra C, et al. Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain. 2005;114:386–396.
241. Kobayashi K, Yamanaka H, Yanamoto F, Okubo M, Noguchi K. Multiple P2Y subtypes in spinal microglia are involved in neuropathic pain after peripheral nerve injury. Glia. 2012;60:1529–1539.
242. Tozaki-Saitoh H, Tsuda M, Miyata H, Ueda K, Kohsaka S, Inoue K. P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci. 2008;28:4949–4956.
243. Jung YH, Kim YO, Lin H, et al. Discovery of potent antiallodynic agents for neuropathic pain targeting P2X3 receptors. ACS Chem Neurosci. 2017;8:1465–1478.
244. Trang T, Salter MW. P2X4 purinoceptor signaling in chronic pain. Purinergic Signal. 2012;8:621–628.
245. Jurga AM, Piotrowska A, Makuch W, Przewlocka B, Mika J. Blockade of P2X4 receptors inhibits neuropathic pain-related behavior by preventing MMP-9 activation and, consequently, pronociceptive interleukin release in a rat model. Front Pharmacol. 2017;8:48.
246. Chen XM, Xu J, Song JG, Zheng BJ, Wang XR. Electroacupuncture inhibits excessive interferon-γ evoked up-regulation of P2X4 receptor in spinal microglia in a CCI rat model for neuropathic pain. Br J Anaesth. 2015;114:150–157.
247. Yamashita T, Yamamoto S, Zhang J, et al. Duloxetine inhibits microglial P2X4 receptor function and alleviates neuropathic pain after peripheral nerve injury. PLoS One. 2016;11:e0165189.
248. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015;385:1198–1205.
249. Saito O, Svensson CI, Buczynski MW, et al. Spinal glial TLR4-mediated nociception and production of prostaglandin E(2) and TNF. Br J Pharmacol. 2010;160:1754–1764.
250. Liu T, Gao YJ, Ji RR. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull. 2012;28:131–144.
251. Watkins LR, Hutchinson MR, Rice KC, Maier SF. The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci. 2009;30:581–591.
252. Jacobsen JH, Watkins LR, Hutchinson MR. Discovery of a novel site of opioid action at the innate immune pattern-recognition receptor TLR4 and its role in addiction. Int Rev Neurobiol. 2014;118:129–163.
253. Christianson CA, Dumlao DS, Stokes JA, et al. Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain. 2011;152:2881–2891.
254. Woller SA, Ravula SB, Tucci FC, et al. Systemic TAK-242 prevents intrathecal LPS evoked hyperalgesia in male, but not female mice and prevents delayed allodynia following intraplantar formalin in both male and female mice: the role of TLR4 in the evolution of a persistent pain state. Brain Behav Immun. 2016;56:271–280.
255. Jurga AM, Rojewska E, Piotrowska A, et al. Blockade of toll-like receptors (TLR2, TLR4) attenuates pain and potentiates buprenorphine analgesia in a rat neuropathic pain model. Neural Plast. 2016;2016:5238730.
256. Connolly DJ, O’Neill LA. New developments in Toll-like receptor targeted therapeutics. Curr Opin Pharmacol. 2012;12:510–518.
257. Lucas K, Maes M. Role of the toll like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol. 2013;48:190–204.
258. Wang X, Smith C, Yin H. Targeting Toll-like receptors with small molecule agents. Chem Soc Rev. 2013;42:4859–4866.
259. Liu F, Wang Z, Qiu Y, et al. Suppression of MyD88-dependent signaling alleviates neuropathic pain induced by peripheral nerve injury in the rat. J Neuroinflammation. 2017;14:70.
260. Svensson CI, Yaksh TL. The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing. Annu Rev Pharmacol Toxicol. 2002;42:553–583.
261. Jones P, Dalziel SR, Lamdin R, Miles-Chan JL, Frampton C. Oral non-steroidal anti-inflammatory drugs versus other oral analgesic agents for acute soft tissue injury. Cochrane Database Syst Rev. 2015:CD007789.
262. Sanghi S, MacLaughlin EJ, Jewell CW, et al. Cyclooxygenase-2 inhibitors: a painful lesson. Cardiovasc Hematol Disord Drug Targets. 2006;6:85–100.
263. Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology. 2013;21:201–232.
264. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology. 2005;102:822–831.
265. Toussaint K, Yang XC, Zielinski MA, et al. What do we (not) know about how paracetamol (acetaminophen) works? J Clin Pharm Ther. 2010;35:617–638.
266. Candido KD, Perozo OJ, Knezevic NN. Pharmacology of acetaminophen, nonsteroidal antiinflammatory drugs, and steroid medications: implications for anesthesia or unique associated risks. Anesthesiol Clin. 2017;35:e145–e162.
267. Wagner K, Inceoglu B, Hammock BD. Soluble epoxide hydrolase inhibition, epoxygenated fatty acids and nociception. Prostaglandins Other Lipid Mediat. 2011;96:76–83.
268. Serhan CN. The resolution of inflammation: the devil in the flask and in the details. FASEB J. 2011;25:1441–1448.
269. Ji RR, Xu ZZ, Strichartz G, Serhan CN. Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci. 2011;34:599–609.
270. Lim JY, Park CK, Hwang SW. Biological roles of resolvins and related substances in the resolution of pain. Biomed Res Int. 2015;2015:830930.
271. Sacerdote P, Franchi S, Moretti S, et al. Cytokine modulation is necessary for efficacious treatment of experimental neuropathic pain. J Neuroimmune Pharmacol. 2013;8:202–211.
272. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest. 2000;117:1162–1172.
273. Tayal V, Kalra BS. Cytokines and anti-cytokines as therapeutics–an update. Eur J Pharmacol. 2008;579:1–12.
274. Milligan ED, Penzkover KR, Soderquist RG, Mahoney MJ. Spinal interleukin-10 therapy to treat peripheral neuropathic pain. Neuromodulation. 2012;15:520–526.
275. Thakur V, Gonzalez M, Pennington K, Chattopadhyay M. Viral vector mediated continuous expression of interleukin-10 in DRG alleviates pain in type 1 diabetic animals. Mol Cell Neurosci. 2016;72:46–53.
276. Zheng W, Huang W, Liu S, et al. Interleukin 10 mediated by herpes simplex virus vectors suppresses neuropathic pain induced by human immunodeficiency virus gp120 in rats. Anesth Analg. 2014;119:693–701.
277. Hao S, Mata M, Glorioso JC, Fink DJ. HSV-mediated expression of interleukin-4 in dorsal root ganglion neurons reduces neuropathic pain. Mol Pain. 2006;2:6.
278. Kiguchi N, Kobayashi Y, Saika F, Sakaguchi H, Maeda T, Kishioka S. Peripheral interleukin-4 ameliorates inflammatory macrophage-dependent neuropathic pain. Pain. 2015;156:684–693.
279. Sun S, Chen D, Lin F, et al. Role of interleukin-4, the chemokine CCL3 and its receptor CCR5 in neuropathic pain. Mol Immunol. 2016;77:184–192.
280. Eijkelkamp N, Steen-Louws C, Hartgring SA, et al. IL4-10 fusion protein is a novel drug to treat persistent inflammatory pain. J Neurosci. 2016;36:7353–7363.
281. Vyklický L, Nováková-Tousová K, Benedikt J, Samad A, Touska F, Vlachová V. Calcium-dependent desensitization of vanilloid receptor TRPV1: a mechanism possibly involved in analgesia induced by topical application of capsaicin. Physiol Res. 2008;57(suppl 3):S59–S68.
282. Jeffry JA, Yu SQ, Sikand P, Parihar A, Evans MS, Premkumar LS. Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia. PLoS One. 2009;4:e7021.
283. Szolcsányi J. Capsaicin and sensory neurones: a historical perspective. Prog Drug Res. 2014;68:1–37.
284. Brown DC. Resiniferatoxin: the evolution of the “molecular scalpel” for chronic pain relief. Pharmaceuticals (Basel). 2016;9:pii: E47.
285. Kissin I, Szallasi A. Therapeutic targeting of TRPV1 by resiniferatoxin, from preclinical studies to clinical trials. Curr Top Med Chem. 2011;11:2159–2170.
286. Brown DC, Iadarola MJ, Perkowski SZ, et al. Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a canine bone cancer model. Anesthesiology. 2005;103:1052–1059.
287. Bevan S, Quallo T, Andersson DA. TRPV1. Handb Exp Pharmacol. 2014;222:207–245.
288. Brown DC, Agnello K, Iadarola MJ. Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain. Pain. 2015;156:1018–1024.
289. Latapy C, Beaulieu JM. β-Arrestins in the central nervous system. Prog Mol Biol Transl Sci. 2013;118:267–295.
290. Wiley RG, Lappi DA. Targeted toxins in pain. Adv Drug Deliv Rev. 2003;55:1043–1054.
291. Todd AJ. Anatomy of primary afferents and projection neurones in the rat spinal dorsal horn with particular emphasis on substance P and the neurokinin 1 receptor. Exp Physiol. 2002;87:245–249.
292. Khasabov SG, Rogers SD, Ghilardi JR, Peters CM, Mantyh PW, Simone DA. Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci. 2002;22:9086–9098.
293. Brown DC, Agnello K. Intrathecal substance P-saporin in the dog: efficacy in bone cancer pain. Anesthesiology. 2013;119:1178–1185.
294. Wiese AJ, Rathbun M, Butt MT, et al. Intrathecal substance P-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation. Anesthesiology. 2013;119:1163–1177.
295. Pellett S. Learning from the past: historical aspects of bacterial toxins as pharmaceuticals. Curr Opin Microbiol. 2012;15:292–299.
296. Pellett S, Yaksh TL, Ramachandran R. Current status and future directions of botulinum neurotoxins for targeting pain processing. Toxins (Basel). 2015;7:4519–4563.
297. Kakegawa W, Yuzaki M. A mechanism underlying AMPA receptor trafficking during cerebellar long-term potentiation. Proc Natl Acad Sci U S A. 2005;102:17846–17851.
298. Marinelli S, Luvisetto S, Cobianchi S, et al. Botulinum neurotoxin type A counteracts neuropathic pain and facilitates functional recovery after peripheral nerve injury in animal models. Neuroscience. 2010;171:316–328.
299. Huang PP, Khan I, Suhail MS, Malkmus S, Yaksh TL. Spinal botulinum neurotoxin B: effects on afferent transmitter release and nociceptive processing. PLoS One. 2011;6:e19126.
300. Lee WH, Shin TJ, Kim HJ, et al. Intrathecal administration of botulinum neurotoxin type A attenuates formalin-induced nociceptive responses in mice. Anesth Analg. 2011;112:228–235.
301. Coelho A, Oliveira R, Rossetto O, Cruz CD, Cruz F, Avelino A. Intrathecal administration of botulinum toxin type A improves urinary bladder function and reduces pain in rats with cystitis. Eur J Pain. 2014;18:1480–1489.
302. Ramachandran R, Yaksh TL. Therapeutic use of botulinum toxin in migraine: mechanisms of action. Br J Pharmacol. 2014;171:4177–4192.
303. Marino MJ, Terashima T, Steinauer JJ, Eddinger KA, Yaksh TL, Xu Q. Botulinum toxin B in the sensory afferent: transmitter release, spinal activation, and pain behavior. Pain. 2014;155:674–684.
304. Sidaway P. Pain: BoNT-A reduces pain in patients with treatment refractory IC/BPS. Nat Rev Urol. 2015;12:300.
305. Mustafa G, Anderson EM, Bokrand-Donatelli Y, Neubert JK, Caudle RM. Anti-nociceptive effect of a conjugate of substance P and light chain of botulinum neurotoxin type A. Pain. 2013;154:2547–2553.
306. Andrews NA, Latrémolière A, Basbaum AI, et al. Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations. Pain. 2016;157:901–909.
307. Yekkirala AS, Roberson DP, Bean BP, Woolf CJ. Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov. 2017;16:545–564.
308. Chizh BA, Greenspan JD, Casey KL, Nemenov MI, Treede RD. Identifying biological markers of activity in human nociceptive pathways to facilitate analgesic drug development. Pain. 2008;140:249–253.
309. Latremoliere A, Costigan M. Combining human and rodent genetics to identify new analgesics (published online ahead of print July 1, 2017). Neurosci Bull. doi: 10.1007/s12264-017-0152-z.
310. White J, Sweet WH. Pain and the Neurosurgeon. 1969.Springfield, IL: Charles Thomas.
Copyright © 2017 International Anesthesia Research Society