It is well established that the monoamines noradrenaline (NA) and 5-hydroxytryptamine (5-HT) have complex modulatory roles in pain signalling. Top-down processing pathways arise in midbrain and brainstem structures and exert powerful inhibitory or excitatory control over dorsal horn neuronal responses; this is predominantly via the actions of the neurotransmitters noradrenaline and 5-HT acting at specific receptor subtypes. Here, we discuss the mechanisms underlying the bidirectional role of the monoamines on pain processing as we consider, in part, their opposing receptor-mediated actions. Compelling evidence attributes pain inhibitions to α2-adrenoceptor activation and pain facilitations to 5-HT3-receptor activation. We highlight recent research regarding analgesics that have monoamine-based mechanisms of action and that interact with descending controls.
Following injury and subsequent tissue and/or nerve damage peripheral mechanisms are likely subjected to a filtering process through central mechanisms so that the relation between the peripheral damage to nerve or tissue can become dissociated from the amount of pain reported. In most pain syndromes, there are multiple pain-signalling mechanisms residing at peripheral sites. Transmission within peripheral nerves follows, and signals are passed to the spinal cord and onwards to the brain. Specifically, the pain message is relayed to the thalamus and cortex where the sensory components of pain are generated, thus allowing us to locate the pain and describe its intensity, whereas parallel pathways transmit the pain message to the limbic brain. This latter part of the brain is where the affective components of pain are produced, which is why chronic pain often goes hand in hand with comorbidities, including depression and anxiety. Importantly, pain perception does not result from activation of these ascending pathways alone but rather from a dialogue between the higher centres of the brain and the spinal cord, so called top-down processing via long pathways that descend from the brain back to the spinal cord. As well as controlling sensory events in the spinal cord, descending controls also influence autonomic and motor events. For the sake of this review, we shall focus only on the former role.
Descending control pathways originate in midbrain and brainstem regions and project to the dorsal horn of the spinal cord. They represent a mechanism through which the transmitted pain signal may be facilitated – this enhances the pain that we are experiencing, or inhibited – thus reducing pain. They have a clear anatomical basis. From the periaqueductal grey in the midbrain (an area which integrates forebrain influences) pathways run to a number of brain stem areas. Succinctly, ensuing projections to the locus coeruleus and to the rostromedial ventral medulla (RVM) are the main sources of descending controls. A major component of the inhibitory bulbo-spinal loop for example is mediated by fibres running in the dorsolateral funiculi [1▪▪]. The RVM exerts inhibitory and facilitatory controls over deep dorsal horn neuronal responses via two opposing systems that originate from RVM pain-modulating neurons. There are three classes of cells that have clear sensitivities to mu opioid receptor (MOR) agonists and are also grouped according to their distinct responses to noxious somatic stimulation prior to a nocifensive reflex withdrawal. Whereas ON cells will start firing rapidly in response to noxious stimuli, OFF cells will cease firing just before a tail flick, for example, and are activated by MOR agonists. Thus the RVM possesses neuronal substrates to enhance or to inhibit pain messages. Neutral cells do not change their firing rate in the presence of noxious input nor according to MOR agonist activity. Given the above, it is of interest that MOR-expressing neurons in the RVM are shown not to be required for analgesia produced by either direct or indirect activation of neurons in the RVM .
The monoamines noradrenaline and 5-HT are the neurotransmitters chiefly implicated in the descending control pain modulatory pathway. Descending noradrenergic projections terminating in the dorsal horn of the spinal cord derive almost entirely from nuclei within the dorsolateral pontine tegmentum, in particular the aforementioned locus coeruleus. It is telling that microstimulation of these areas is known to be antinociceptive through activation of the α2-adrenoceptor  which can be activated by drugs such as clonidine and dexmedetomidine. Fast forward 30 years and a plethora of evidence supports that noradrenaline plays a prominent role in inhibition of spinal cord activity that originates in supraspinal areas. Further, research now suggests that an interaction with the noradrenergic system via release of noradrenaline and activation of α1, α2C, and β-adrenoceptors is in actual fact an essential mechanism underlying the peripheral antinociception induced by the NSAIDs [4▪].
Mechanisms underlying other central inhibitory effects of noradrenaline include activation of α1 adrenoceptors on gamma-aminobutyric acid-ergic and glycinergic inhibitory interneurons, increasing inhibitory drive to projection neurons . Interestingly, although it is true that there is significant engagement of noradrenergic inhibitory pathways during extended period of noxious nociceptive drive  there is also evidence for the existence of a tonic noradrenergic control of spinal excitability since there is an ongoing α-2 adrenoceptor control of spinal excitability that is lost after nerve injury . More recently, restoration of this diminished noradrenergic control through use of a noradrenaline reuptake inhibitor (NRI) was shown to reduce neuropathic hypersensitivity [8▪▪].
Electrical stimulation of the RVM, which receives substantial projections from mid brain regions, evokes the spinal release of 5-HT, and supports an overall inhibitory influence on dorsal horn neuronal responses to noxious stimulation. It is clear, however, that parallel inhibitory and excitatory pathways originate from the RVM with the latter appearing to be predominant . The story with 5-HT in terms of its role in pain modulation initially appears complex because of the myriad of spinal cord receptors that it can act upon. Via 5-HT2 and 5-HT3 receptors, 5-HT is a key transmitter in descending facilitations. In contrast spinal cord 5-HT7 and 5-HT2A receptors are classified as inhibitory. Overall a recent study shows that selective activation of RVM 5-HT neurons enhances pain sensitivity [10▪▪] supporting the idea that facilitations may dominate over inhibitions. However, the antidepressant tianeptine increases 5-HT uptake in the brain, and is reported to have antinociceptive effects; its efficacy in spinal nerve ligated rats is proposed to be in part dependent on modulation of inhibitory 5-HT7 receptors [11▪]. Thus the particular 5-HT receptor activated under different circumstances will determine the direction of effect.
The dopaminergic system represents another potential chronic pain treatment target. Dopaminergic agonists were recently shown to promote recovery of locomotor function following spinal cord injury [12▪] serving as a reminder that, following spinal cord injury at least, a complementary monoaminergic multitherapy strategy could be employed to great effect. Indeed noradrenaline, 5-HT and dopamine (DA) are shown to adjust actions of the nociceptive machinery via modulation of presynaptic inhibition in the mouse spinal cord [13▪]. The mechanism of nefopam is proposed to involve inhibition of noradrenaline, 5-HT and DA reuptake. Recently, spinal noradrenergic modulation alone (via the α2-adrenoceptor) was shown to play an important role in the antinociceptive effect of nefopam against inflammatory acute pain but not facilitated pain [14▪]. Studies manipulating DA with the aim of translation to clinical therapy will be hampered by the important roles of DA in movement and reward systems.
Abnormalities in the central processing of pain are commonly believed to underlie refractory chronic pain; alterations in those descending control systems that act to enhance or reduce the pain that we are experiencing can contribute to pain chronification (as recently discussed by Ossipov and colleagues, [15▪▪]). The clinical relevance and implication of the monoaminergic neurotransmitters involved in the descending control pain pathways continues to be at the forefront of research concerning many varied pathological conditions .
The modulatory feedback loop for the control of spinal neuronal excitability during prolonged noxious stimulation is dynamic. Signalling circuits change following physio-pathological events such as those seen in the two broad major types of pain, neuropathic and inflammatory pain where, respectively, nerves or tissue are damaged. Low back pain and cancer pain can be one or the other or a combination, and may be termed mixed pains. The peripheral processes of these types of pain are very different. With neuropathy, nerves are lesioned or diseased and so ion channels drive the pain, whereas with inflammatory pains, chemicals from the damaged tissues are at the origins. As a consequence, treatments aimed at the source of pain differ. However, within the central nervous system the mechanisms of pain and pain control appear to be more common. In pains such as fibromyalgia or opioid-induced hyperalgesia the underlying mechanisms are more likely to be central than peripheral. A pivotal central common mechanism would appear to be the descending controls, alterations in which have been seen following neuropathy, inflammation, and in cancer pain models.
Central mechanisms of pain modulation
Although the periphery provides a level of painful input into the central nervous system, central mechanisms transform this into a personal pain experience with emotional content. The periphery provides the basic ingredients but then the spinal cord can amplify the messages enormously and on the other hand, it is proposed that descending inhibitions can switch pain down, illustrated by placebo. Recently, placebo analgesia was shown to enhance descending pain-related effective connectivity [17▪▪] although some claim this may not always stretch to inhibition of the nociceptive input at the spinal level . However, it is agreed that both spinal and higher order sensory processes are modulated during placebo analgesia.
The analgesic effects of many drugs are dependent on activity in the descending circuits. The Food and Drug Administration approves drugs that target the descending pain facilitatory and inhibitory systems for use in chronic pain [19▪▪].
Following nerve injury there is plasticity in descending noradrenergic pathways as evidenced by the increased potency of α2-adrenoceptor agonists in this particular pain state. In chronic neuropathy, it has been shown that there is a transient excess of descending monoaminergic drive when that pathway has been previously primed using a tonic pain paradigm such as the formalin test. This results in inhibition of subsequent nociceptive behaviours. Here, the authors propose that earlier activation of those descending pain pathways could then contribute to the establishment of chronic neuropathic pain [20▪]. In rats subjected to spinal nerve injury, it has been shown that activation of 5HT5A and 5HT1A/1B/1D receptors reduces pain processing, stressing the importance of these receptors in the descending pain inhibitory circuit [21▪▪].
Contributory mechanisms in neuropathic pain include aberrant ectopic activity in nociceptive nerves as well as central sensitization and impaired inhibitory modulation. First line treatments include the tricyclic antidepressants (TCAs), serotonin, noradrenaline reuptake inhibitors (SNRIs), and anticonvulsants such as pregabalin and gabapentin, although it is recognized that individualized, multidisciplinary rehabilitation approaches will be crucial for the optimal outcome of patient treatment . It is frustrating that only a minority of patients with neuropathic pain have an adequate response to drug therapy; clinical trial modifications could help reduce therapeutic failures [23▪▪].
It is possible to monitor a form of descending inhibition in patients and this allows prediction of treatment responses. Preclinically α2-adrenoceptor-mediated mechanisms are shown to underlie a unique kind of descending inhibitory control, so called diffuse noxious inhibitory controls (DNIC). DNIC are spinal inhibitory mechanisms utilizing descending controls, where one pain can inhibit another from elsewhere in the body. In nerve-injured animals DNIC are restored either by blocking 5-HT3 receptor-mediated descending facilitations or by enhancing noradrenaline modulation through use of NRIs with or without MOR activity [24▪]. In the clinic, the same phenomenon, termed conditioned pain modulation (CPM), is reduced in chronic pain patients, indicative of altered descending modulation and predictive of the actions of duloxetine, an SNRI [25,26]. Similarly, tapentadol, a MOR-NRI, restores CPM in patients with a painful diabetic neuropathy [27▪].
Altering activity at monoamine synapses is the proposed mechanism underlying the analgesic effects of the aforementioned TCAs and SNRIs. The clinical success of drugs that enhance, for example, spinal noradrenaline activity, suggests that a strong descending inhibitory system may normally be engaged aiding protection against the development of chronic pain. The monoamines and their spinal cord concentration also play a key role in terms of the analgesic efficacy of SNRIs and TCAs. The noradrenaline/5-HT increase in the spinal cord following use of reuptake inhibitors is considered the main mechanism of action of the therapeutic benefit of antidepressants in neuropathic pain. This increase is crucial to the antihyperalgesic efficacy of duloxetine – SNRI, and amitriptyline – TCA, although the plastic change of the descending noradrenaline system that occurs, for example, at certain time points following a nerve injury, does not obviously effect the analgesic efficacy of either drug [28▪]. The TCAs and SNRIs have greater efficacy than the serotonin reuptake inhibitors (SRI's) in neuropathic pain, perhaps explicable in terms of the discussed and well established inhibitory noradrenaline tone and the widely pronociceptive action of 5-HT.
A recent study looked at the effect of a NRI vs. a SRI on the antinociceptive action of morphine in mice under a stress condition. Pretreatment with the NRI but not the SRI improved the antinociceptive action of morphine suggesting that under conditions of chronic stress the actions of morphine would be improved by activation of the noradrenaline but not serotonergic system [29▪].
Milnacipran inhibits the reuptake of the monoamines and also inhibits neuronal glutamatergic N-methyl-D-aspartate receptor activity in the dorsal horn of the spinal cord, revealing a shared mechanism of action regarding the analgesia induced by this antidepressant . Milnacipran is also prescribed for fibromyalgia where the beneficial effects observed are proposed to be because of effects on central pain modulation. Whether this efficacy depends on the performance of pain inhibitory controls is being investigated; in the clinic new trials are being developed that would allow estimation of the beneficial effect of milnacipran on pain and on descending pain pathways, as well as evaluating whether the performance of the modulatory system could be predictive of its efficacy in reducing pain .
NSAIDs, anticonvulsants, and opioid-based drugs
It is universally agreed that the mechanism of action of pregabalin and gabapentin is dependent on activity within functioning descending pathways . Because there can be individual variations in pain comorbidities, variations in limbic function, and consequently descending controls may explain why there are variable responses to such treatments in otherwise apparently uniform pain groups.
Tramadol and tapentadol have MOR activity as well as reuptake inhibitory action (SNRI and NRI, respectively). The analgesic effects of tapentadol clearly rely on altering activity at monoamine synapses, and therefore are dependent on activity in the descending circuits, with which the opioids interact also to produce direct supraspinal interactions. In addition, the interactive components of tapentadol are observed at supra-spinal sites, including the right central nucleus of the amygdala, where there is a dose-dependent reduction in neuronal activity after nerve injury [33▪▪].
The synergistic relationship between opioid and α2-adrenoceptor agonists as analgesics is complex when considering that α2-adrenoceptor antagonists can inhibit opioid-based analgesia. It is suggested in fact that the α2-adrenoceptor has bidirectional modulatory effects on opioid antinociception since noradrenaline action at the α2-adrenoceptor facilitates morphine antinociception and ligand-free α2-adrenoceptors inhibit opioid analgesia. Clearly, there is a complex interplay of sometimes opposing actions, therefore, between the opioid receptor and the α2-adrenoceptor .
As mentioned the NSAIDs induce peripheral antinociception by interaction with the adrenergic system [4▪]. The central analgesic effect of ibuprofen in the human brain includes activation of descending modulatory circuits in the postsurgical state [35▪].
Altering the synaptic levels of noradrenaline and 5-HT works to great effect in terms of pain scores and treatment outcomes in the clinic. We recognize the need for continued preclinical and clinical research to further advance the successful manipulation of the monoaminergic system in pain modulation.
K.B. is supported by: a strategic award to the Wellcome Trust Pain Consortium and the London Pain Consortium (grant number 162819).
Financial support and sponsorship
K.B. receives funding from a strategic award to the Wellcome Trust Pain Consortium and the London Pain Consortium.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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Reassuringly the research highlights the importance of brainstem centres in the effects of spinal cord stimulation; fibres running in the dorsolateral funiculi form a major component of the inhibitory spinal-supraspinal-spinal loop.
2. Harasawa I, Johansen JP, Fields HL, et al. Alterations in the rostral ventromedial medulla after the selective ablation of mu-opioid receptor expressing neurons. Pain 2016; 157:166–173.
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4▪. Silva LC, Miranda e Castor MG, Souza TC, et al. NSAIDs induce peripheral antinociception by interaction with the adrenergic system. Life Sci 2015; 130:7–11.
The authors neatly demonstrate the interaction of the noradrenergic inhibitory system and the anti-inflammatory drugs diclofenac and dipyrone for peripheral antinociception.
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8▪▪. Hughes S, Hickey L, Donaldson LF, et al. Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone. Pain 2015; 156:328–334.
The study investigated the proposed loss of a tonic inhibitory noradrenergic drive following nerve injury. The authors showed that by increasing the amount of noradrenaline available using a NRI the pain associated with the tibial nerve transection was reduced, thus providing evidence for an ongoing α2-adrenoceptor control of spinal excitability in the normal situation.
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10▪▪. Cai YQ, Wang W, Hou YY, et al. Optogenetic activation of brainstem serotonergic neurons induces persistent pain sensitization. Mol Pain 2014; 10:1617–1624.
Here, the authors provided a beautiful study evidencing the facilitatory influence of 5-HT in descending pathways from RVM to spinal cord. It is shown directly that RVM 5-HT neurons predominantly enhance pain under control conditions.
11▪. Lin H, Heo BH, Kim WM, et al. Antiallodynic effect of tianeptine via modulation of the 5-Ht7 receptor of gabaergic interneurons in the spinal cord of neuropathic rats. Neurosci Lett 2015; 598:91–95.
It is neatly demonstrated that the antinociceptive action of tianeptine is in part governed by an interaction with the 5-HT7 receptor.
12▪. Sharples SA, Koblinger K, Humphreys JM, et al. Dopamine: a parallel pathway for the modulation of spinal locomotor networks. Front Neural Circuits 2014; 8:55.
The authors propose that dopaminergic agonists can promote recovery of function following spinal cord injury. Interesting parallels are drawn with serotonergic and noradrenergic modulatory effects on spinal cord responses.
13▪. Garcia-Ramirez DL, Calvo JR, Hochman S, et al. Serotonin, dopamine and noradrenaline adjust actions of myelinated afferents via modulation of presynaptic inhibition in the mouse spinal cord. PLoS One 2014; 9:e89999.
Here, the synergy between descending monoamine transmitters and reduced dorsal root potentials and monosynaptic transmission in the dorsal horn of the spinal cord is discussed.
14▪. Jeong SH, Heo BH, Park SH, et al. Spinal noradrenergic modulation and the role of the alpha-2 receptor in the antinociceptive effect of intrathecal nefopam in the formalin test. Korean J Pain 2014; 27:23–29.
The antinociceptive effect of nefopam is shown to involve spinal noradrenergic modulation in an inflammatory model of acute pain as opposed to facilitated pain.
15▪▪. Ossipov MH, Morimura K, Porreca F. Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care 2014; 8:143–151.
The review serves as a timely reminder that dysregulation in descending pain modulation, whereby modulatory circuits are tipped in favour of descending facilitation, promotes, and maintains chronic pain.
16. Kwon M, Altin M, Duenas H, et al. The role of descending inhibitory pathways on chronic pain modulation and clinical implications. Pain Pract 2014; 14:656–667.
17▪▪. Sevel LS, Craggs JG, Price DD, et al. Placebo analgesia enhances descending pain-related effective connectivity: a dynamic causal modeling study of endogenous pain modulation. J Pain 2015; 16:760–768.
An excellent human imaging study further demonstrating the fact that placebo analgesia has a neuro-biological basis that would include engagement of descending pathways.
18. Martini M, Lee MC, Valentini E, et al. Intracortical modulation, and not spinal inhibition, mediates placebo analgesia. Eur J Neurosci 2015; 41:498–504.
19▪▪. Finnerup NB, Attal N. Pharmacotherapy of neuropathic pain: time to rewrite the rulebook? Pain Manag 2015; [Epub ahead of print].
A helpful up to date guide to the different treatments for neuropathic pain.
20▪. Parent AJ, Tetreault P, Roux M, et al. Descending nociceptive inhibition is modulated in a time-dependent manner in a double-hit model of chronic/tonic pain. Neurosci 2015; 315:
A study showing how painful stimuli can prime altered function in descending pathways in subsequent pain.
21▪▪. Avila-Rojas SH, Velazquez-Lagunas I, Salinas-Abarca AB, et al. Role of spinal 5-HT5a, and 5-HT1a/1b/1d, receptors in neuropathic pain induced by spinal nerve ligation in rats. Brain Res 2015; 1622:377–385.
The bidirectional role that 5-HT plays in pain processing is complicated in part by the myriad of receptors that it can work on. Here, the authors show that a subset of 5-HT5 and 5-HT1 receptors act to reduce neuropathic pain, and therefore form part of the descending pain inhibitory system.
22. Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc 2015; 90:532–545.
23▪▪. Attal N, Bouhassira D. Pharmacotherapy of neuropathic pain: which drugs, which treatment algorithms? Pain 2015; 156 (Suppl 1):S104–114.
A helpful up to date guide to the different treatments for neuropathic pain.
24▪. Bannister K, Patel R, Goncalves L, et al. Diffuse noxious inhibitory controls and nerve injury: restoring an imbalance between descending monoamine inhibitions and facilitations. Pain 2015; 156:1803–1811.
By demonstrating an underlying noradrenergic mechanism in this particular type of descending inhibitory control the authors explain the relationship between CPM and the successful use of tapentadol and duloxetine in neuropathic pain patients.
25. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol 2010; 23:611–615.
26. Yarnitsky D, Granot M, Nahman-Averbuch H, et al. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain 2012; 153:1193–1198.
27▪. Niesters M, Proto PL, Aarts L, et al. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. Br J Anaesth 2014; 113:148–156.
A clever clinical study illustrating that tapentadol produces analgesia by restoring endogenous descending inhibitions.
28▪. Hoshino H, Obata H, Saito S. Antihyperalgesic effect of duloxetine and amitriptyline in rats after peripheral nerve injury: influence of descending noradrenergic plasticity. Neurosci Lett 2015; 602:
Interestingly, the authors propose that the change observed in the descending noradrenergic system after nerve injury does not affect the efficacy of duloxetine, SNRI, and amitriptyline, TCA.
29▪. Ide S, Satoyoshi H, Minami M, et al. Amelioration of the reduced antinociceptive effect of morphine in the unpredictable chronic mild stress model mice by noradrenalin but not serotonin reuptake inhibitors. Mol Pain 2015; 11:
A reduced antinociceptive effect of morphine was observed in rats under the stress conditions outlined by the authors but interestingly this was not the case in the presence of a NRI. This supports the proposed synergy between the noradrenergic and opioidergic systems for antinociception.
30. Kohno T, Kimura M, Sasaki M, et al. Milnacipran inhibits glutamatergic N-methyl-D-aspartate receptor activity in spinal dorsal horn neurons. Mol Pain 2012; 8:
31. Macian N, Pereira B, Shinjo C, et al. Fibromyalgia, milnacipran and experimental pain modulation: study protocol for a Double Blind Randomized Controlled Trial. Trials 2015; 16:
32. Suzuki R, Rahman W, Rygh LJ, et al. Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin. Pain 2005; 117:292–303.
33▪▪. Goncalves L, Friend LV, Dickenson AH. The influence of mu-opioid and noradrenaline reuptake inhibition in the modulation of pain responsive neurones in the central amygdala by tapentadol in rats with neuropathy. Eur J Pharmacol 2015; 749:
The authors succesfully demonstrate a suppression of neuronal responses following treatment with tapentadol, a MOR-NRI, in limbic brain areas; thus the actions of tapentadol are not limited to the synergy between the MOR and adrenergic system seen at the spinal level.
34. Chabot-Dore AJ, Millecamps M, Naso L, et al. Dual allosteric modulation of opioid antinociceptive potency by alpha2a-adrenoceptors. Neuropharmacology 2015; 99:
35▪. Hodkinson DJ, Khawaja N, O’Daly O, et al. Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen. Pain 2015; 156:1301–1310.
The cerebral response to ibuprofen was investigated in pre and postsurgical states. The authors show that postsurgery there is an increase in top-down circuit activity and that independently of its antinociceptive action ibuprofen has no effect on cerebral blood flow under pain-free conditions.