One size does not fit all: towards optimising the therapeutic potential of endogenous pain modulatory systems : PAIN

Journal Logo

Topical Review

One size does not fit all: towards optimising the therapeutic potential of endogenous pain modulatory systems

Bannister, Kirstya,*; Hughes, Samb

Author Information
PAIN 164(1):p e5-e9, January 2023. | DOI: 10.1097/j.pain.0000000000002697
  • Open
  • Editor's Choice
  • Global Year 2023

1. Introduction

Top–down processing pathways modulate neuronal transmission at the level of the spinal cord dorsal horn and thus govern, in part, the percept of pain. In health, these descending control systems can give rise to a naturally occurring form of pain inhibition. Despite a high therapeutic potential, the clinical applicability of harnessing such endogenous systems has not been fully realised. We propose that this is due to several complicating issues. First, the descending pain modulatory system (DPMS) is influenced by sensory as well as affective brain circuits. Thus, because of the bidirectional nature of the DPMS, pain may be facilitated or inhibited in a manner that corresponds not only to the degree of injury but also to the emotional status of the individual. This relates to the second issue; the DPMS, traditionally viewed as an encompassed “whole” for top–down processing, is in fact comprised of distinct neuronal networks. Emerging data highlight that a blanket pharmacological approach does not consider that diverse circuits, despite overlapping functionality and neurochemistry, require unique intervention. Meaning that, for DPMS-targeted analgesia, activity must be altered in the relevant pathway where cortical influences must also be considered.

Here, we review what is known about the neuroanatomical framework by which distinct descending pathways are subserved, citing evidence from both preclinical (animal) and clinical (human) studies. This is timely because movement towards selective therapeutic intervention (ie, relevant to specific features of pathological pain conditions and their comorbidities) will depend on recognition of top–down controls within the DPMS as functionally unique systems that are engaged by specific environmental or affective “drivers.” For this to occur, studies that define the anatomical and pharmacological nature of the circuits therein, and translational delineation of the mechanisms underlying key descending control pathways, are key.

2. The descending pain modulatory system

Dissecting the functionality of discrete descending modulatory pathways, where each mechanism likely represents a distinct system, would allow identification of precise and disease-specific novel targets. This has implications for patient stratification (eg, based on correlation or relationships between cognitive or affective processes and pain modulatory pathway efficiency) and related mechanistic therapeutic approaches. Toward this notion, we begin by evidencing the known relationship between “drivers” and neurophysiological systems that affect activity in the DPMS.

2.1. Modulators, integrators, and effectors

Endogenous analgesic circuitry can be modulated by pharmacological3,8,25,30,35,40,72 or psychological interventions.10,16,19,36,42,49 Emotional changes,23 mindfulness therapy,73 exercise,22 and cognitive status43,68 may affect brain–spinal cord nociceptive transmission4 where convoluted underlying mechanisms influence the centrifugal descending modulation of spinal nociceptive transmission. Take noradrenaline as an example. Opposing alpha 2 adrenoreceptor-mediated facilitatory signalling in the brainstem has been demonstrated,70 and the locus coeruleus (LC), a traditionally viewed inhibitory component of the DPMS,18 evokes a bidirectional change in thermal nociception in rats when optogenetically activated.33 Its modular functional organisation lends the LC to multiple pain-modulatory influences.9,34,50 Recently, its propain mechanism has been linked to a regulatory role on noncoerulean noradrenergic cell group(s),45 highlighting the functional nuance of seemingly comparable brainstem with spinal cord projection circuits.

Serotonergic, opioidergic, and GABAergic mechanisms are also recruited by descending pathways, in which distinct (even if overlapping) governance of specific circuits occurs. For example, the caudal raphe sends descending projections to the dorsal horn,37 and the rostral ventromedial medulla (RVM) harbours neuronal populations involved in antinociceptive and pronociceptive behavioural responses. Most of the transmission is dual GABA and opioidergic.21 Interestingly, this unique circuit integrates stress information to limit the presynaptic inhibition of afferent neurons terminating in the same region, representing a network whereby endogenous analgesic processes are influenced by environmental factors. Mechanistically, this links with the influence of higher brain centres on final modulatory output. For example, the forebrain targets caudal medullary regions, and emotional and cognitive processing is implicated in the control of pain transmission through a direct impact on brainstem loci.51,74 The dorsal reticular nucleus (DRt) can enhance nociceptive responses,52 and circuitry between brainstem sites including the DRt, RVM, and midbrain periaqueductal grey (PAG) provides a substrate for emotional and cognitive modulation of pain, where the targeting of afferent neurons links the “dynamic pain connectome” to integrated pain responses.53 Thus, although defining discrete nucleus–spinal cord projection sites is an important first hurdle, identifying their cortical control is crucial for movement towards selective therapeutic interventions.

The rostral anterior cingulate cortex (ACC) explicitly regulates spinal nociceptive processing whereby separable effects on sensory and affective components of the pain descriptive axes are evident,25,61 while a basolateral amygdala–prefrontal cortex–PAG–spinal cord pathway that ordinarily drives feed-forward inhibitions contributes to sensory hypersensitivity in animal models of disease.38 Amygdala activity influences nocifensive behaviours by projections that affect activity in the pain neuraxis55,64 and lateralised outputs from the amygdala and brainstem modulate spinal nociceptive processing by opioidergic mechanisms differentially in health and disease.60 This is also evident when considering ACC–spinal cord, right central nucleus of the amygdala–spinal cord, and RVM–spinal cord circuits.14 Identifying affective influences on brainstem–spinal cord pathway functionality is complicated; activity in key nuclei may operate as “brake on” or “brake off” systems for the expression of specific circuits. Nonetheless, since defining the top–down regulation of brainstem origin spinally projecting pathways becomes clinically relevant when the anatomical and pharmacological underpinning of those pathways is known, the process is crucial.

3. Discrete circuits

External factors can manipulate descending pathway functionality, and yet, there remains an untapped source of clinically relevant targets (linked to mechanisms involved in descending control expression) that could be exploited for improved analgesia. Functional delineation of endogenous pain modulatory systems would allow the development of mechanism-driven therapeutic approaches (for a variety of chronic pain conditions) to be expedited. This is only beneficial, for optimal analgesic prescription, if (1) the circuitry of the pathways being targeted is known and (2) the descending pathways comprising the DPMS have distinct governance.

3.1. Descending pain modulatory system pathway governance

Naturally occurring mechanisms by which external factors can manipulate modulatory control expression are exemplified by the application of paradigms that seek to evoke stress-induced analgesia (SIA), diffuse noxious inhibitory controls (DNICs), and offset analgesia (OA), among others. The separable nature of the paradigms evidences the nuanced nature of top–down control activation within the DPMS.

Mechanistically, psychological stress recruits RVM-mediated modulatory mechanisms.67 This, coupled with the fact that RVM-driven circuits integrate stress information to limit the presynaptic inhibition of afferent neurons terminating in the same region hints at the functionality (anatomy and pharmacology) of an “SIA descending control pathway.” SIA, a pain suppression system instigated on exposure to unconditioned or conditioned stressful stimuli,11 is governed by an interplay between endocannabinoid and endogenous opioid systems in a manner that is specific to the paradigm applied.2 More research is required in order that therapeutic targeting strategies for stress and pain-related disease may be finessed. Meanwhile, the noradrenergic DNIC pathway inhibits the spinal neuronal activity when activated by a conditioning stimulus.7,48 Conditioned pain modulation (CPM), the proposed human counterpart of DNIC, is dysfunctional in patients with chronic pain 27,72 and its maladaptive expression is associated with increased postoperative pain and persistent pain.71 Underlying noradrenergic mechanisms explain the relationship between dysfunctional CPM and the beneficial use of tapentadol (μ-opioid receptor agonist and noradrenaline reuptake inhibitor) and duloxetine (serotonin noradrenaline reuptake inhibitor)62,72 in a manner that back translates.6,7 However, the fact that noradrenergic brainstem–spinal cord pathways are distinctly governed in a “one mechanism does not fit all” manner,45 argues that the functionality of discrete pathways is crucial for understanding sensorimotor modulation in health and disease.

The separable nature of specific DPMS-encompassed pathways can also be considered according to those pharmacological mechanisms not involved in key circuits. Opioid-independent mechanisms underlie the phenomenon whereby lowered pain scores accompany a small decrease in temperature during noxious thermal stimulation,54,59 a paradigm used to evoke OA. Such as SIA and DNIC, OA is a potent example of a situation in which stimulus manipulation induces an adaptive change in sensory processing. Previously, the reduction in pain experience evoked by application of the OA paradigm was correlated with DPMS activity originating in the PAG and RVM in a human fMRI study.13 However, the precise mechanistic underpinning is unknown. Onset hyperalgesia (OH) meanwhile describes a situation whereby a disproportionate increase in pain intensity is experienced at a given stimulus intensity when this intensity is preceded by a rise from a lower temperature.1 Despite the paradoxical to OA outcome, we hypothesise that OH is a phenomenon of the same pathway but with some separable governance. Indeed, these latest investigations provide evidence for the separable nature of descending modulatory circuits, even those as closely related (for the paradigm applied) as OA and OH.

The clinical benefit of defining DPMS controls will rely in part on optimally prescribing currently available pharmacotherapies according to the dysfunction in question. While mu-opioid receptor expression in the DPMS underlies opioid antinociception65 neither morphine nor naloxone impact CPM expression in humans.20,32 Previously, pain facilitative CPM observed in patients with fibromyalgia was mechanistically linked to attenuation of pain inhibitory as well as amplification of pain facilitative processes in the central nervous system.28 Meanwhile, tapentadol's analgesic mechanism was shown not to extend to an impact on the magnitude of the OA response in diabetic polyneuropathy patients, indicative of a preferential top–down effect for CPM alone.62 Cumulatively, the data indicate distinct yet intertwined descending analgesic mechanisms, which are differentially modulated according to the pain state; it is likely the case that multiple endogenous analgesic systems could be dysfunctional in nociplastic patient groups. For example, since CPM is associated with a distinct pharmacological and functional pathway within the DPMS, where wakefulness affects the overall expression status of the mechanistic DNIC underpinning,5 it is highly probable that a chronic pain patient with a normal CPM response may have alterations within a separate analgesic system. Thus, optimal analgesic strategies could encompass pharmacological and nonpharmacological interventions that are specific to 1 or 2 cortical and brainstem circuits. This kind of precision medicine requires further translational research efforts; the advent of bedside tests that allow rapid delineation of functionality in key pain processing pathways will first rely on delineation of the pathways in question.

So far, the influence of SIA or DNIC or OA on DPMS functionality and the nature of the underlying mechanisms that lead to dysregulation of DPMS-encompassed vs the specified pathways in chronic pain (where environmental influences on endogenous analgesic processes are likely) are unknown. If, for example, there is a switch in the dominant brainstem noradrenergic nucleus influencing spinal nociceptive processing in chronic pain (or indeed the functionality of reciprocal connection), then the pharmacotherapeutic target has changed. This has implications for age and disease-associated decrements in endogenous analgesic responses, where there is a need to compare pain measures (including activity in discrete modulatory pathways) across the adult lifespan and disease course.15,44,47 Plasticity in the pathways comprising the DPMS is a key factor in the transition from acute to chronic pain. Although this topic is outside the scope of the present review, we emphasise that, following the identification of distinct circuits that comprise the DPMS, understanding the nature of the plasticity therein in chronicity (where each circuit, as in health, is likely to undergo changes that are unique to the pathway itself) is going to be a key factor in the eventual optimisation of therapeutically targeting endogenous pain modulatory systems.

4. Psychological and environmental influences

Endogenous analgesic circuits may be influenced by psychological and environmental factors; understanding the biomedical mechanisms requires consideration of psychological social theories, further complicating the process of untangling singular controls. Recent NICE guidelines have suggested that nonpharmacological approaches including cognitive behavioural therapy, mindfulness, exercise, and acupuncture should be encouraged even as blanket treatment options for chronic pain conditions driven by centrally mediated changes in the absence of obvious injury (ie, nociplastic pain). Pain catastrophizing is often linked to a vicious cycle of fear avoidance, pain hypervigilance, disability, depression, and ultimately a worsening of chronic pain.12,69 Patients with fibromyalgia with high pain catastrophizing scores also showed stronger activation of the ACC suggesting an increased affective processing of their pain,26 and patients with knee osteoarthritis with high levels of pain hypervigilance show facilitated temporal summation of pain31. Interestingly, mindfulness therapy has been linked with reduced pain catastrophizing in a heterogeneous group of patients with chronic pain,66 and a neuroimaging study in healthy volunteers has demonstrated changes in the ACC during a mindfulness paradigm, which was related to a reduction in pain-intensity ratings.73 Similar cortical regions have been implicated in pain relief mediated through physical exercise in patients with fibromyalgia, with more activity reported in the dorsolateral PFC following exercise.17 Acupuncture has also been shown to cause increased opioid binding in the ACC, which was associated with clinically relevant reduction in pain in patients with fibromyalgia.29 Even the ability to mind wander is affiliated with changes in top–down antinociceptive systems and the PAG.46 Activation of CPM-dependent mechanisms are also believed to occur during exposure to immersive virtual reality environments, which can also work to attenuate experimentally induced secondary hyperalgesia in human pain models.43,58 Taken together, these findings have helped shape our understanding of how psychological therapies known to improve clinical pain symptoms interact with cortical regions implicated in the DPMS. Linking mechanisms of pain relief with activity in a specific circuit is still lacking. However, from these data, an outline therapeutic strategy is formed, whereby application of specific modulatory control–activating paradigms in carefully stratified patient cohorts may, for example, reveal those top–down influences that act as a gatekeeper to the expression of a specific control. This would inform the tools required for back translational studies, where, ideally, patient observations are recapitulated with faithful paradigms at the bench.

5. Harnessing cortical influences over descending pain modulatory system pathways

There is a growing body of evidence that suggests harnessing top–down cortical influences over brainstem endogenous analgesic systems could provide a feasible route to precision manipulation of descending control circuits and, thus, precision medicine. Through effective screening for dysfunction in discrete cortically driven cognitive or affective pathways, psychological interventions which target specific DPMS pathways can be tailored to the correct patient. The future of neurotechnology for the treatment of chronic pain also holds promise. Despite the overall poor clinical evidence for transcranial direct current stimulation (tDCS) as a treatment for chronic pain,63 it is increasingly apparent that analgesic effect sizes are bigger during dynamic sensory testing paradigms or when sensitisation is present, having minimal effects over acute pain thresholds.24 A number of experimental “healthy human” studies have shown that tDCS applied over the primary motor cortex can exert an influence on brainstem regions involved in endogenous pain control,57 directly boost CPM efficiency,19 and attenuate facilitated spinal pain mechanisms.39,41,42 Indeed, baseline CPM efficiency was related to the analgesic effects of tDCS applied over the DLPFC in patients with chronic low back pain,56 which others have linked to changes in activity within the posterior insula cortex.49 A systems-based approach, whereby screening for specific endogenous analgesic mechanisms (eg, CPM dysfunction), may lead to improved efficacy in future randomised controlled trials. Clinically speaking, optimising the therapeutic potential of these endogenous inhibitory systems through improved patient profiling, and centrally acting targeted interventions, is within reach.

Conflict of interest statement

The authors have no conflict of interest to declare.


K. Bannister is funded by a Medical Research Council NIRG grant (MR/W004739/1). S. Hughes is funded by the Academy of Medical Sciences, Anthony Mellow Fellowship, and the Engineering and Physical Sciences Research Council (EPSRC).


[1]. Alter BJ, Aung MS, Strigo IA, Fields HL. Onset hyperalgesia and offset analgesia: transient increases or decreases of noxious thermal stimulus intensity robustly modulate subsequent perceived pain intensity. PLoS One 2020;15:e0231124.
[2]. Atwal N, Winters BL, Vaughan CW. Endogenous cannabinoid modulation of restraint stress-induced analgesia in thermal nociception. J Neurochem 2020;152:92–102.
[3]. Baba Y, Kohase H, Oono Y, Fujii-Abe K, Arendt-Nielsen L. Effects of dexmedetomidine on conditioned pain modulation in humans. Eur J Pain 2012;16:1137–47.
[4]. Bannister K. Descending pain modulation: influence and impact. Curr Opin Physiol 2019;11:62–6.
[5]. Bannister K, Kucharczyk MW, Graven-Nielsen T, Porreca F. Introducing descending control of nociception: a measure of diffuse noxious inhibitory controls in conscious animals. PAIN 2021;162:1957–9.
[6]. Bannister K, Lockwood S, Goncalves L, Patel R, Dickenson AH. An investigation into the inhibitory function of serotonin in diffuse noxious inhibitory controls in the neuropathic rat. Eur J Pain 2017;21:750–60.
[7]. Bannister K, Patel R, Goncalves L, Townson L, Dickenson AH. Diffuse noxious inhibitory controls and nerve injury: restoring an imbalance between descending monoamine inhibitions and facilitations. PAIN 2015;156:1803–11.
[8]. Bannister K, Qu C, Navratilova E, Oyarzo J, Xie JY, King T, Dickenson AH, Porreca F. Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain. PAIN 2017;158:2386–95.
[9]. Brightwell JJ, Taylor BK. Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain. Neuroscience 2009;160:174–85.
[10]. Brooks JC, Davies WE, Pickering AE. Resolving the brainstem contributions to attentional analgesia. J Neurosci 2017;37:2279–91.
[11]. Butler RK, Finn DP. Stress-induced analgesia. Prog Neurobiol 2009;88:184–202.
[12]. Cook AJ, Brawer PA, Vowles KE. The fear-avoidance model of chronic pain: validation and age analysis using structural equation modeling. PAIN 2006;121:195–206.
[13]. Derbyshire SW, Osborn J. Offset analgesia is mediated by activation in the region of the periaqueductal grey and rostral ventromedial medulla. Neuroimage 2009;47:1002–6.
[14]. Dickenson AH, Navratilova E, Patel R, Porreca F, Bannister K. Supraspinal opioid circuits differentially modulate spinal neuronal responses in neuropathic rats. Anesthesiology 2020;132:881–94.
[15]. Edwards RR, Fillingim RB, Ness TJ. Age-related differences in endogenous pain modulation: a comparison of diffuse noxious inhibitory controls in healthy older and younger adults. PAIN 2003;101:155–65.
[16]. Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, Buchel C. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 2009;63:533–43.
[17]. Ellingson LD, Stegner AJ, Schwabacher IJ, Koltyn KF, Cook DB. Exercise strengthens central nervous system modulation of pain in fibromyalgia. Brain Sci 2016;6:8.
[18]. Fields HL, Heinricher MM, Mason P. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 1991;14:219–45.
[19]. Flood A, Waddington G, Cathcart S. High-definition transcranial direct current stimulation enhances conditioned pain modulation in healthy volunteers: a randomized trial. J Pain 2016;17:600–5.
[20]. France CR, Burns JW, Gupta RK, Buvanendran A, Chont M, Schuster E, Orlowska D, Bruehl S. Expectancy effects on conditioned pain modulation are not influenced by naloxone or morphine. Ann Behav Med 2016;50:497–505.
[21]. Francois A, Low SA, Sypek EI, Christensen AJ, Sotoudeh C, Beier KT, Ramakrishnan C, Ritola KD, Sharif-Naeini R, Deisseroth K, Delp SL, Malenka RC, Luo L, Hantman AW, Scherrer G. A brainstem-spinal cord inhibitory circuit for mechanical pain modulation by GABA and enkephalins. Neuron 2017;93:822–39. e826.
[22]. Geva N, Defrin R. Enhanced pain modulation among triathletes: a possible explanation for their exceptional capabilities. PAIN 2013;154:2317–23.
[23]. Geva N, Defrin R. Opposite effects of stress on pain modulation depend on the magnitude of individual stress response. J Pain 2018;19:360–71.
[24]. Giannoni-Luza S, Pacheco-Barrios K, Cardenas-Rojas A, Mejia-Pando PF, Luna-Cuadros MA, Barouh JL, Gnoatto-Medeiros M, Candido-Santos L, Barra A, Caumo W, Fregni F. Noninvasive motor cortex stimulation effects on quantitative sensory testing in healthy and chronic pain subjects: a systematic review and meta-analysis. PAIN 2020;161:1955–75.
[25]. Gomtsian L, Bannister K, Eyde N, Robles D, Dickenson AH, Porreca F, Navratilova E. Morphine effects within the rodent anterior cingulate cortex and rostral ventromedial medulla reveal separable modulation of affective and sensory qualities of acute or chronic pain. PAIN 2018;159:2512–21.
[26]. Gracely RH, Geisser ME, Giesecke T, Grant MA, Petzke F, Williams DA, Clauw DJ. Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain 2004;127:835–43.
[27]. Graven-Nielsen T, Wodehouse T, Langford RM, Arendt-Nielsen L, Kidd BL. Normalization of widespread hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients after knee replacement. Arthritis Rheum 2012;64:2907–16.
[28]. Harper DE, Ichesco E, Schrepf A, Hampson JP, Clauw DJ, Schmidt-Wilcke T, Harris RE, Harte SE. Resting functional connectivity of the periaqueductal gray is associated with normal inhibition and pathological facilitation in conditioned pain modulation. J Pain 2018;19:635 e1–e15.
[29]. Harris RE, Zubieta JK, Scott DJ, Napadow V, Gracely RH, Clauw DJ. Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs). Neuroimage 2009;47:1077–85.
[30]. Hayashida K, Obata H, Nakajima K, Eisenach JC. Gabapentin acts within the locus coeruleus to alleviate neuropathic pain. Anesthesiology 2008;109:1077–84.
[31]. Herbert MS, Goodin BR, Pero STt, Schmidt JK, Sotolongo A, Bulls HW, Glover TL, King CD, Sibille KT, Cruz-Almeida Y, Staud R, Fessler BJ, Bradley LA, Fillingim RB. Pain hypervigilance is associated with greater clinical pain severity and enhanced experimental pain sensitivity among adults with symptomatic knee osteoarthritis. Ann Behav Med 2014;48:50–60.
[32]. Hermans L, Nijs J, Calders P, De Clerck L, Moorkens G, Hans G, Grosemans S, Roman De Mettelinge T, Tuynman J, Meeus M. Influence of morphine and naloxone on pain modulation in rheumatoid arthritis, chronic fatigue syndrome/fibromyalgia, and controls: a double-blind, randomized, placebo-controlled, cross-over study. Pain Pract 2018;18:418–30.
[33]. Hickey L, Li Y, Fyson SJ, Watson TC, Perrins R, Hewinson J, Teschemacher AG, Furue H, Lumb BM, Pickering AE. Optoactivation of locus ceruleus neurons evokes bidirectional changes in thermal nociception in rats. J Neurosci 2014;34:4148–60.
[34]. Hirschberg S, Li Y, Randall A, Kremer EJ, Pickering AE. Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats. Elife 2017;6:e29808.
[35]. Hodkinson DJ, Khawaja N, O'Daly O, Thacker MA, Zelaya FO, Wooldridge CL, Renton TF, Williams SC, Howard MA. Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen. PAIN 2015;156:1301–10.
[36]. Hoffman HG, Richards TL, Bills AR, Van Oostrom T, Magula J, Seibel EJ, Sharar SR. Using FMRI to study the neural correlates of virtual reality analgesia. CNS Spectr 2006;11:45–51.
[37]. Hornung JP. The human raphe nuclei and the serotonergic system. J Chem Neuroanat 2003;26:331–43.
[38]. Huang J, Gadotti VM, Chen L, Souza IA, Huang S, Wang D, Ramakrishnan C, Deisseroth K, Zhang Z, Zamponi GW. A neuronal circuit for activating descending modulation of neuropathic pain. Nat Neurosci 2019;22:1659–68.
[39]. Hughes S, Grimsey S, Strutton PH. Primary motor cortex transcranial direct current stimulation modulates temporal summation of the nociceptive withdrawal reflex in healthy subjects. Pain Med 2019;20:1156–65.
[40]. Hughes S, Hickey L, Donaldson LF, Lumb BM, Pickering AE. Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone. PAIN 2015;156:328–34.
[41]. Hughes SW, Ali M, Sharma P, Insan N, Strutton PH. Frequency-dependent top-down modulation of temporal summation by anodal transcranial direct-current stimulation of the primary motor cortex in healthy adults. Eur J Pain 2018. doi: 10.1002/ejp.1238 [Epub ahead of print].
[42]. Hughes SW, Ward G, Strutton PH. Anodal transcranial direct current stimulation over the primary motor cortex attenuates capsaicin-induced dynamic mechanical allodynia and mechanical pain sensitivity in humans. Eur J Pain 2020;24:1130–7.
[43]. Hughes SW, Zhao H, Auvinet EJ, Strutton PH. Attenuation of capsaicin-induced ongoing pain and secondary hyperalgesia during exposure to an immersive virtual reality environment. Pain Rep 2019;4:e790.
[44]. Kucharczyk MW, Derrien D, Dickenson AH, Bannister K. The stage-specific plasticity of descending modulatory controls in a rodent model of cancer-induced bone pain. Cancers (Basel) 2020;12:3286.
[45]. Kucharczyk MW, Di Domenico F, Bannister K. Distinct brainstem to spinal cord noradrenergic pathways inversely regulate spinal neuronal activity. Brain 2022. doi: 10.1093/brain/awac085 [Epub ahead of print].
[46]. Kucyi A, Salomons TV, Davis KD. Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks. Proc Natl Acad Sci U S A 2013;110:18692–7.
[47]. Lariviere M, Goffaux P, Marchand S, Julien N. Changes in pain perception and descending inhibitory controls start at middle age in healthy adults. Clin J Pain 2007;23:506–10.
[48]. Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. PAIN 1979;6:283–304.
[49]. Lin RL, Douaud G, Filippini N, Okell TW, Stagg CJ, Tracey I. Structural connectivity variances underlie functional and behavioral changes during pain relief induced by neuromodulation. Sci Rep 2017;7:41603.
[50]. Llorca-Torralba M, Borges G, Neto F, Mico JA, Berrocoso E. Noradrenergic Locus Coeruleus pathways in pain modulation. Neuroscience 2016;338:93–113.
[51]. Llorca-Torralba M, Suarez-Pereira I, Bravo L, Camarena-Delgado C, Garcia-Partida JA, Mico JA, Berrocoso E. Chemogenetic silencing of the locus coeruleus-basolateral amygdala pathway abolishes pain-induced anxiety and enhanced aversive learning in rats. Biol Psychiatry 2019;85:1021–35.
[52]. Martins I, de Vries MG, Teixeira-Pinto A, Fadel J, Wilson SP, Westerink BH, Tavares I. Noradrenaline increases pain facilitation from the brain during inflammatory pain. Neuropharmacology 2013;71:299–307.
[53]. Martins I, Tavares I. Reticular formation and pain: the past and the future. Front Neuroanat 2017;11:51.
[54]. Martucci KT, Eisenach JC, Tong C, Coghill RC. Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information. PAIN 2012;153:1232–43.
[55]. McGaraughty S, Farr DA, Heinricher MM. Lesions of the periaqueductal gray disrupt input to the rostral ventromedial medulla following microinjections of morphine into the medial or basolateral nuclei of the amygdala. Brain Res 2004;1009:223–7.
[56]. McPhee ME, Graven-Nielsen T. Medial prefrontal high-definition transcranial direct current stimulation to improve pain modulation in chronic low back pain: a pilot randomized double-blinded placebo-controlled crossover trial. J Pain 2021;22:952–67.
[57]. Meeker TJ, Keaser ML, Khan SA, Gullapalli RP, Seminowicz DA, Greenspan JD. Non-invasive motor cortex neuromodulation reduces secondary hyperalgesia and enhances activation of the descending pain modulatory network. Front Neurosci 2019;13:467.
[58]. Mehesz E, Karoui H, Strutton PH, Hughes SW. Exposure to an immersive virtual reality environment can modulate perceptual correlates of endogenous analgesia and central sensitization in healthy volunteers. J Pain 2021. doi: 10.1016/j.jpain.2020.12.007 [Epub ahead of print].
[59]. Naugle KM, Cruz-Almeida Y, Fillingim RB, Riley JL III. Offset analgesia is reduced in older adults. PAIN 2013;154:2381–7.
[60]. Navratilova E, Nation K, Remeniuk B, Neugebauer V, Bannister K, Dickenson AH, Porreca F. Selective modulation of tonic aversive qualities of neuropathic pain by morphine in the central nucleus of the amygdala requires endogenous opioid signaling in the anterior cingulate cortex. PAIN 2020;161:609–18.
[61]. Navratilova E, Xie JY, Meske D, Qu C, Morimura K, Okun A, Arakawa N, Ossipov M, Fields HL, Porreca F. Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain. J Neurosci 2015;35:7264–71.
[62]. Niesters M, Proto PL, Aarts L, Sarton EY, Drewes AM, Dahan A. Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy. Br J Anaesth 2014;113:148–56.
[63]. O'Connell NE, Marston L, Spencer S, DeSouza LH, Wand BM. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev 2018;4:CD008208.
[64]. Phelps CE, Navratilova E, Dickenson AH, Porreca F, Bannister K. Kappa opioid signaling in the right central amygdala causes hind paw specific loss of diffuse noxious inhibitory controls in experimental neuropathic pain. PAIN 2019;160:1614–21.
[65]. Pinto M, Castro AR, Tshudy F, Wilson SP, Lima D, Tavares I. Opioids modulate pain facilitation from the dorsal reticular nucleus. Mol Cell Neurosci 2008;39:508–18.
[66]. Schutze R, Rees C, Preece M, Schutze M. Low mindfulness predicts pain catastrophizing in a fear-avoidance model of chronic pain. PAIN 2010;148:120–7.
[67]. Terman GW, Shavit Y, Lewis JW, Cannon JT, Liebeskind JC. Intrinsic mechanisms of pain inhibition: activation by stress. Science 1984;226:1270–7.
[68]. Torta DM, De Laurentis M, Eichin KN, von Leupoldt A, van den Broeke EN, Vlaeyen JWS. A highly cognitive demanding working memory task may prevent the development of nociceptive hypersensitivity. PAIN 2020;161:1459–69.
[69]. Vlaeyen JWS, Kole-Snijders AMJ, Boeren RGB, van Eek H. Fear of movement/(re)injury in chronic low back pain and its relation to behavioral performance. PAIN 1995;62:363–72.
[70]. Wei H, Pertovaara A. Spinal and pontine alpha2-adrenoceptors have opposite effects on pain-related behavior in the neuropathic rat. Eur J Pharmacol 2006;551:41–9.
[71]. Yarnitsky D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr Opin Anaesthesiol 2010;23:611–15.
[72]. Yarnitsky D, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. PAIN 2012;153:1193–8.
[73]. Zeidan F, Martucci KT, Kraft RA, Gordon NS, McHaffie JG, Coghill RC. Brain mechanisms supporting the modulation of pain by mindfulness meditation. J Neurosci 2011;31:5540–8.
[74]. Zhang L, Zhang Y, Zhao ZQ. Anterior cingulate cortex contributes to the descending facilitatory modulation of pain via dorsal reticular nucleus. Eur J Neurosci 2005;22:1141–8.
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.