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. 2017 May 26;595(13):4159–4166. doi: 10.1113/JP274165

The plasticity of descending controls in pain: translational probing

Kirsty Bannister 1,✉, A H Dickenson 1
PMCID: PMC5491855  PMID: 28387936

Abstract

Descending controls, comprising pathways that originate in midbrain and brainstem regions and project onto the spinal cord, have long been recognised as key links in the multiple neural networks that interact to produce the overall pain experience. There is clear evidence from preclinical and clinical studies that both peripheral and central sensitisation play important roles in determining the level of pain perceived. Much emphasis has been put on spinal cord mechanisms in central excitability, but it is now becoming clear that spinal hyperexcitability can be regulated by descending pathways from the brain that originate from predominantly noradrenergic and serotonergic systems. One pain can inhibit another. In this respect diffuse noxious inhibitory controls (DNIC) are a unique form of endogenous descending inhibitory pathway since they can be easily evoked and quantified in animals and man. The spinal pharmacology of pathways that subserve DNIC are complicated; in the normal situation these descending controls produce a final inhibitory effect through the actions of noradrenaline at spinal α2‐adrenoceptors, although serotonin, acting on facilitatory spinal 5‐HT3 receptors, influences the final expression of DNIC also. These descending pathways are altered in neuropathy and the effects of excess serotonin may now become inhibitory through activation of spinal 5‐HT7 receptors. Conditioned pain modulation (CPM) is the human counterpart of DNIC and requires a descending control also. Back and forward translational studies between DNIC and CPM, gauged between bench and bedside, are key for the development of analgesic therapies that exploit descending noradrenergic and serotonergic control pathways.

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Keywords: CPM, descending, DNIC, modulation

Abbreviations

ACC

anterior cingulate cortex

CPM

conditioned pain modulation

DNIC

diffuse noxious inhibitory controls

LC

locus coeruleus

MOR

mu opioid receptor agonist

NA

noradrenaline

NRI

noradrenaline reuptake inhibitor

PAG

periaqueductal grey

RVM

rostral ventral medial medulla

SRD

subnucleus reticularis dorsalis

SNL

spinal nerve ligation

SNRI

serotonin noradrenaline reuptake inhibitors

SSRI

selective serotonin reuptake inhibitors

TCAs

tricyclic antidepressant

Introduction

When considering pain perception, the oft‐thought‐of neuronal route from peripheral insult to spinal cord dorsal horn to brain may spring to mind before consideration of descending pathways. These endogenous top‐down controls, originating from specific brain regions, project to the spinal cord and act to control the spinal processing of incoming nociceptive messages and consequently the level of pain in humans. The key neurotransmitters implicated in descending modulation are noradrenaline (NA) and serotonin (5‐HT) although it is important to mention that both GABA and endogenous opioids have been implicated, the latter with regard to DNIC in animals and man (Le Bars et al. 1981; Willer et al. 1990). Interestingly these particular monoaminergic systems are additionally implicated in the control of emotions, fear, anxiety, thermoregulation and the sleep cycle, and so may be involved in these pain‐induced co‐morbidities (Briley & Moret, 2008; Bee & Dickenson, 2009; Doan et al. 2015). By forming a link between emotional states and levels of pain, these pathways may be one route by which coping and catastrophising can alter the sensory components of pain at the level of the first relays. As an interesting aside, the levels of midbrain generated modulation, both positive and negative, may be a key factor in individual variations in pain, thus contributing to some ‘dysfunctional’ pain states such as fibromyalgia where the pain state appears to arise from problems of central modulation rather more than peripheral drives that accompany peripheral inflammation and neuropathy (Staud et al. 2001; Perrot et al. 2008).

Descending modulation

While descending inhibition is predominantly via actions at the α2‐adrenoceptor (Jones & Gebhart, 1986), the excitatory influences of serotonin acting at specific receptor subtypes are likely to contribute to the development and maintenance of pain by acting alongside central sensitisation in the spinal cord (Ali et al. 1996; Suzuki et al. 2004). Overall the balance between descending controls, both excitatory and inhibitory, can be altered in various pain states ranging from nerve injury to cancer pain. Recent work shows altered activity related to worse pain scores based on increased periaqueductal grey (PAG) activity in patients with severe pain from osteoarthritis, that we believe may reflect altered descending controls (Gwilym et al. 2009). The potential for higher cognitive function through cortical controls that project to the cells of origin of descending controls to influence spinal function allows for top‐down processing of pain.

As one would expect given their hugely important role in the pain response, a number of analgesic drugs interact with descending controls. Opioids have direct supraspinal interactions with descending modulatory systems (Helmstetter et al. 1993; Pavlovic et al. 1996), the actions of pregabalin and gabapentin are regulated by descending pathways (Suzuki et al. 2005; Hayashida et al. 2007, 2008; Sikandar & Dickenson, 2011), and the tricyclic antidepressants (TCAs) and 5‐HT–NA reuptake inhibitors (SNRIs) alter NA and 5‐HT availability (Sawynok et al. 2001; Marks et al. 2009) including potential spinal cord actions (Tamano et al. 2016). Tramadol and tapentadol have mixed mu opioid receptor and reuptake inhibitory actions, the former with dual NA–5‐HT re‐uptake actions, the latter with NA only (Raffa et al. 1992; Guay, 2009). In the clinic TCAs and SNRIs have greater efficacy than selective serotonin reuptake inhibitors (SSRIs) in neuropathic pain (Finnerup & Attal, 2015), and tapentadol is effective in several patient groups (Baron et al. 2016; Guay, 2009). Thus increasing 5‐HT levels appears to reduce the analgesic effects of various molecules. Preclinical data can explain this on the basis that descending NA actions clearly mediate inhibition through spinal α2‐adrenoceptor receptors (Jones & Gebhart, 1986) whereas 5‐HT, via 5‐HT2 and 5‐HT3 receptors, is the key transmitter in descending facilitation (Ali et al. 1996; Green et al. 1998). Both these pathways, in normal conditions, appear to be tonically active or at least activated by a noxious stimulus since blocking these receptors alters the coding properties of spinal neurons. Animal data reveal a loss of descending inhibitory noradrenaline controls alongside a gain of 5‐HT3 receptor‐mediated facilitation after neuropathy (Xu et al. 1999; Howorth et al. 2009; De Felice et al. 2011; Hughes et al. 2013; Bannister & Dickenson, 2016).

Diffuse noxious inhibitory controls and conditioned pain modulation

Diffuse noxious inhibitory controls (DNIC) describe a type of descending inhibitory control system that is triggered by a noxious stimulus distant to the control response (Le Bars et al. 1979). These endogenous top‐down controls act on all activities of deep wide dynamic range neurons, noxious or innocuous, and can be activated by thermal, mechanical, visceral and somatic chemical modalities, as long as the conditioning stimulus is noxious. With such a broad inhibitory influence, the effect of DNIC is most likely to be mediated through a postsynaptic inhibition acting on the cell body of spinal neurons, since the conditioning stimulus inhibits all activities of deep dorsal horn neurons and this is borne out of the ability of a distant stimulus to block direct activation of the neurons by glutamate (Villanueva et al. 1984). Recent studies have investigated the pharmacological basis for DNIC in rats (Bannister et al. 2015, 2016). However, DNIC are not simply a rodent mechanism. One pain can inhibit another and counter‐irritation is the term used for this. More recently, protocols have been developed to allow quantification of the human counterpart, now known as conditioned pain modulation (CPM) (Yarnitsky, 2010). Like DNIC any modality of stimulation can be used and the conditioned stimulus can be innocuous or noxious (Kosek & Ordeberg, 2000) while the conditioning stimulus must be noxious; a common approach is painful cold on the foot vs. heat or mechanical induced pain on the arm (Lewis et al. 2012). CPM has been reported in many studies in healthy volunteers but it is reduced in certain pain patients. DNIC requires intact descending pathways since it is absent after spinal transection (Dickenson & Le Bars, 1983). In patients with Wallenberg syndrome CPM is absent, suggesting clear roles of the brainstem in this phenomena. This is strong evidence for similar descending inhibitory pathways from the brainstem in rodents and man (Roby‐Brami et al. 1987; De Broucker et al. 1990). 5‐HT mechanisms are involved in the expression of CPM since serotonin transporter gene polymorphisms in healthy volunteers have a bearing on its magnitude. Individuals with low transporter activity would be expected to have high synaptic 5‐HT and have reduced CPM compared to those with high activity (Lindstedt et al. 2011). The changes in pain perception appear to be altered through higher mechanisms since spinal reflexes were not altered. In animals, higher 5‐HT3 receptor‐mediated facilitation, acting at spinal levels, can also swamp DNIC/CPM (Bannister et al. 2015). As animal models have reported a shift from a balanced inhibition and facilitation in acute pain to a loss of modulation and gain of facilitation during the transition to chronic pain, it is interesting to note that in patients with a wide and varied set of painful conditions that include neuropathy, osteoarthritis, fibromyalgia, opioid‐induced hyperalgesia and headaches, there is a failure or diminution of CPM (Lautenbacher et al. 2007; Arendt‐Nielsen et al. 2010; Yarnitsky et al. 2012). Interestingly in patients with cluster headache CPM could not be elicited during the active phase yet was restored during remission, suggesting plasticity and dynamic changes in the descending controls rather than a complete loss (Perrotta et al. 2013). Indeed, the animal data on NA indicates a similar control since although descending NA α2‐adrenoceptor‐mediated effects on responses to lower mechanical forces are lost after nerve injury, which may contribute to the mechanical hypersensitivity (Rahman et al. 2008), the receptors can still be activated with agonists (Suzuki et al. 2002) and the modulation can be brought back with reboxetine, an NRI (Bannister et al. 2015).

The pharmacological basis of DNIC

Defining the pharmacological basis of DNIC, and whether it was absent and could be subsequently restored after neuropathy, has been recently investigated. Intriguingly DNIC were shown present in control and sham‐operated animals but were abolished after neuropathy. Our group showed that α2‐adrenoceptor‐mediated mechanisms sub‐serve DNIC because the antagonists yohimbine and atipamezole abolished it. Further, by using the antagonist ondansetron to block 5‐HT3 receptor‐mediated descending facilitation, we were able to restore DNIC in spinal nerve ligated (SNL) animals. This was also possible by augmenting NA levels with the NRI reboxetine or by systemic tapentadol (Bannister et al. 2015). The restoration of DNIC by blocking descending facilitation via the 5‐HT3 receptor or by enhancing NA inhibition indicates that the pathways of DNIC must be inactivated after nerve injury by neurobiological mechanisms rather than neuropathology. Importantly active noradrenergic mechanisms at the spinal cord level speed the recovery from hypersensitivity of rodents following a surgical incision (Arora et al. 2016).

We further studied the role of 5‐HT in a set of experiments that were based on the use of SNRI and SSRI drugs in patients. Once again we recorded the activity of deep dorsal horn wide dynamic range (WDR) neuronal responses to peripherally applied von Frey filaments in the absence then presence of a noxious ear pinch (to induce DNIC) in isoflurane‐anaesthetised rats. In keeping with the original studies (Bannister et al. 2015) there was a clear expression of DNIC upon presentation of the conditioning stimulus and this was lost in SNL rats. Now, following spinal application of the SSRIs citalopram or fluoxetine, DNIC were restored. Joint application of SSRI plus SB‐269970, a 5‐HT7 receptor antagonist or atipamezole, the α2‐adrenoceptor antagonist, abolished this revelatory effect. After nerve injury we have previously reported a dominant role of 5‐HT at the 5‐HT3 receptor which overrides the noradrenergic inhibition elicited by the second conditioning stimulus since blocking this serotonergic drive reveals DNIC (Bannister et al. 2015). Here the presumption would be that neuropathy induces greater 5‐HT3‐mediated facilitations through increased activity in this pathway. However, further increases in spinal 5‐HT following spinal application of the SSRI now switch the effect of this amine to allow inhibitory actions of 5‐HT to predominate, mediated via spinal 5‐HT7 receptors (Bannister et al. 2016). Ultimately the observed inhibitory effects of DNIC result from noradrenergic inhibitory tone via the α2‐adrenoceptor.

It was proposed that under normal conditions the release of spinal NA by a distant stimulus is able to overcome the on‐going descending facilitation mediated via facilitatory 5‐HT3 receptors. However, the former pathway is quiescent after nerve injury and the facilitation swamps the inhibition. Indeed, there is good evidence for a loss of ongoing NA α2‐adrenoceptor‐mediated controls and a gain of 5‐HT3 receptor facilitation after neuropathy (Bannister et al. 2015). Both these tonic controls seem likely to be presynaptic since they have selective actions on activity evoked by low and high mechanical forces, respectively, unlike DNIC which are presumed postsynaptic (Villanueva et al. 1984) and indeed inhibit all activities of these neurons. However, the changes in both tonic and evoked monoamine controls mirror each other in the SNL model in that both are abolished. If the levels of 5‐HT are elevated further by spinal SSRI, then a 5‐HT7 receptor‐mediated inhibition can be observed. Thus we suggest that in the normal state, 5‐HT levels are low and there is a degree of 5‐HT3 and 5‐HT2 receptor‐mediated facilitation that is increased as levels and/or activity in the pathway increase after neuropathy. Further increases in spinal 5‐HT then lead to the inhibitory effects of the 5‐HT7 receptor. Indeed, early studies on DNIC using depletion of the monoamine and what were non‐selective antagonists did suggest an inhibitory role for this monoamine in DNIC (Dickenson et al. 1981; Chitour et al. 1982).

The results from such studies could be a basis for pharmacological strategies using manipulation of the monoaminergic system that could be used to enhance DNIC in patients, so possibly reducing chronic pain. The continuation of DNIC in sham‐operated animals is interesting since these animals have no pain phenotype beyond an initial acute sensitivity whilst in patients undergoing total knee replacement, low CPM predicts a higher risk of persistent postsurgical pain (Arendt‐Nielsen et al. 2010). Furthermore, DNIC in a behavioural study were shown to involve NA function (in terms of postsurgical pain models) and again showed a protective role of the inhibition. Inhibition of spinal neurons by a distant conditioning stimulus was abolished after blockade of the spinal α2‐adrenoceptor (Peters et al. 2015). These studies indicate the protective function of descending NA against persistent pain and a landmark paper revealed that, by comparing strains of rats with SNL, those that had recruited a descending NA control did not have mechanical hypersensitivity, although peripheral and spinal markers of neuropathy were identical to those who had not (Xu et al. 1999; De Felice et al. 2011).

Plasticity in descending pathways

The existence of common characteristics between DNIC and CPM and the preclinical knowledge of the pharmacology of CPM allows for both forward and back translation. It is not possible to study the basis for CPM using receptor antagonists in patients since many of the selective drugs are not approved for human use and would also need to be given spinally. Two studies strongly support the idea of a shared pharmacology. In groups of patients with diabetic neuropathy CPM was measured as well as pain scores. The studies employed the pain relieving effects of duloxetine (SNRI) and tapentadol (MOR‐NRI). In patients with a low CPM at the time of the study, duloxetine was effective, presumably since it restored the functionality of descending inhibition whereas patients with a good CPM had no benefit from the drug presumably because they had intact descending inhibition (Yarnitsky et al. 2012). In the second study, as pain scores were reduced compared with placebo after a regime of tapentadol CPM was recovered (Niesters et al. 2014). The underlying common denominator in both agents is enhancement of NA synaptic levels through NRI actions, which could underlie the link to CPM.

And what about the descending facilitation? After neuropathy, in rodent studies block of the facilitatory 5‐HT3 receptors allowed DNIC to be induced, suggesting that excitations can swamp inhibition (Bannister et al. 2015). Many patients in the duloxetine study who lacked inhibitory CPM actually had increased pain reports when the second painful stimulus was given, indicating predominant facilitation. It is plausible that fibromyalgia may arise from disordered monoamine function given the roles of NA and 5‐HT in mood, sleep and pain and given that the pain is at least partly due to abnormal descending controls (Perrot et al. 2008). In a population of patients with fibromyalgia, not only was CPM less likely to induce pain reduction but the proportion of patients who reported enhanced pain to the second stimulus was considerably higher (Potvin & Marchand, 2016).

Anatomical substrates for descending inhibition

So what are the pathways behind these descending systems? The noradrenergic projections terminating in the dorsal horn of the spinal cord derive in particular from the locus coeruleus (LC). Micro‐stimulation of these areas is anti‐nociceptive via activation of the α2‐adrenoceptor (Jones & Gebhart, 1986). Although available data strongly supports the role of this receptor, additional modulation through α1‐ and β‐receptors at the spinal cord may also be important (Millan, 2002; Llorca‐Torralba et al. 2016). Meanwhile evoked spinal release of 5‐HT from the RVM may be nociceptive or anti‐nociceptive depending on the receptor that is activated (Eide & Hole, 1993). In the RVM both ON and OFF cells are found but the transmitters in these opposing projections are as yet unclear, although 5‐HT has been strongly implicated by some in the facilitatory effects of ON cell activity (Pedersen et al. 2011). There is little doubt that there are interactions between the NA systems and RVM in the brainstem but more detail is needed. In some of the original studies on DNIC a role for spinal serotonergic mechanisms in the inhibition was reported (Dickenson et al. 1981; Kraus et al. 1982) alongside more recent data showing that noradrenergic signalling is a key underlying component of DNIC (Bannister et al. 2015; Arora et al. 2016). This particular inhibitory control was proposed to derive from the subnucleus reticularis dorsalis (SRD) (Bouhassira et al. 1992), since lesions of this nucleus diminish DNIC yet lesions of PAG or RVM are without effect. It remains unclear how both these monoamines interact at both brainstem and spinal levels to determine the level of DNIC. However, it is clear that there is a complex interplay between these and pathways comprising the dorsolateral funiculus (Okada‐Ogawa et al. 2009). The descending nature of DNIC is verified by its loss after spinal transection. However, it is unclear how the SRD communicates with the final common output to the cords which is mediated by NA. Theoretically projections from this nucleus to the LC seem a likely substrate.

Recent human studies have shed light on this and verify the role of the SRD in CPM. Here a second noxious thermal test stimulus was used to induce CPM where the first stimulus was a moderately noxious thermal stimulus applied to the face. During the conditioning stimulus a reduction in the activity of the trigeminal complex was accompanied by a reduction in the signals from the parabrachial nucleus and SRD – changes in RVM were not observed. This suggests that the parabrachial relays noxious stimuli required for the conditioned and conditioning stimulus, and that the SRD is key to one pain inhibiting another Youssef et al. 2016b). At first sight, the data could suggest that the SRD must be silenced for the inhibition to occur, but fMRI cannot distinguish activity from excitatory from inhibitory signalling so a more parsimonious conclusion would be that ongoing inhibitory activity in the SRD suppresses CPM. Reductions in this activity allows the final noradrenergic pathway to become active. Another very recent human study has shown that activity in the prefrontal and cingulate cortices is associated with a lack of CPM across a population (Youssef et al. 2016a. This then sets up a neural system whereby in the normal population CPM is effective in a large majority yet in many persistent pain states CPM is lost, as is DNIC in neuropathic animals.

The anterior cingulate cortex (ACC) is involved in processing the affective component of pain, and so is part of the neural circuits that are responsible for expressing emotional aspects of pain and driving goal‐directed behaviour (Johansen et al. 2001). It may be the changes in these functions, so common in patients with persistent pain, that drive the failure of DNIC and so link higher brain functions with spinal sensory processes.

Conclusion

Uniquely, one pain inhibiting another can be a tool to probe the integrity of descending inhibition in animals and humans, and the preclinical data on the pharmacology of these systems appears to be aligned with human data. The pain relieving effects of current drugs deloxetine and tapentadol are through interactions with CPM, which then allows steps towards mechanism‐based treatments for patients in pain. Further probing of the pathways subserving DNIC and CPM and deciphering the complex pharmacology of the monoamine interactions could be valuable in further back and forward translation and better treatments of human pain types.

Additional information

Competing interest

The authors have no competing interests to declare.

Funding

This work was funded by a strategic award to the Wellcome Trust Pain Consortium and the London Pain Consortium (Grant number: 162819).

Biography

Kirsty Bannister, a senior research associate, and Tony Dickenson, professor of Neuropharmacology, both work in the Neuroscience, Physiology and Pharmacology Department of UCL, have worked together for 9 years on the neural and pharmacological systems that sub‐serve pain transmission and modulation in the spinal cord and brain. Their research interests are pharmacology of the brain, including the mechanisms of pain and how pain can be controlled in both normal and pathophysiological conditions, and how to translate basic science to the patient. Kirsty graduated from UCL before completing a PhD in epigenetics at Imperial College London and returning to UCL as a post‐doctoral researcher. Tony did postgraduate research in Paris before joining UCL. They are funded by the Wellcome Trust Pain Consortium and due to firmly believing in translational research both speak widely to scientists and clinicians.

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This review was presented at the symposium “Top‐down control of pain”, which took place at Physiology 2016, Dublin, Ireland, 29–31 July 2016.

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