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.
The supraspinal modulatory influences on pain processing are well connected, complicated and fervently researched. Descending drives originating from superficial dorsal horn NK1‐expressing neurons (themselves activated by a primary afferent input) will relay through the parabrachial, a vital component of the machinery that processes ascending nociceptive information. From these nuclei inputs may relay to the limbic brain, hypothalamus and the periaqueductal grey (PAG) with which they make extensive reciprocal connections. The parabrachial also has a functional connection with the rostroventral medial medulla (RVM), allowing the spinobrachial pathway to access descending control systems as part of a recurrent circuit. Serotonergic projections from the RVM will have excitatory influences on pain transmission via actions at the 5‐HT2 and 5‐HT3 receptors (5‐HT2/3R) in the dorsal horn of the spinal cord while actions at the 5‐HT7 receptor (5‐HT7R) are inhibitory. Noradrenergic projections from the locus coeruleus (LC) will have predominantly inhibitory influences on pain transmission via actions at spinal α2‐adrenoceptors (AR). The pain modulatory actions observed following activation of diffuse noxious inhibitory controls (DNIC) involve, to some extent, activation of descending inhibitory pathways from the subnucleus reticularis dorsalis (SRD) to the dorsal horn of the spinal cord. However, complex brainstem interactions ultimately impact on all aspects of top down modulatory processing; inactivating the RVM will reinstate DNIC in chronic morphine treated animals.
Gabapentin (GBP) is a first-line therapy for neuropathic pain, but its mechanisms and sites of action remain uncertain. We investigated GBP-induced modulation of neuropathic pain following spinal ...nerve ligation (SNL) in rats. Intravenous or intrathecal GBP reversed evoked mechanical hypersensitivity and produced conditioned place preference (CPP) and dopamine (DA) release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal GBP also significantly inhibited dorsal horn wide-dynamic-range neuronal responses to a range of evoked stimuli in SNL rats. By contrast, GBP microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP, and elicited NAc DA release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on wide-dynamic-range neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous GBP-induced CPP and NAc DA release but failed to block its inhibition of tactile allodynia. Gabapentin, therefore, can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity, and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from nonopioid analgesics, GBP requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain-motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of GBP's analgesic effects in patients.
The amygdala is a key subcortical region believed to contribute to emotional components of pain. As opioid receptors are found in both the central (CeA) and basolateral (BLA) nuclei of the amygdala, ...we investigated the effects of morphine microinjection on evoked pain responses, pain-motivated behaviors, dopamine release in the nucleus accumbens (NAc), and descending modulation in rats with left-side spinal nerve ligation (SNL). Morphine administered into the right or left CeA had no effect on nerve injury-induced tactile allodynia or mechanical hyperalgesia. Right, but not left, CeA morphine produced conditioned place preference (CPP) and increased extracellular dopamine in the NAc selectively in SNL rats, suggesting relief of aversive qualities of ongoing pain. In SNL rats, CPP and NAc dopamine release following right CeA morphine was abolished by blocking mu opioid receptor signaling in the rostral anterior cingulate cortex (rACC). Right CeA morphine also significantly restored SNL-induced loss of the diffuse noxious inhibitory controls, a spino-bulbo-spinal pain modulatory mechanism, termed conditioned pain modulation in humans. Microinjection of morphine into the BLA had no effects on evoked behaviors and did not produce CPP in nerve-injured rats. These findings demonstrate that the amygdalar action of morphine is specific to the right CeA contralateral to the side of injury and results in enhancement of net descending inhibition. In addition, engagement of mu opioid receptors in the right CeA modulates affective qualities of ongoing pain through endogenous opioid neurotransmission within the rACC, revealing opioid-dependent functional connections from the CeA to the rACC.
Descending control of nociception (DCN; also known as conditioned pain modulation CPM, the behavioral correlate of diffuse noxious inhibitory controls) is the phenomenon whereby pain inhibits pain in ...another part of the body and is the subject of increasing study because it may represent a biomarker of chronic pain. We recently discovered that pain modulation on the application of a DCN paradigm involving low-intensity test stimuli occurs in the direction of hyperalgesia in healthy mice and rats, whereas the use of high-intensity stimuli produces analgesia. To elucidate the physiological mechanisms underlying hyperalgesic DCN, we administered agonists and antagonists of norepinephrine (NE) and serotonin (5-HT) receptors, key neurochemical players in the production of analgesic DCN. We find that 3 different monoamine reuptake inhibitors-the NE-selective reboxetine, the 5-HT-selective fluoxetine, and the dual NE/5-HT agonist duloxetine-all abolish hyperalgesic DCN when administered into the spinal cord (but not systemically), with no effect on heat or mechanical pain sensitivity. The reversal by reboxetine of hyperalgesic DCN is mediated by α 2 -adrenergic receptors (ie, blocked by atipamezole), and the fluoxetine reversal is mediated by 5-HT 7 receptors (ie, blocked by SB269970). By contrast, analgesic DCN was found to be reversed by atipamezole and SB269970 themselves, with no effect of reboxetine or fluoxetine. Thus, hyperalgesic DCN seems to be the neurochemical opposite to analgesic DCN. These data further validate and help elucidate a preclinical paradigm that mimics dysfunctional CPM and thus may form the basis of translational experiments that aim to reveal preventative pharmacological strategies for individuals predisposed to persistent pain.
Modulation of pain may result from engagement of opioid receptors in multiple brain regions. Whether sensory and affective qualities of pain are differentially affected by brain opioid receptor ...circuits remains unclear. We previously reported that opioid actions within the rostral anterior cingulate cortex (ACC) produce selective modulation of affective qualities of neuropathic pain in rodents, but whether such effects may occur in other areas of the ACC is not known. Here, morphine was microinjected into 3 regions of the ACC or into the rostral ventromedial medulla (RVM), and pain behaviors in naive, sham, or spinal nerve ligated (SNL) rats were evaluated. In naive animals, the tail-flick response was inhibited by RVM, but not ACC, morphine. Anterior cingulate cortex morphine did not affect tactile allodynia (the von Frey test) or mechanical (Randall-Selitto) or thermal (Hargreaves) hyperalgesia in spinal nerve ligated rats. In contrary, RVM morphine reduced tactile allodynia and produced both antihyperalgesic and analgesic effects against mechanical and thermal stimuli as well as conditioned place preference selectively in nerve-injured rats. Within the RVM, opioids inhibit nociceptive transmission reflected in both withdrawal thresholds and affective pain behaviors. Activation of mu opioid receptors within specific rostral ACC circuits, however, selectively modulates affective dimensions of ongoing pain without altering withdrawal behaviors. These data suggest that RVM and ACC opioid circuits differentially modulate sensory and affective qualities of pain, allowing for optimal behaviors that promote escape and survival. Targeting specific ACC opioid circuits may allow for treatment of chronic pain while preserving the physiological function of acute pain.
Background
Reporting in conditioned pain modulation (CPM) studies is not standardised. Here, two CPM protocols were performed in populations of healthy human subjects in order to investigate the ...influence of the CPM paradigm and stringent analyses parameters on the identification of a net CPM effect.
Methods
A standard thermal or mechanical CPM protocol was carried out on 25 and 17 subjects, respectively. The standard error of measurement (SEM) of the CPM effect was calculated in order to determine a change in pain thresholds greater than that due to measurement error or ‘real’ change in test scores. In addition, each individual underwent a minimum of two control CPM sessions, which were paired with the CPM test sessions. To quantify a net CPM effect, the intrasession difference between baseline and conditioning was subtracted from the difference calculated at the same time points during the control session.
Results
For both protocols, excellent reliability for intrasession repeats of the test stimulus at baseline was demonstrated for thermal and mechanical stimulation (ICC > 0.9). Test‐retest subject responses (in terms of experimental Session 1 versus. Session 2) showed excellent reliability for mechanical (ICC > 0.8), compared to thermal stimulation, which ranged from poor to moderate (ICC < 0.4‐>0.75). However, calculating the net CPM effect using control session data demonstrated poor‐fair reliability for both protocols (ICC < 0.4–0.59).
Conclusion
Calculating the net CPM effect should be optimised and standardised for comparison of CPM data collected from global research groups. Recommendation is made for the performance of a multicentre, test‐retest study.
Neck pain, with or without radiculopathy, can have significant negative effects on physical and mental wellbeing. Mental health symptoms are known to worsen prognosis across a range of ...musculoskeletal conditions. Understanding the association between mental health symptoms and health outcomes in this population has not been established. Our aim was to systematically review the association between psychosocial factors and/or mental health symptoms on health outcomes in adults with neck pain, with or without radiculopathy.
A systematic review of published and unpublished literature databases was completed. Studies reporting mental health symptoms and health outcomes in adults with neck pain with or without radiculopathy were included. Due to significant clinical heterogeneity, a narrative synthesis was completed. Each outcome was assessed using GRADE.
Twenty-three studies were included (N = 21,968 participants). Sixteen studies assessed neck pain only (N = 17,604 participants); seven studies assessed neck pain with radiculopathy (N = 4,364 participants). Depressive symptoms were associated with poorer health outcomes in people with neck pain and neck pain with radiculopathy. These findings were from seven low-quality studies, and an additional six studies reported no association. Low-quality evidence reported that distress and anxiety symptoms were associated with poorer health outcomes in people with neck pain and radiculopathy and very low-quality evidence showed this in people with neck pain only. Stress and higher job strain were negatively associated with poorer health outcomes measured by the presence of pain in two studies of very low quality.
Across a small number of highly heterogenous, low quality studies mental health symptoms are negatively associated with health outcomes in people with neck pain with radiculopathy and neck pain without radiculopathy. Clinicians should continue to utilise robust clinical reasoning when assessing the complex factors impacting a person's presentation with neck pain with or without radiculopathy.
CRD42020169497.
Pain resulting from metastatic bone disease is a major unmet clinical need. Studying spinal processing in rodent models of cancer pain is desirable since the percept of pain is influenced in part by ...modulation at the level of the transmission system in the dorsal horn of the spinal cord. Here, a rodent model of cancer-induced bone pain (CIBP) was generated following syngeneic rat mammary gland adenocarcinoma cell injection in the tibia of male Sprague Dawley rats. Disease progression was classified as "early" or "late" stage according to bone destruction. Even though wakeful CIBP rats showed progressive mechanical hypersensitivity, subsequent in vivo electrophysiological measurement of mechanically evoked deep dorsal horn spinal neuronal responses revealed no change. Rather, a dynamic reorganization of spinal neuronal modulation by descending controls was observed, and this was maladaptive only in the early stage of CIBP. Interestingly, this latter observation corresponded with the degree of damage to the primary afferents innervating the cancerous tissue. Plasticity in the modulation of spinal neuronal activity by descending control pathways reveals a novel opportunity for targeting CIBP in a stage-specific manner. Finally, the data herein have translational potential since the descending control pathways measured are present also in humans.
The aim of the study was to explore beliefs about pain and related coping strategies of individuals experiencing abdominal pain during remitted inflammatory bowel disease (IBD), and their perception ...of irritable bowel syndrome (IBS) in the context of IBD. In-depth semi-structured interviews were conducted with 23 participants who self-reported experiences of abdominal pain during remitted IBD. The study was embedded in the constructivism tradition and reflexive thematic analysis was used to analyse the interviews. Results encompass 1) How IBS is perceived; 2) How individuals monitor symptoms to distinguish active from quiescent IBD; 3) Coping strategies employed to navigate the pain; 4)How manageability of pain guides the distinction between active and quiescent disease; v. How context influences pain interpretation and management; 5) What role illness history and health literacy play in the meaning of ongoing pain. The IBS label was perceived by some as invalidating, although it helped some people to worry less about ongoing pain and symptoms during remitted IBD. However, even for the latter individuals, IBS did not bring a clear understanding of painful symptoms. Participants' responses highlight a need for explanations that incorporate both the complexity of IBD and underlying causes of ongoing pain during remission. Communication would benefit from the appreciation of pain (and symptoms) in the wider context of illness history and health literacy.
The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent α
2-adrenoceptor-mediated inhibitory system and ...5-HT
3 (and likely also 5-HT
2) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control.
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