A critical brainstem relay for mediation of diffuse noxious inhibitory controls.

The CNS houses naturally occurring pathways that project from the brain to modulate spinal neuronal activity. The noradrenergic locus coeruleus (the A6 nucleus) originates such a descending control whose influence on pain modulation encompasses an interaction with a spinally projecting non-cerulean noradrenergic cell group. Hypothesizing the origin of an endogenous pain inhibitory pathway, our aim was to identify this cell group. A5 and A7 noradrenergic nuclei also spinally project. We probed their activity using an array of optogenetic manipulation techniques during in vivo electrophysiological experimentation. Interestingly, noxious stimulus evoked spinal neuronal firing was decreased upon opto-activation of A5 neurons (two-way ANOVA with Tukey post hoc, P < 0.0001). Hypothesizing that this may reflect activity in the noradrenergic diffuse noxious inhibitory control circuit, itself activated upon application of a conditioning stimulus, we opto-inhibited A5 neurons with concurrent conditioning stimulus application. Surprisingly, no spinal neuronal inhibition was observed; activity in the diffuse noxious inhibitory control circuit was abolished (two-way ANOVA, P < 0.0001). We propose that the A5 nucleus is a critical relay nucleus for mediation of diffuse noxious inhibitory controls. Given the plasticity of diffuse noxious inhibitory controls in disease, and its back and forward clinical translation, our data reveal a potential therapeutic target.

CGRP monoclonal antibody prevents the loss of diffuse noxious inhibitory controls (DNIC) in a mouse model of post-traumatic headache.

AIM: Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice. METHODS: Mild traumatic brain injury was induced in lightly anesthetized male C57BL/6J mice by a weight drop onto a closed and unfixed skull, which allowed free head rotation after the impact. We first determined possible alterations in the diffuse noxious inhibitory controls, a measure of net descending pain inhibition called conditioned pain modulation in humans at day 2 following mild traumatic brain injury. Diffuse noxious inhibitory control was assessed as the latency to a thermally induced tail-flick that served as the test stimulus in the presence of right forepaw capsaicin injection that provided the conditioning stimulus. Post-traumatic headache-like behaviors were assessed by the development of cutaneous allodynia in the periorbital and hindpaw regions after mild traumatic brain injury. We then determined if intraperitoneal fremanezumab, an anti-calcitonin-gene related peptide monoclonal antibody or vehicle administered 2 h after sham or mild traumatic brain injury induction could alter cutaneous allodynia or diffuse noxious inhibitory control responses on day 2 post mild traumatic brain injury. RESULTS: In naïve and sham mice, capsaicin injection into the forepaw elevated the latency to tail-flick, reflecting the antinociceptive diffuse noxious inhibitory control response. Periorbital and hindpaw cutaneous allodynia, as well as a loss of diffuse noxious inhibitory control, was observed in mice 2 days after mild traumatic brain injury. Systemic treatment with fremanezumab blocked mild traumatic brain injury-induced cutaneous allodynia and prevented the loss of diffuse noxious inhibitory controls in mice subjected to a mild traumatic brain injury. INTERPRETATION: Sequestration of calcitonin-gene related peptide in the initial stages following mild traumatic brain injury blocked the acute allodynia that may reflect mild traumatic brain injury-related post-traumatic headache and, additionally, prevented the loss of net descending inhibition within central pain modulation pathways. As loss of conditioned pain modulation has been linked to multiple persistent pain conditions, dysregulation of descending modulatory pathways may contribute to the persistence of post-traumatic headache. Additionally, evaluation of the conditioned pain modulation/diffuse noxious inhibitory controls response may serve as a biomarker of vulnerability for chronic/persistent pain. These findings suggest that early anti-calcitonin-gene related peptide intervention has the potential to be effective both for the treatment of mild traumatic brain injury-induced post-traumatic headache, as well as inhibiting mechanisms that may promote post-traumatic headache persistence.

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats.

Diffuse noxious inhibitory controls (DNIC) are a mechanism of endogenous descending pain modulation and are deficient in a large proportion of chronic pain patients. However, the pathways involved remain only partially determined with several cortical and brainstem structures implicated. This study examined the role of the dorsal reticular nucleus (DRt) and infralimbic (ILC) region of the medial prefrontal cortex in DNIC. In vivo electrophysiology was performed to record from dorsal horn lamina V/VI wide dynamic range neurones with left hind paw receptive fields in anaesthetised sham-operated and L5/L6 spinal nerve-ligated (SNL) rats. Evoked neuronal responses were quantified in the presence and absence of a conditioning stimulus (left ear clamp). In sham rats, DNIC were reproducibly recruited by a heterotopically applied conditioning stimulus, an effect that was absent in neuropathic rats. Intra-DRt naloxone had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. In addition, intra-DRt naloxone blocked DNIC in sham rats, but had no effect in SNL rats. Intra-ILC lidocaine had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. However, differential effects were observed in relation to the expression of DNIC; intra-ILC lidocaine blocked activation of DNIC in sham rats but restored DNIC in SNL rats. These data suggest that the ILC is not directly involved in mediating DNIC but can modulate its activation and that DRt involvement in DNIC requires opioidergic signalling.

Attenuation of the Diffuse Noxious Inhibitory Controls in Chronic Joint Inflammatory Pain Is Accompanied by Anxiodepressive-Like Behaviors and Impairment of the Descending Noradrenergic Modulation.

The noradrenergic system is paramount for controlling pain and emotions. We aimed at understanding the descending noradrenergic modulatory mechanisms in joint inflammatory pain and its correlation with the diffuse noxious inhibitory controls (DNICs) and with the onset of anxiodepressive behaviours. In the complete Freund's adjuvant rat model of Monoarthritis, nociceptive behaviors, DNICs, and anxiodepressive-like behaviors were evaluated. Spinal alpha2-adrenergic receptors (a2-AR), dopamine beta-hydroxylase (DBH), and noradrenaline were quantified concomitantly with a2-AR pharmacologic studies. The phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) were quantified in the Locus coeruleus (LC), amygdala, and anterior cingulate cortex (ACC). DNIC was attenuated at 42 days of monoarthritis while present on days 7 and 28. On day 42, in contrast to day 28, noradrenaline was reduced and DBH labelling was increased. Moreover, spinal a2-AR were potentiated and no changes in a2-AR levels were observed. Additionally, at 42 days, the activation of ERKs1/2 was increased in the LC, ACC, and basolateral amygdala. This was accompanied by anxiety- and depressive-like behaviors, while at 28 days, only anxiety-like behaviors were observed. The data suggest DNIC is attenuated in prolonged chronic joint inflammatory pain, and this is accompanied by impairment of the descending noradrenergic modulation and anxiodepressive-like behaviors.

An investigation into the noradrenergic and serotonergic contributions of diffuse noxious inhibitory controls in a monoiodoacetate model of osteoarthritis.

Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal α2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal α2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.

Intense and sustained pain reduces cortical responses to auditory stimuli: Implications for the interpretation of the effects of heterotopic noxious conditioning stimulation in humans.

Phasic pain stimuli are inhibited when they are applied concomitantly with a conditioning tonic stimulus at another body location (heterotopic noxious conditioning stimulation, HNCS). While the effects of HNCS are thought to rely on a spino-bulbo-spinal mechanism in animals (termed diffuse noxious inhibitory controls, DNIC), the underlying neurophysiology in humans may involve other pathways. In this study, we investigated the role of concomitant supraspinal mechanisms during HNCS by presenting auditory stimuli during a conditioning tonic painful stimulus (the cold pressor test, CPT). Considering that auditory stimuli are not conveyed through the spinal cord, any changes in brain responses to auditory stimuli during HNCS can be ascribed entirely to supraspinal mechanisms. Electroencephalography (EEG) was recorded during HNCS, and auditory stimuli were administered in three blocks, before, during and after HNCS. Nociceptive withdrawal reflexes (NWRs) were recorded at the same time points to investigate spinal processing. Our results showed that AEPs were significantly reduced during HNCS. Moreover, the amplitude of the NWR was significantly diminished during HNCS in most participants. Given that spinal and supraspinal mechanisms operate concomitantly during HNCS, the possibility of isolating their individual contributions in humans is questionable. We conclude that the net effects of HCNS are not independent from attentional/cognitive influences.

Inhibitory effects of heterotopic noxious counter-stimulation on perception and brain activity related to Aß-fibre activation.

Heterotopic noxious counter-stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non-nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter-balanced sessions, including non-nociceptive (selective Aß-fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20-min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0-100 scale, where 0 is no pain and 100 the worst pain imaginable). Non-nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII-reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non-nociceptive (P < 0.001) and nociceptive (P < 0.001) stimulation. SEP peak-to-peak amplitude at Cz was significantly decreased by HNCS for non-nociceptive (P < 0.01) and nociceptive (P < 0.05) stimulation. These results indicate that perception and brain activity related to Aß-fibre activation are inhibited by HNCS. The mechanisms of this effect remain to be investigated to clarify whether it involves inhibition of spinal wide-dynamic-range neurons by diffuse noxious inhibitory controls, supraspinal processes or both.

Inventory of Personal Factors Influencing Conditioned Pain Modulation in Healthy People: A Systematic Literature Review.

BACKGROUND: Conditioned pain modulation (CPM) is believed to play an important role in the development and exacerbation of chronic pain, because dysfunction of CPM is associated with a shift in balance between pain facilitation and pain inhibition. In many patients with central sensitization, CPM is less efficacious. Besides that, efficacy of CPM is highly variable in healthy people. Consequently, it seems that several individual variables may influence CPM. A systematic review examining personal factors influencing CPM was conducted. METHODS: This systematic review follows the PRISMA guidelines. "Pubmed" and "Web of Science" were searched using different synonyms of CPM. Full-text clinical reports addressing the influence of personal factors on CPM in healthy adults were included. Checklists for RCTs and case-control studies provided by the Dutch Institute for Healthcare Improvement (CBO) and the Dutch Cochrane Centre were utilized to assess methodological quality. Levels of evidence and strength of conclusion were assigned using the CBO guidelines. RESULTS: Forty-six articles were identified that reported the influence of personal factors on CPM. Quality assessment revealed 10 studies with a methodological quality less than 50% wherefore they were excluded (21.8%), resulting in a general total methodological quality score of 72.5%. Overall younger adult age, male gender, ovulatory phase, positive expectations, attention to the conditioning stimulus, and carrier of the 5-HTTLPR long allele result in better CPM. CONCLUSION: It is advised for future studies to take these factors into account. Further research regarding the influence of oral contraceptives, catastrophizing, information about conditioning stimulation, distraction, physical activity, and genetics on CPM magnitude is required.

An endogenous pain control system is altered in subjects with interstitial cystitis.

PURPOSE: Multiple studies have demonstrated that in healthy subjects, painful stimuli applied to one part of the body inhibit pain sensation in other parts of the body, a phenomenon referred to as conditioned pain modulation. Conditioned pain modulation is related to the presence of endogenous pain control systems. Studies have demonstrated deficits in conditioned pain modulation associated inhibition in many but not all chronic pain disorders. In this study we determine whether conditioned pain modulation is altered in subjects with interstitial cystitis/bladder pain syndrome. MATERIALS AND METHODS: Female subjects with and without the diagnosis of interstitial cystitis/bladder pain syndrome were studied psychophysically using quantitative cutaneous thermal, forearm ischemia and ice water immersion tests. Conditioned pain modulation was assessed by quantifying the effects of immersion of the hand in ice water (conditioning stimulus) on threshold and tolerance of cutaneous heat pain (test stimulus) applied to the contralateral lower extremity. RESULTS: The conditioned pain modulation responses of the subjects with interstitial cystitis/bladder pain syndrome were statistically different from those of healthy control subjects for cutaneous thermal threshold and tolerance measures. Healthy control subjects demonstrated statistically significant increases in thermal pain tolerance whereas subjects with the diagnosis of interstitial cystitis/bladder pain syndrome demonstrated statistically significant reductions in thermal pain tolerance. CONCLUSIONS: An endogenous pain inhibitory system normally observed with conditioned pain modulation was altered in subjects with interstitial cystitis/bladder pain syndrome. This finding identifies interstitial cystitis/bladder pain syndrome as similar to several other chronic pain disorders such as fibromyalgia and irritable bowel syndrome, and suggests that a deficit in endogenous pain inhibitory systems may contribute to such chronic pain disorders.

Chronic temporomandibular disorders are not necessarily associated with a compromised endogenous analgesic system.

AIMS: To test whether temporomandibular disorders (TMD) case-control differences in conditioned pain modulation (CPM) exist, using a mechanically evoked temporal summation (TS) model. METHODS: A series of 10 repetitive, mildly noxious, mechanical stimuli were applied to the fingers of 30 women with TMD, who had a primary diagnosis of masticatory myofascial pain, and 30 age-matched healthy women. The subjects rated the pain intensity caused by the 1st, 5th, and 10th stimuli in the series. To evaluate CPM, the same series of mechanical stimulations were applied with concomitant exposure of the other hand to a painfully cold water bath. Statistical inferences were based on t tests, chi-square tests, or analysis of variance (ANOVA), as appropriate. RESULTS: Pain ratings increased significantly with stimulus repetition (P < .01) and CPM significantly reduced TS of pain (P < .01). Of particular note, both groups showed very similar degrees of CPM, with no significant group difference. CONCLUSION: Painful TMD is not necessarily associated with a compromised ability to engage the endogenous analgesic system in an experimental setting.