Modulation Of Pain Sensitivity Research Articles

The effects of C-tactile stimulation on temporal summation of second pain: A study of the central and peripheral neural correlates

Affective touch is mediated by specialized receptors sensitive to gentle and slow touch called C-tactile afferents (CT). The activation of these receptors has shown promise in reducing subjective pain ratings, however, how this type of touch can affect central sensitization processes is poorly studied. This work aimed to investigate if affective touch is able to modulate pain sensitization and its electrophysiological correlates during Temporal Summation of Second Pain (TSSP), a phenomenon characterized by an increase in pain perception due to repeated noxious stimuli.Thirty-seven participants underwent a TSSP protocol involving three conditions: TSSP alone, TSSP during vibrotactile stimulation, and TSSP during CT stimulation (administered with a brush mounted in a robot arm). We measured subjective pain ratings, electroencephalographic (N2-P2 complex) and electrocardiographic activity during these conditions.Participants reported a significantly lower increase of pain during CT stimulation compared to vibrotactile stimulation, but not to TSSP alone. In addition, TSSP was reduced when administered in the ipsilateral arm compared to the other somatosensory stimulation. Subjective reports of attention towards painful stimuli, amplitude of the N2-P2 complex, and heart rate were also reduced during CT stimulation. Conclusion: Our results indicated that the activation of CT receptors may reduce sensitization compared to other types of somatosensory stimulation, which is possibly related to the reduction of the attention devoted to nociceptive stimulation. Our results suggest that activation of CT receptors may alleviate the occurrence of central pain sensitization.

Artificial pain-perceptual nociceptor emulation based on graphene oxide synaptic transistors

Pain-perceptual nociceptors play a crucial role as sensory neurons, detecting noxious stimuli and enabling the human body to respond effectively while accurately perceiving atypical or hazardous situations in reality. Hence, the utilization of emerging devices in hardware to incorporate pain-perceptual nociceptors can significantly enhance the effectiveness of bionic devices by providing them with varying sensitivities towards external stimuli based on specific objectives. In this study, we have developed a pain-perceptive nociceptor by combining a temperature sensor with a synaptic transistor. To emulate synaptic functions and features of nociceptors, a graphene oxide synaptic transistor with sodium alginate electrolyte as gate dielectric is utilized. This device has the ability to replicate significant attributes of pain-perceptive nociceptors, including the threshold for pain, memory of prior injury, and modulation of pain sensitivity. For the purpose of perceiving pain, temperature sensing is achieved by employing a MoS2 temperature sensor for the pain-perceptual nociceptors. The suggested device has the potential to create novel possibilities for the applications of advanced neuromorphic brain-like systems, like electronic skins, wearable sensing and implantable bioelectronics.

Modulating the Pronociceptive Effect of Sleep Deprivation: A Possible Role for Cholinergic Neurons in the Medial Habenula.

Sleep deprivation has been shown to exacerbate pain sensitivity and may contribute to the onset of chronic pain, yet the precise neural mechanisms underlying this association remain elusive. In our study, we explored the contribution of cholinergic neurons within the medial habenula (MHb) to hyperalgesia induced by sleep deprivation in rats. Our findings indicate that the activity of MHb cholinergic neurons diminishes during sleep deprivation and that chemogenetic stimulation of these neurons can mitigate the results. Interestingly, we did not find a direct response of MHb cholinergic neurons to pain stimulation. Further investigation identified the interpeduncular nucleus (IPN) and the paraventricular nucleus of the thalamus (PVT) as key players in the pro-nociceptive effect of sleep deprivation. Stimulating the pathways connecting the MHb to the IPN and PVT alleviated the hyperalgesia. These results underscore the important role of MHb cholinergic neurons in modulating pain sensitivity linked to sleep deprivation, highlighting potential neural targets for mitigating sleep deprivation-induced hyperalgesia.

Modulation of Pain Sensitivity by a Hyperventilatory Breathing Exercise and Cold Exposure Training.

Evidence indicates that healthy individuals who follow a training program comprised hyperventilatory breathing exercises and cold exposure can voluntarily activate their sympathetic nervous system and attenuate their systemic inflammatory response during experimental endotoxemia (intravenous administration of bacterial endotoxin). Furthermore, trained participants reported less endotoxemia-induced flu-like symptoms. However, it remained to be determined whether the effects on symptoms are due to the mitigated inflammatory response or involve direct analgesic effects of (elements of) the training program. In the present study, we used Nijmegen-Aalborg Screening Quantitative sensory testing (NASQ) to objectively map pain sensitivity using non-invasive stimuli to address this question. First, NASQ parameters were evaluated in 20 healthy volunteers before, during, and after the conduct of the hyperventilatory breathing exercise. Second, NASQ measurements were performed before and after 48 healthy volunteers followed different modalities of the training program: breathing exercise training, cold exposure training, the combination of both, or no training. Lastly, NASQ measurements were performed in these 48 subjects during experimental endotoxemia. Electrical pain detection thresholds increased during the breathing exercise (p = 0.001) as well as four hours afterwards (p = 0.03). Furthermore, cold exposure training resulted in lower VAS scores during hand immersion in ice water (p < 0.001). Systemic inflammation induced by administration of endotoxin nullified the decreased pain perception during the ice water test in subjects trained in cold exposure. A hyperventilatory breathing exercise decreases pain perception induced by an electrical stimulus. Furthermore, cold exposure training may decrease pain perception induced by hand immersion in ice water.

JMJD8 regulates neuropathic pain by affecting spinal cord astrocyte differentiation

The demethylase JmjC structural domain-containing protein 8 (JMJD8) has been demonstrated to be involved in cellular inflammatory responses. Neuropathic pain (NP) is a chronic pain, and it is unclear whether JMJD8 is involved in the regulation of NP. Using a chronic constriction injury (CCI) mouse model of NP, we investigated the expression levels of JMJD8 during NP and the influences of JMJD8 on regulating pain sensitivity. We found that JMJD8 expression in the spinal dorsal horn was reduced after CCI. Immunohistochemistry showed that JMJD8 was colabeled with GFAP in naïve mice. Knockdown of JMJD8 in the spinal dorsal horn astrocytes induced pain behavior. Further study showed that overexpression of JMJD8 in the spinal dorsal horn astrocytes not only reversed pain behavior but also activated the spinal dorsal horn A1 astrocytes. These results suggest that JMJD8 may modulate pain sensitivity by affecting activated the spinal dorsal horn A1 astrocytes and may be a potential therapeutic target for NP.

Low-Intensity Blood Flow Restriction Exercises Modulate Pain Sensitivity in Healthy Adults: A Systematic Review

Low-intensity exercise with blood flow restriction (LIE-BFR) has been proposed as an effective intervention to induce hypoalgesia in both healthy individuals and patients with knee pain. Nevertheless, there is no systematic review reporting the effect of this method on pain threshold. We aimed to evaluate the following: (i) the effect of LIE-BFR on pain threshold compared to other interventions in patients or healthy individuals; and (ii) how different types of applications may influence hypoalgesic response. We included randomized controlled trials assessing the effectiveness of LIE-BFR alone or as an additive intervention compared with controls or other interventions. Pain threshold was the outcome measure. Methodological quality was assessed using the PEDro score. Six studies with 189 healthy adults were included. Five studies were rated with 'moderate' and 'high' methodological quality. Due to substantial clinical heterogeneity, quantitative synthesis could not be performed. All studies used pressure pain thresholds (PPTs) to assess pain sensitivity. LIE-BFR resulted in significant increases in PPTs compared to conventional exercise at local and remote sites 5 min post-intervention. Higher-pressure BFR results in greater exercise-induced hypoalgesia compared to lower pressure, while exercise to failure produces a similar reduction in pain sensitivity with or without BFR. Based on our findings, LIE-BFR can be an effective intervention to increase pain threshold; however, the effect depends on the exercise methodology. Further research is necessary to investigate the effectiveness of this method in reducing pain sensitivity in patients with pain symptomatology.

Distorted body schema after mastectomy with immediate breast reconstruction: a 4-month follow up study.

BackgroundAfter breast cancer, some patients report residual pain-related upper limb disability without physical impairment. Although pain and altered proprioception are known to affect the working body schema (WBS), there is little available evidence investigating the WBS of breast cancer survivors (BrCS). WBS—body representations in the brain—affect the “neuromatrix” that modulates pain sensitivity and the threshold for threatening stimuli. The aim of this study was to investigate whether WBS was disrupted after mastectomy with immediate breast reconstruction (IBR) for breast cancer and whether pain and proprioceptive changes affected WBS.MethodsThirty-five BrCS participated in the 4-month follow-up study. They were observed at 1 and 4 months postoperatively. The main outcome measures were the left right judgement test (LRJT) results, absolute angle error, pectoralis minor length index (PMI), pain, and Quick-Disabilities of the Arm, Shoulder, and Hand (Q-DASH) score. They were measured at each observation, and parametric tests were performed to identify the nature of WBS.ResultsBoth the reaction time and accuracy of the hand LRJT were poorer than those of the foot and back LRJT (p < 0.001). The hand LRJT reaction time and accuracy were unchanged over the total follow-up period (p = 0.77 and p = 0.47, respectively). There was a weak correlation between the LRJT reaction time and PMI (r = −0.26, p = 0.07), pain severity (r = 0.37, p = 0.02), and Q-DASH score (r = 0.37, p = 0.02). There was also a weak correlation between LRJT accuracy and Q-DASH score (r = −0.31, p = 0.04). The LRJT accuracy of BrCS who underwent surgery on their dominant side was higher than that of BrCS who underwent surgery on their non-dominant side (p = 0.002). Regression analysis found a weak but significant relationship between the early hand LRJT results and late pain severity (adjusted R2 = 0.179, p = 0.007). A similar relationship was found between early hand LRJT results and Q-DASH score (adjusted R2 = 0.099, p = 0.039).ConclusionTo the best of our knowledge, this is the first study providing the nature of WBS after mastectomy with IBR. In this population, it is necessary to postoperatively preserve WBS integrity for pain and upper limb disability.

Expectations affect pain sensitivity changes during massage

ABSTRACT Background Pain-inducing massage produces comparable changes in pain sensitivity as a cold pressor task, suggesting shared neurophysiological mechanisms of conditioned pain modulation. Manual therapy and conditioned pain modulation are influenced by positive and negative expectations. Therefore, the purpose of this study was to examine the effects of positive and negative expectations on pain-free and pain-inducing massage. Methods 56 healthy participants were randomly assigned to receive a positive or negative expectation instructional set followed by a pain-inducing or a pain-free massage. Pressure pain threshold (PPT) was measured followed by each interval of massage. A repeated measures ANCOVA controlling for post-randomization differences in sex tested for massage x expectation set x PPT interaction effects, as well as two-way interaction effects. Results A significant three-way interaction effect (p = 0.04) and time x expectation interaction effect was observed for individuals receiving pain inducing massage (p = 0.02). Individuals who received the positive expectation instructional set demonstrated significantly higher PPT at minutes 3 and 4 of massage compared to individuals who received the negative expectation instructional set. Conclusions Expectations impact pain sensitivity changes produced during massage. Clinicians planning to provide pain-inducing massage should consider the role of expectations in modulating pain sensitivity changes.

The Role of Melanocortin Plasticity in Pain-Related Outcomes After Alcohol Exposure.

The global COVID-19 pandemic has shone a light on the rates and dangers of alcohol misuse in adults and adolescents in the US and globally. Alcohol exposure during adolescence causes persistent molecular, cellular, and behavioral changes that increase the risk of alcohol use disorder (AUD) into adulthood. It is established that alcohol abuse in adulthood increases the likelihood of pain hypersensitivity and the genesis of chronic pain, and humans report drinking alcohol to relieve pain symptoms. However, the longitudinal effects of alcohol exposure on pain and the underlying CNS signaling that mediates it are understudied. Specific brain regions mediate pain effects, alcohol effects, and pain-alcohol interactions, and neural signaling in those brain regions is modulated by neuropeptides. The CNS melanocortin system is sensitive to alcohol and modulates pain sensitivity, but this system is understudied in the context of pain-alcohol interactions. In this review, we focus on the role of melanocortin signaling in brain regions sensitive to alcohol and pain, in particular the amygdala. We also discuss interactions of melanocortins with other peptide systems, including the opioid system, as potential mediators of pain-alcohol interactions. Therapeutic strategies that target the melanocortin system may mitigate the negative consequences of alcohol misuse during adolescence and/or adulthood, including effects on pain-related outcomes.

The role of dorsal root ganglia alpha-7 nicotinic acetylcholine receptor in complete Freund's adjuvant-induced chronic inflammatory pain.

Alpha-7 nicotinic acetylcholine receptor (α7nAChR) was reported to have a critical role in the regulation of pain sensitivity and neuroinflammation. However, the expression level of α7nAChR in dorsal root ganglion (DRG) and the underlying neuroinflammatory mechanisms associated with hyperalgesia are still unknown. In the present study, the expression and mechanism of α7nAChR in chronic inflammatory pain was investigated using a complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model. Subsequently, a series of assays including immunohistochemistry, western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. α7nAChR was mostly colocalized with NeuN in DRG and upregulated after CFA injection. Microinjection of α7nAChR siRNA into ipsilateral L4/5 DRGs aggravated the CFA-induced pain hypersensitivity. Intrathecal α7nAChR agonist GTS-21 attenuated the development of CFA-induced mechanical and temperature-related pain hypersensitivities. In neuronal the SH-SY5Y cell line, the knockdown of α7nAChRs triggered the upregulation of TRAF6 and NF-κB under CFA-induced inflammatory conditions, while agitation of α7nAChR suppressed the TRAF6/NF-κB activation. α7nAChR siRNA also exacerbated the secretion of pro-inflammatory mediators from LPS-induced SH-SY5Y cells. Conversely, α7nAChR-specific agonist GTS-21 diminished the release of interleukin-1beta (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNFα) in SH-SY5Y cells under inflammatory conditions. Mechanistically, the modulation of pain sensitivity and neuroinflammatory action of α7nAChR may be mediated by the TRAF6/NF-κB signaling pathway. The findings of this study suggest that α7nAChR may be potentially utilized as a therapeutic target for therapeutics of chronic inflammatory pain.

Ischemic Preconditioning: Modulating Pain Sensitivity and Exercise Performance.

Purpose The purpose of this study was to examine whether an individual’s IPC-mediated change in cold pain sensitivity is associated with the same individual’s IPC-mediated change in exercise performance.Methods Thirteen individuals (8 males; 5 females, 27 ± 7 years, 55 ± 5 ml.kgs–1.min–1) underwent two separate cold-water immersion tests: with preceding IPC treatment and without. In addition, each participant undertook two separate 5-km cycling time trials: with preceding IPC treatment and without. Pearson correlation coefficients were used to assess the relationship between an individual’s change in cold-water pain sensitivity following IPC with their change in 5-km time trial performance following IPC.Results During the cold-water immersion test, pain intensity increased over time (p < 0.001) but did not change with IPC (p = 0.96). However, IPC significantly reduced the total time spent under pain (−9 ± 7 s; p = 0.001) during the cold-water immersion test. No relationship was found between an individual’s change in time under pain (r = −0.2, p = 0.6) or pain intensity (r = −0.3, p = 0.3) following IPC and their change in performance following IPC.Conclusion These findings suggest that IPC can modulate sensitivity to a painful stimulus, but this altered sensitivity does not explain the ergogenic efficacy of IPC on 5-km cycling performance.

Active role of the central amygdala in widespread mechanical sensitization in rats with facial inflammatory pain.

Widespread or ectopic sensitization is a hallmark symptom of chronic pain, characterized by aberrantly enhanced pain sensitivity in multiple body regions remote from the site of original injury or inflammation. The central mechanism underlying widespread sensitization remains unidentified. The central nucleus of the amygdala (also called the central amygdala, CeA) is well situated for this role because it receives nociceptive information from diverse body sites and modulates pain sensitivity in various body regions. In this study, we examined the role of the CeA in a novel model of ectopic sensitization of rats. Injection of formalin into the left upper lip resulted in latent bilateral sensitization in the hind paw lasting >13 days in male Wistar rats. Chemogenetic inhibition of gamma-aminobutyric acid-ergic neurons or blockade of calcitonin gene-related peptide receptors in the right CeA, but not in the left, significantly attenuated this sensitization. Furthermore, chemogenetic excitation of gamma-aminobutyric acid-ergic neurons in the right CeA induced de novo bilateral hind paw sensitization in the rats without inflammation. These results indicate that the CeA neuronal activity determines hind paw tactile sensitivity in rats with remote inflammatory pain. They also suggest that the hind paw sensitization used in a large number of preclinical studies might not be simply a sign of the pain at the site of injury but rather a representation of the augmented CeA activity resulting from inflammation/pain in any part of the body or from activities of other brain regions, which has an active role of promoting defensive/protective behaviors to avoid further bodily damage.

Spinal manipulation and modulation of pain sensitivity in persistent low back pain: a secondary cluster analysis of a randomized trial

BackgroundPain hypersensitivity can be assessed using Quantitative Sensory Testing (QST) and is associated with persistent low back pain. Spinal manipulation appears to modify pain hypersensitivity, and this could function as one mechanism leading to clinical improvements. In the current study, we applied a comprehensive QST battery to assess pain sensitivity in a cohort of low back pain patients before and after spinal manipulation to improve our understanding of the association between QST and clinical improvements. This study addresses two questions: Are clinical improvements following spinal manipulation in low back pain patients contingent on pain hypersensitivity, and does pain sensitivity change following spinal manipulation?MethodsWe performed a secondary analysis of data from a randomized clinical trial. One hundred and thirty-two participants with persistent LBP were treated with spinal manipulation four times over two weeks. Patient-reported outcomes and QST were assessed at baseline, after the fourth spinal manipulation session, and 14-days later. The clinical outcomes were changes in low back pain intensity and disability. Using latent profile analysis, we categorized the participants into clusters depending on their baseline QST scores. We used linear mixed models to examine the association between clusters and changes in patient-reported outcomes and QST.ResultsTwo clusters emerged: a Sensitized and a Not sensitized. The former had significantly lower regional pressure and thermal pain thresholds, remote pressure pain tolerance, and lower inhibitory conditioned pain modulation than the Not sensitized group. However, we only found between-cluster differences for regional pressure pain threshold following spinal manipulation. Thus, the clusters were not associated with patient-reported pain and disability changes or the remaining QST outcomes.ConclusionsWe report that the baseline QST profile was not associated with clinical improvements following spinal manipulation. We did observe a substantial change for regional pressure pain threshold, which suggests that any effect of spinal manipulation on pain sensitivity is most likely to be observed as changes in regional, mechanical pain threshold. However, the mechanism that invokes clinical improvement and pain sensitivity changes appear distinct. Due to methodological caveats, we advise caution when interpreting the results.Trial registrationClinical.Trial.gov identifier: NCT04086667, registered 11 September 2019 – Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04086667

The µ-δ opioid heteromer masks latent pain sensitization in neuropathic and inflammatory pain in male and female mice

The episodic nature of chronic pain can be studied in the rodent model of latent pain sensitization. After remission, central sensitization is opposed by activation of opioid receptors. At the behavioral level, latent pain sensitization is unmasked when pain hypersensitivity is reinstated by opioid receptor (OR) antagonism. Previous studies have focused on inflammatory pain and male rodents. Whether latent pain sensitization occurs in models of chemotherapy-induced neuropathic pain in female and male mice is unknown. The first aim of this study was to investigate whether μ- and δ-OR suppress latent pain sensitization in our model of chemotherapy-induced neuropathic pain in both sexes.Mounting evidence suggests that μ-and δ-ORs form a heteromer and that the heteromer modulates pain sensitivity. Potential implications of the μ-δ OR heteromer in latent pain sensitization have not been fully explored due to a lack of tools to effectively modulate the heteromer. To specifically target the μ-δ OR heteromer, we used a specific interfering peptide blocking the heteromerization. The second aim of this study was to investigate whether disruption of the μ-δOR heteromer, after remission, reinstates pain hypersensitivity.After remission from cisplatin-induced neuropathic pain, antagonism of µ-OR and δOR reinstates pain hypersensitivity in both sexes. After remission from cisplatin-induced neuropathic pain and postoperative pain, disruption of the μ-δOR heteromer reinstates pain hypersensitivity in both sexes. Taken together our findings suggest that the μ-δOR heteromer plays a crucial role in remission in various pain models and may represent a novel therapeutic target to prevent the relapse to pain and the transition to chronic pain.

The Effect of Heat Shock Protein 90 Inhibitor on Pain in Cancer Patients: A Systematic Review and Meta-Analysis.

Background and objectives: Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an essential role in tumor growth. Numerous Hsp90 inhibitors have been discovered and tested in preclinical and clinical trials. Recently, several preclinical studies have demonstrated that Hsp90 inhibitors could modulate pain sensitization. However, no studies have evaluated the impact of Hsp90 inhibitors on pain in the patients. This study aims to summarize the pain events reported in clinical trials assessing Hsp90 inhibitors and to determine the effect of Hsp90 inhibitors on pain in patients. Materials and Methods: We searched PubMed, EBSCOhost, and clinicaltrials.gov for Hsp90 inhibitor clinical trials. The pain-related adverse events were summarized. Meta-analysis was performed using the data reported in randomized controlled trials. Results: We identified 90 clinical trials that reported pain as an adverse effect, including 5 randomized controlled trials. The most common types of pain reported in all trials included headache, abdominal pain, and back pain. The meta-analysis showed that Hsp90 inhibitors increased the risk of abdominal pain significantly and appeared to increase the risk for back pain. Conclusions: In conclusion, Hsp90 inhibitor treatment could potentially increase the risk of pain. However, the meta-analysis demonstrated only moderate evidence for the connection between Hsp90 inhibitor and pain.

Freestanding Dual-Gate Oxide-Based Neuromorphic Transistors for Flexible Artificial Nociceptors

A nociceptor is a type of sensory receptor with the ability to perceive noxious stimuli, which is very important for the survival and health of organisms. Several neuromorphic devices have been proposed to emulate this sensory receptor. The basic pain perception functions of a nociceptor can be emulated. However, those artificial nociceptors lack functional tunability and intelligent adaptability. Here, freestanding oxide-based neuromorphic transistors with dual-gate structures were fabricated on proton-conducting electrolyte membranes and used for flexible artificial nociceptor emulation. Such a freestanding biomimetic device can not only capture the pain perception functions to peripheral inputs. What is more, the modulation of pain sensitivity can be emulated in this device by the voltage applied on the second gate electrode. Our artificial nociceptors open a new avenue in the design of an artificial sensory system with sensory alarm function and intelligent adaptability.

Scorpion toxin MeuNaTxα-1 sensitizes primary nociceptors by selective modulation of voltage-gated sodium channels.

Venoms are a rich source of highly specific toxins, which allow the identification of novel therapeutic targets. We have now applied high content screening (HCS) microscopy to identify toxins that modulate pain sensitization signaling in primary sensory neurons of rat and elucidated the underlying mechanism. A set of venoms and fractions thereof were analyzed for their ability to activate type II protein kinase A (PKA-II) and extracellular signal-regulated kinases (ERK1/2). We identified MeuNaTxα-1, a sodium channel-selective scorpion α-toxin from Mesobuthuseupeus, which affected both PKA-II and ERK1/2. Recombinant MeuNaTxα-1 showed identical activity to the native toxin on mammalian voltage-gated sodium channels expressed in Xenopuslaevis oocytes and induced thermal hyperalgesia in adult mice. The effect of MeuNaTxα-1 on sensory neurons was dose-dependent and tetrodotoxin-sensitive. Application of inhibitors and toxin mutants with altered sodium channel selectivity demonstrated that signaling activation in sensory neurons depends on NaV 1.2 isoform. Accordingly, the toxin was more potent in neurons from newborn rats, where NaV 1.2 is expressed at a higher level. Our results demonstrate that HCS microscopy-based monitoring of intracellular signaling is a novel and powerful tool to identify and characterize venoms and their toxins affecting sensory neurons.

Localization of prostaglandin E2 synthases and E-prostanoid receptors in the spinal cord in a rat model of neuropathic pain

Prostaglandin E2 (PGE2) is a lipid mediator which plays a role in the generation of inflammatory and neuropathic pain. In the peripheral nervous system, PGE2 sensitizes nociceptive afferent neurons through E-prostanoid (EP) receptors. In the central nervous system, PGE2 modulates pain sensitivity and contributes to the development of neuropathic pain. However, the distribution of PGE2 and EP receptors in the spinal cord remains unclear. In the present study, we examined the expression of PGE2 synthases (microsomal PGE synthase [mPGES]-1, mPGES-2, and cytosolic PGE synthase [cPGES]) and EP receptors (EP1-4) in a rat model of neuropathic pain.We identified that mPGES-1 mRNA was upregulated in spinal endothelial cells after nerve injury and exhibited co-localization with cyclooxygenase-2 (COX-2). We detected that mPGES-2 mRNA and cPGES mRNA were expressed in spinal neurons and noted that their expression level was not affected by nerve injury. With respect to EP receptors, EP2 mRNA and EP4 mRNA were expressed in spinal neurons in the dorsal horn. EP3 mRNA was expressed in motor neurons, whereas EP1 mRNA was not detected in the spinal cord. Intrathecal injection of tumor necrosis factor alpha (TNFα) upregulated mPGES-1 mRNA in blood vessels in the spinal cord. Intrathecal injection of a TNFα-neutralizing antibody partially inhibited the upregulation of mPGES-1 mRNA after nerve injury.These results indicate that PGE2 is synthesized by COX-2/mPGES-1 in spinal endothelial cells after nerve injury. These results suggest that in neuropathic pain condition, endothelial cell-derived PGE2 may act on EP2 and EP4 receptors on spinal neurons and modulate pain sensitivity.

Sensory satellite glial Gq-GPCR activation alleviates inflammatory pain via peripheral adenosine 1 receptor activation

Glial fibrillary acidic protein expressing (GFAP+) glia modulate nociceptive neuronal activity in both the peripheral nervous system (PNS) and the central nervous system (CNS). Resident GFAP+ glia in dorsal root ganglia (DRG) known as satellite glial cells (SGCs) potentiate neuronal activity by releasing pro-inflammatory cytokines and neuroactive compounds. In this study, we tested the hypothesis that SGC Gq-coupled receptor (Gq-GPCR) signaling modulates pain sensitivity in vivo using Gfap-hM3Dq mice. Complete Freund’s adjuvant (CFA) was used to induce inflammatory pain, and mechanical sensitivity and thermal sensitivity were used to assess the neuromodulatory effect of glial Gq-GPCR activation in awake mice. Pharmacogenetic activation of Gq-GPCR signaling in sensory SGCs decreased heat-induced nociceptive responses and reversed inflammation-induced mechanical allodynia via peripheral adenosine A1 receptor activation. These data reveal a previously unexplored role of sensory SGCs in decreasing afferent excitability. The identified molecular mechanism underlying the analgesic role of SGCs offers new approaches for reversing peripheral nociceptive sensitization.

Sensitization of glutamate receptor-mediated pain behaviour via nerve growth factor-dependent phosphorylation of transient receptor potential V1 under inflammatory conditions.

Glutamate and metabotropic glutamate (mGlu) receptors on primary sensory neurons are crucial in modulating pain sensitivity. However, it is unclear how inflammation affects mGlu receptor-mediated nociceptive responses. We therefore investigated the effects of mGlu1/5 receptor agonists on pain-related behaviour during persistent inflammation and their underlying mechanisms. Effects of a mGlu1/5 receptor agonist on pain-related behaviour during inflammation was assessed in mice. Intracellular calcium responses, membrane current responses, and protein expression in primary sensory neurons were examined using cultured dorsal root ganglion (DRG) neurons, dissociated from wild-type and gene knockout mice. Persistent inflammation induced by complete Freund's adjuvant increased the duration of mGlu1/5 receptor-mediated pain behaviour, which was antagonized by inhibition of nerve growth factor (NGF)-tropomyosin receptor kinase A (TrkA) signalling. Calcium imaging revealed that NGF treatment increased the number of cultured DRG neurons responding to mGlu1/5 receptor activation. Stimulation of mGlu1/5 receptors in NGF-treated DRG neurons induced inward currents through TRPV1 channels in association with PLC but not with IP3 receptors. NGF treatment also increased the number of neurons responding to a DAG analogue via TRPV1 channel activation. Furthermore, NGF up-regulated expression of TRPV1 and A-kinase anchoring protein 5 (AKAP5), resulting in increased AKAP5-dependent TRPV1 phosphorylation. AKAP5 knockout mice did not exhibit mGlu1/5 receptor-mediated excitation in NGF-treated DRG neurons or pain response facilitation under inflammatory conditions. NGF augments glutamate- and mGlu1/5 receptor-mediated excitation of nociceptive neurons by AKAP5-dependent phosphorylation of TRPV1 channels, potentiating hypersensitivity to glutamate in inflamed tissues.