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Glutamate is a neurotransmitter present in most excitatory synapses in the nervous system. It also plays a key role in the spinal cord's physiological excitatory circuit and is involved in pathological neurotransmissions such as those observed in inflammatory and neuropathic pain conditions. The actions of glutamate are mediated by different types of ionotropic (iGluRs) and metabotropic (mGluRs) receptors. Although expressions of iGluRs are well studied, those of mGluRs are not fully elucidated in the spinal cord. In this study, we examined the expressions of mGluRs (mGluR1-8) and investigated which mGluR subtypes can modulate pain transmission in the dorsal horn of the spinal cord using an inflammatory pain model. Reverse transcription-polymerase chain reaction revealed that mGluR mRNAs, except for mGluR2 and 6 mRNAs, were detected in the spinal cord. Double labeling analysis, in situ hybridization histochemistry with immunohistochemistry, was used to examine the distribution of each mGluR in neurons or glial cells in the lamina I-II of the spinal dorsal horn. mGluR1, 5, and 7 were generally, and 4 and 8 were frequently, expressed in neurons. mGluR3 was expressed not only in neurons but also in oligodendrocytes. We next examined the distribution of mGluR4 and 8 were expressed in excitatory or inhibitory neurons. Both mGluR4 and 8 were preferentially expressed in inhibitory neurons rather than in excitatory neurons. Futhermore, intrathecal delivery of CPPG, an antagonist for mGluR 4 and 8, attenuated nocifensive behaviors and the increase in fos positive-excitatory neurons of the dorsal horn induced by intraplantar injection of formalin. These findings suggest that mGluR4 and 8, which are preferentially expressed in inhibitory neurons, may play roles in the modulation of pain transmission through mGluRs in the spinal dorsal horn.
Learn More >Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment.
Learn More >Spicy-food intake has been shown to affect various human physiological systems and diseases. This study tested the analgesia effect caused by stimulation of a spicy sensation (spicy stimulation) and explored the effect of spicy-food consumption on human basal pain sensitivity. A total of 60 healthy undergraduates were included in the primary study. Placebo and sweet stimulation were used as reference interventions. Pressure and cold-pain thresholds were measured before and after taste stimulation. The frequency of spicy-food intake was also evaluated. An additional 100 subjects were recruited to validate the results. Compared to placebo stimulation, both pressure and cold-pain thresholds increased during spicy stimulation (P<0.05). The increased thresholds remained, even when the taste stimulation residue was nearly eliminated (P<0.05). The pressure (10.0[2.1]vs.12.7[3.0]kg/cm, P<0.001) and cold-pain (4.4[1.6]vs.6.2[2.7]seconds, P=0.003) thresholds in subjects who consume spicy food ≥ 3 days/week were significantly lower than in those who consume it < 3 days/week. In the validation population, the frequency of spicy-food intake was negatively associated with subjects' pressure (β=-0.218, P=0.013) and cold-pain (β=-0.205, P=0.035) thresholds. Spicy stimulation has an analgesia effect on adults that persists even after the taste stimulation stops. Conversely, a long-term spicy diet can reduce the human basal pain threshold. TRIAL REGISTRATION: The study protocol was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Army Medical University, People's Liberation Army (identification No., 2017-023-01), and it was registered on the Chinese Clinical Trial Registry at www.chictr.org.cn (No. ChiCTR1800015053). PERSPECTIVE: This study directly examined the effects of stimulation of a spicy sensation on adult pain sensitivity and was the first to explore the relationship between long-term spicy-food intake and human pain sensitivity. The results provide evidence for future clinical pain intervention and individualized pain treatment.
Learn More >Inflammatory bowel disease (IBD), mainly comprising Crohn's disease and ulcerative colitis, is characterized by chronic inflammation in the digestive tract. Approximately 60% of the patients experience abdominal pain during acute IBD episodes, which severely impairs their quality of life. Both peripheral and central mechanisms are thought to be involved in such abdominal pain in IBD. Although much attention has been paid to peripheral mechanisms of abdominal pain in IBD pathophysiology, the involvement of supraspinal mechanisms remains poorly understood. To address this issue, we investigated regional brain activity in response to colorectal distension (CRD) in normal and IBD model rats using voxel-based statistical analysis of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET imaging. The rat IBD model was generated by colorectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS), a chemical compound widely used to generate colitis. Tissue damage and inflammation were induced and dynamically changed with time after TNBS injection, while CRD-induced visceromotor response showed corresponding temporal changes. We found that characteristic brain activations were observed in response to visceral innocuous and noxious CRD and supraspinal nociception shared some physiological sensory pathway. Moreover, widespread brain regions were activated, and the functional coupling between the central medial thalamic nucleus (CMT) and anterior cingulate cortex (ACC) was enhanced after noxious CRD in IBD model of rats. Increased brain activity in the anterior insular cortex (aINS) and ACC positively correlated with noxious CRD-induced pain severity in normal and IBD rats respectively. These findings suggest that the pain matrix was shifted following persistent colonic inflammation, and thalamocortical sensitization in the pathway from CMT to ACC might be a central mechanism of the visceral hyperalgesia in IBD pathophysiology.
Learn More >Cochrane is an international non-profit organization established in 1993 to produce and disseminate high quality and unbiased systematic reviews of evidence on health care interventions. At the forefront of systematic review methodology, Cochrane is generally accepted to be among the most carefully prepared and rigorous sources of systematic review evidence. There are numerous Cochrane reviews on nonpharmacologic interventions for pain and multiple Cochrane reviews evaluating acupuncture therapy in pain conditions. But how complete and up to date are those reviews relative to other rigorous systematic reviews with meta-analyses of acupuncture therapy for pain published in the literature? In this 'snapshot' overview, we found 22 relevant Cochrane reviews, some concluding that acupuncture therapy is probably useful for treating specific pain conditions. However, many of the conditions for which acupuncture is most commonly used are either not represented in Cochrane reviews or the existing Cochrane reviews are seriously outdated and do not reflect current evidence. This creates confusion with the risks of adverse effects and addiction liability associated with pain medications, the prevalence of chronic pain, the ongoing opioid epidemic and the need for evidence-based options for pain as part of comprehensive pain care. Clinicians and patients want clarification on safe and effective options to treat pain. Issues involving reviewed trials' inadequate use of sham comparators, of acupuncture as a complex intervention with interactive components and a shift in research focus from efficacy trials to real-world pragmatic trials are discussed in relation to updating Cochrane reviews of acupuncture therapy for pain.
Learn More >Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability. PRL and PRLR expression were higher in females. CRISPR-mediated editing of PRLR-L promoted nociceptor sensitization and allodynia in naïve, uninjured female mice that depended on circulating PRL. Opioids, but not trauma-induced nerve injury, decreased PRLR-L promoting OIH through activation of PRLR-S in female mice. Deletion of both PRLR-L and PRLR-S (total PRLR) prevented, whereas PRLR-L overexpression rescued established OIH selectively in females. Inhibition of circulating PRL with cabergoline, a dopamine D2 agonist, up-regulated PRLR-L and prevented OIH only in females. The PRLR-L isoform therefore confers protection against PRL-promoted pain in females. Limiting PRL/PRLR-S signaling pharmacologically or with gene therapies targeting the PRLR may be effective for reducing pain in a female-selective manner.
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