Accepted

Mas-related G protein-coupled receptors (Mrgprs) are a newly discovered class of G protein-coupled receptors consisting of more than 50 members in recent years. MRGPRX1 can be activated by bovine adrenal medulla peptide 8-22 (BAM8-22), triggering Ca influx and then causing pain and itch. It is very important for the discovery of analgesic and antipruritic drugs to elucidate the molecular mechanism of MRGPRX1 recognizing BAM8-22. Here, we identified the functional domains and residues of the receptor MRGPRX1 activating BAM8-22 through molecular model, mutation and living cell calcium imaging. The molecular docking predicted that BAM8-22 interacted with N-terminus, TM4, TM5, TM6 and ECL3 of MRGPRX1. Both ECL3 and TM6 domains were further revealed to play a critical role in the BAM8-22-induced MRGPRX1 activation, whereas TM3 region performed a secondary function. Moreover, the mutation F237A of MRGPRX1 completely lost the activation ability of BAM8-22. These results were consistent with the cryogenic electron microscopy (cryo-EM) structure of MRGPRX1-G in complex with BAM8-22 reported most recently. Taken together, our work shows insights into the molecular mechanism of the interaction between the receptor MRGPRX1 and the peptide agonist BAM8-22, and will also provide some valuable clues for the design of analgesic and antipruritic drugs targeting MRGPRX1.

Nocebo effects are thought to influence the rate of reported adverse events (AEs) and subject withdrawal in both the treatment and placebo groups of randomized clinical trials (RCTs). Neuromodulators are commonly prescribed to treat disorders of gut-brain interaction (DGBIs), but adherence to these medications is often limited by side effects such as headache, dry mouth, fatigue, and altered bowel habits. We performed a systematic review and meta-analysis to assess the proportion and risk difference of patients who experienced side effects leading to withdrawal in the placebo arm versus the treatment arm of RCTs of neuromodulators for DGBIs. We also sought to estimate the risk of developing any AE in the placebo arm of these studies as well as the rate of specific individual adverse events.

Sleep deprivation can trigger migraine, and migraineurs often choose to sleep to relieve headaches during acute migraine. This study aimed to explore the effect of acute sleep deprivation on hyperalgesia induced by nitroglycerin in mice. In part one, after either 6-hour sleep deprivation or 6-hour normal sleep, mice were intraperitoneally injected with nitroglycerin or saline. The mechanical pain threshold and withdrawal latency of the hindpaw were measured every 30 minutes for 6 hours. Next, the same sleep deprivation and injection procedure was performed with new mice, and mice were sacrificed 4.5 hours after injection. The trigeminal nucleus caudalis and upper cervical spinal segments were taken for immunofluorescence Fos staining. In part two, after injection of saline or nitroglycerin, the mice were either deprived of sleep for 6 hours or allowed to sleep without interference. The mechanical and thermal pain threshold were measured after 6 hours. In part three, we compared the sleep time of mice after intraperitoneal injection of saline or nitroglycerin without interference. Sleep deprivation for 6 hours did not cause any changes in the baseline pain thresholds in mice. However, pretreatment with 6-hour sleep deprivation significantly prolonged the duration of hyperalgesia induced by nitroglycerin. Additionally, the expression of Fos at 4.5 hours was significantly higher in the 6-hour sleep deprivation and nitroglycerin group than in the other three groups. When intraperitoneal injection was given first, the mechanical pain threshold of the hind paw was significantly lower in the group that received nitroglycerin with 6-hour sleep deprivation than in the other groups. Compared to the saline injection, one-time nitroglycerin injection would result in a significant increase in sleep latency and decrease in sleep duration for the normal mice. Acute sleep deprivation significantly aggravated the hyperalgesia induced by nitroglycerin in mice, which highlights the importance of sleep disorders for migraine.

Irritable bowel syndrome (IBS) related chronic visceral pain affects 20% of people worldwide. The treatment options are very limited. Although the scholarly reviews have appraised the potential effects of the intestinal microbiota on intestinal motility and sensation, the exact mechanism of intestinal microbiota in IBS-like chronic visceral pain remains largely unclear. The purpose of this study is to investigate whether Folic Acid (FA) attenuated visceral pain and its possible mechanisms.

Long-term use of opioids such as morphine has negative side effects, such as morphine analgesic tolerance and morphine-induced hyperalgesia (MIH). These side effects limit the clinical use and analgesic efficacy of morphine. Elucidation of the mechanisms and identification of feasible and effective methods or treatment targets to solve this clinical phenomenon are important. Here, we discovered that YTHDF1 and TNF receptor-associated factor 6 (TRAF6) are crucial for morphine analgesic tolerance and MIH. The m6A reader YTHDF1 positively regulated the translation of TRAF6 mRNA, and chronic morphine treatments enhanced the m6A modification of TRAF6 mRNA. TRAF6 protein expression was drastically reduced by YTHDF1 knockdown, although TRAF6 mRNA levels were unaffected. By reducing inflammatory markers such as IL-1β, IL-6, TNF-α and NF-κB, targeted reduction of YTHDF1 or suppression of TRAF6 activity in ventrolateral periaqueductal gray (vlPAG) slows the development of morphine analgesic tolerance and MIH. Our findings provide new insights into the mechanism of morphine analgesic tolerance and MIH indicating that YTHDF1 regulates inflammatory factors such as IL-1β, IL-6, TNF-α and NF-κB by enhancing TRAF6 protein expression.

College students who experience chronic pain are a frequently overlooked population. This research attempts to provide insight into the language that college students use to describe their experiences with chronic pain, challenges they face and coping strategies they use. Over the course of 4 consecutive days, participants responded to an expressive writing prompt asking them to reflect on their emotions and thoughts related to being a college student with chronic pain. Writing samples were then analysed to identify themes pertaining to words with a positive or negative emotional valence, terms used to characterise pain, metaphors used to describe pain, challenges faced, and positive and negative coping strategies used. Results showed that participants were more likely to use negatively valenced words than positively valenced words to describe their pain. Several common words and phrases were used to characterise pain, including metaphors. Finally, participants reported a number of challenges associated with their lived-experience of chronic pain, as well as positive and negative strategies used to cope with those challenges. These findings help to put into perspective the language used to understand, and attempt to cope with, the challenges faced by college students experiencing chronic pain. Research must continue to investigate the needs of this population so that they can be properly supported physically, emotionally, socially and academically.

The objective of the present study was to explore the diversity, quality, severity and distribution of symptoms in patients with radicular pain and a lumbar disc herniation.

Interstitial cystitis (=painful bladder syndrome) is a chronic bladder syndrome characterised by pelvic and bladder pain, urinary frequency and urgency, and nocturia. Transient receptor potential (TRP) channels are an attractive target in reducing the pain associated with interstitial cystitis. The current study aims to determine the efficacy of combination of TRP vanilloid 1 (TRPV1) and TRP melastatin 8 (TRPM8) channel inhibition in reducing the pain associated with experimental cystitis in guinea pigs.

: This review aims to analyze the last years' experience of applying spinal cord stimulation (SCS) in complex regional pain syndrome (CRPS) patients with persistent or refractory chronic pain. : This is a narrative review which was executed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was carried out through the following databases: PUBMED and Cochrane Library. Also, a search for trials in the metaRegister of controlled trials (www.clinicaltrials.gov) was performed. : SCS provides pain reduction and improves sensory, vasomotor and sudomotor symptoms. It can reduce opioid using, offering better life quality for the patients. : SCS found to be an excellent therapeutic alternative for patients with CRPS. It offers immediate pain relief and allows patients to regain functionality and have a better quality of life.

Neuropathic pain is a chronic pain caused by a disease or damage to the somatosensory nervous system. The knowledge about the complete mechanisms is incomplete, but the role of oxidative compounds has been evaluated. In this context, we highlight the transient potential receptor vanilloid 4 (TRPV4), a non-selective cation channel, that can be activated by oxidated compounds. In clinical trials, the TRPV4 antagonist (GSK2798745) has been well-tolerated in healthy volunteers. The TRPV4 activation by oxidative compounds, such as hydrogen peroxide (HO) and nitric oxide (NO), has been researched in neuropathic pain models. Thus, the modulation of TRPV4 activation by decreasing oxidated compounds could represent a new pharmacological approach for neuropathic pain treatment. Most models evaluated the TRPV4 using knockout mice, antagonist or antisense treatments and detected mechanical allodynia, hyposmotic solution-induced nociception and heat hyperalgesia, but this channel is not involved in cold allodynia. Only HO and NO were evaluated as TRPV4 agonists, so one possible target to reduce neuropathic pain should focus on reducing these compounds. Therefore, this review outlines how the TRPV4 channel represents an innovative target to tackle neuropathic pain signaling in models induced by trauma, surgery, chemotherapy, cancer, diabetes and alcohol intake.