Single-cell RNA sequencing uncovers the cell type-dependent transcriptomic changes in the retrosplenial cortex after peripheral nerve injury.

The retrosplenial cortex (RSC) is a vital area for storing remote memory and has recently been found to undergo broad changes after peripheral nerve injury. However, little is known about the role of RSC in pain regulation. Here, we examine the involvement of RSC in the pain of mice with nerve injury. Notably, reducing the activities of calcium-/calmodulin-dependent protein kinase type II-positive splenial neurons chemogenetically increases paw withdrawal threshold and extends thermal withdrawal latency in mice with nerve injury. The single-cell or single-nucleus RNA-sequencing results predict enhanced excitatory synaptic transmissions in RSC induced by nerve injury. Local infusion of 1-naphthyl acetyl spermine into RSC to decrease the excitatory synaptic transmissions relieves pain and induces conditioned place preference. Our data indicate that RSC is critical for regulating physiological and neuropathic pain. The cell type-dependent transcriptomic information would help understand the molecular basis of neuropathic pain.

Cingulate protein arginine methyltransferases 1 regulates peripheral hypersensitivity via fragile X messenger ribonucleoprotein.

The deficit of fragile X messenger ribonucleoprotein (FMRP) leads to intellectual disability in human and animal models, which also leads to desensitization of pain after nerve injury. Recently, it was shown that the protein arginine methyltransferases 1 (PRMT1) regulates the phase separation of FMRP. However, the role of PRMT1 in pain regulation has been less investigated. Here we showed that the downregulation of PRMT1 in the anterior cingulate cortex (ACC) contributes to the development of peripheral pain hypersensitivity. We observed that the peripheral nerve injury decreased the expression of PRMT1 in the ACC; knockdown of the PRMT1 via shRNA in the ACC decreased the paw withdrawal thresholds (PWTs) of naïve mice. Moreover, the deficits of FMRP abolished the effects of PRMT1 on pain sensation. Furthermore, overexpression of PRMT1 in the ACC increased the PWTs of mice with nerve injury. These observations indicate that the downregulation of cingulate PRMT1 was necessary and sufficient to develop peripheral hypersensitivity after nerve injury. Thus, we provided evidence that PRMT1 is vital in regulating peripheral pain hypersensitivity after nerve injury via the FMRP.

Targeting long-term depression of excitatory synaptic transmission for the treatment of neuropathic pain.

Injury or disease in the somatosensory nervous system may cause broad molecular changes and lead to neuropathic pain. Excitatory synaptic transmission in somatosensory pathways conveys the somatosensory information from the peripheral to the central nervous system. Long-term effects of excitatory synaptic transmission on the pain pathway contribute to neuropathic pain hypersensitivity. Synaptic strength is dynamically regulated and undergoes bidirectional changes, manifested by two primary forms of synaptic plasticity, long-term potentiation and long-term depression (LTD), which are mediated by insertion and endocytosis of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), respectively. Molecular mechanisms of LTP have been extensively studied; on the other hand, the role of AMPAR endocytosis in the pain-related synaptic enhancement is less well known. Recent research in the anterior cingulate cortex reveals that loss of LTD contributes to the maintenance of neuropathic pain, which provides the novel perspective of the mechanism of LTD also being critical for maintaining neuropathic pain. More importantly, exploring the molecular mechanism of LTD may help with the development of novel analgesic strategies to manage neuropathic pain.

Chronic stress influences nociceptive sensitivity of female rats in an estrous cycle-dependent manner.

Exposure to chronic stress can influence nociception and further induce hyperalgesia. Whether stress modulation of pain in female animals occurs in an estrous cycle-specific manner is still unclear. We profiled the changes in nociception (thermal, mechanical, formalin-evoked acute and inflammatory pain) of female Sprague-Dawley rats after treatment with chronic unpredictable mild stress (CUMS) and investigated whether these changes occur in an estrous cycle-dependent manner. The results showed that CUMS female rats exhibited a lower mechanical withdrawal threshold in proestrus and estrus, a longer formalin-evoked licking time in metestrus and diestrus, but no changes in the latency time on the tail-flick test. The present study findings suggest that chronic stress induces mechanical and formalin-evoked acute hyperalgesia of female rats in an estrous cycle-dependent manner.SUMMARYOur studies showed that chronic stress increased nociceptive sensitivity of female rats. Furthermore females had different stress-induced pain responses in different estrous phases: mechanical hyperalgesia in proestrus and estrus, formalin-evoked acute hyperalgesia in metestrus and diestrus.

Duloxetine for pain in fibromyalgia in adults: a systematic review and a meta-analysis.

Objectives: The objective of this systematic review was to assess the analgesic efficacy of duloxetine (DLX) for fibromyalgia (FM) and find out which dosage between 60 mg/d DLX and 120 mg/d DLX was more suitable for clinical application.Methods: A systematic search through multiple databases (Cochrane Central Register of Controlled Trials (CENTRAL), ProQuest, PubMed) was conducted from 2000 until 7 March 2019. All steps were performed by two or more independent reviewers. The meta-analysis was performed to report the effects of DLX on pain reduction and its accompanied adverse events.Results: This meta-analysis, including seven studies with 2642 FM patients, demonstrated that DLX could produce greater pain relief in FM than placebo (standardized mean difference (SMD) -0.26; 95% confidence interval (CI) -0.37 to -0.16). The risk ratio (RR) of at least 30% pain relief was 1.31 (95% CI 1.19 to 1.44); the RR of at least 50% pain relief was 1.46 (95% CI 1.28 to 1.67). However, the patients with DLX who suffered adverse events were more common than the ones with placebo (RR 1.17, 95% CI 1.12 to 1.23). The withdrawal effect included adverse event withdrawal and lack of efficacy withdrawal. The subgroup analyses of withdrawal effects demonstrated that 120 mg/d DLX had a higher incidence (RR 0.96, 95% CI 0.80 to 1.15) than 60 mg/d DLX (RR 0.77, 95% CI 0.63 to 0.93).Conclusions: In general, DLX was a great choice for pain relief in FM. Moreover, 60 mg/d DLX produced less withdrawal effects than 120 mg/d DLX. HighlightsFibromyalgia (FM) is a chronic condition of unknown aetiology, characterized by widespread pain and often associated with other symptoms.Duloxetine (DLX), a serotonin norepinephrine (noradrenaline) reuptake inhibitor (SNRI), is used to treat FM in many countries.DLX can produce greater pain relief in FM than placebo.DLX can bring about more adverse events than placebo.60 mg/d DLX produces less withdrawal than 120 mg/d DLX for FM patients.

The role of glutamate and its receptors in central nervous system in stress-induced hyperalgesia.

PURPOSE: To explore the potential mechanisms of glutamate and its receptors in stress-induced hyperalgesia. MATERIALS AND METHODS: The stress-induced hyperalgesia, glutamate and its receptors are listed as key items in the pubmed database and the related articles are searched. RESULTS: Glutamate level is increased under stress and associated with stress-induced hyperalgesia. Moreover, the role of glutamate in stress-induced hyperalgesia depends on its subtypes of its receptors. CONCLUSIONS: Increased glutamate during stress connect with ionotropic glutamate receptors can prompt hyperalgesia, but connect with metabotropic glutamate receptors can inhibit hyperalgesia.

Effects of fluoxetine on changes of pain sensitivity in chronic stress model rats.

Exposure to stress could facilitate or inhibit pain responses (stress-induced hyperalgesia or hypoalgesia, respectively). Fluoxetine is a selective serotonin (5-HT) reuptake inhibitor antidepressant. There have been contradictory reports on whether fluoxetine produces antinociceptive effects. The purpose of this study was to elucidate changes in pain sensitivity after chronic stress exposure, and the effects of fluoxetine on these changes. We measured thermal, mechanical, and formalin-induced acute and inflammatory pain by using the tail-flick, von Frey, and formalin tests respectively. The results showed that rats exposed to chronic stress exhibited thermal and formalin-induced acute and inflammatory hypoalgesia and transient mechanical hyperalgesia. Furthermore, fluoxetine promoted hypoalgesia in thermal and inflammatory pain and induced mechanical hyperalgesia. Our results indicate that the 5-HT system could be involved in hypoalgesia of thermal and inflammatory pain and induce transient mechanical hyperalgesia after stress exposure.