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Capsaicin is a widely utilized experimental pain stimulus; however, few studies have reported on ethnic differences in pain responses to capsaicin. The present study used infrared thermography to 1) measure differences in capsaicin-induced neurogenic flare between non-Hispanic black (NHB) and non-Hispanic white (NHW) adults and 2) determine the association between neurogenic flare and secondary hyperalgesia.
Learn More >Secondary analysis of health administrative databases is indispensable to enriching our understanding of health trajectories, health care utilization, and real-world risks and benefits of drugs among large populations.
Learn More >Chronic pelvic pain (CPP) in women is often associated with marked emotional distress and disability, with particular impairments in sexual functioning. Research supports the efficacy of interdisciplinary chronic pain rehabilitation programs (ICPRPs) in treating chronic pain, however less is known about their utility in CPP. This retrospective study examined pain-related sexual impairment, emotional symptoms, and pain severity in CPP patients before and after completing a 3-4 week ICPRP. Predictors of post-treatment sexual impairment were also investigated. Participants included 58 female CPP patients and 58 age-matched females with non-pelvic chronic pain (NPCP). All participants reported robust improvements across outcome measures. Women with CPP reported greater pre- and post-treatment impairment in sexual function than NPCP patients, despite significant treatment-related improvements. In contrast, CPP patients also reported higher levels of depression at baseline but showed greater treatment related-improvements. In participants with CPP, treatment-related improvements in depression, alexithymia, and pain severity significantly explained decreases in pain-related sexual impairment following treatment, whereas none of these variables explained sexual impairment outcomes in women with NPCP. Results demonstrate that ICPRPs can effectively treat CPP, particularly through changes in depression and alexithymia. Future research should examine whether specific interventions can be added in ICPRPS to address CPP-related sexual impairment.
Learn More >Osteoarthritis (OA) is the most prevalent joint disorder associated with severe chronic pain. Although synovial inflammation is well correlated with pain severity, the molecular mechanism responsible for OA pain remains unclear. Here, we show that extracellular miR-21 released from synovial tissue mediates knee OA pain in surgical OA model rats. miR-21 was the most abundant among increased microRNAs (miRNAs) in the synovial tissue. miR-21 was released into extracellular space from the synovial tissue and increased in the synovial fluid. A single intra-articular injection of miR-21 inhibitor exerted long-term analgesia of knee OA pain, whereas miR-21 injection in naive rats caused knee joint pain. miR-21 mutant, which lacks the Toll-like receptor (TLR) binding motif, but not in the seed sequence, did not cause joint pain, suggesting a non-canonical mode of action different from translational repression. Consistent with this, the algesic effect of miR-21 was blocked by antagonizing TLR7. The TLR7 antagonist also exerted a long-lasting analgesic effect on knee OA pain. Therefore, extracellular miR-21 released from synovial tissue mediates knee OA pain through TLR7 activation in surgical OA model rats. Extracellular miRNA in the joint may be a plausible target for pain therapy, providing a novel analgesic strategy for OA.
Learn More >The objective of this study was to examine the efficacy of complementary and integrative health (CIH) approaches for reducing pain intensity (primary outcome) and depressive symptoms (secondary outcome) as well as improving physical functioning (secondary outcome) among U.S. military personnel living with chronic pain. Studies were retrieved from bibliographic databases, databases of funded research, and reference sections of relevant articles. Studies that (a) evaluated a CIH approach to promote chronic pain management among military personnel, (b) used a randomized controlled trial design, and (c) assessed pain intensity were included. Two coders extracted data from each study and calculated effect sizes. Discrepancies between coders were resolved through discussion. Comprehensive searches identified 12 studies (k = 15 interventions) that met inclusion criteria. CIH practices included cognitive-behavioral therapies (k = 5), positive psychology (k = 3), yoga (k = 2), acupuncture (k = 2), mindfulness-based interventions (k = 2), and biofeedback (k = 1). Across these studies, participants who received the intervention reported greater reductions in pain intensity (d+ = 0.44, 95% CI [0.21, 0.67], k = 15) compared to controls. Statistically significant improvements were also observed for physical functioning (d+ = 0.36, 95% CI [0.11, 0.61], k = 11) but not for depressive symptoms (d+ = 0.21, 95% CI [-0.15, 0.57], k = 8). CIH approaches reduced pain intensity and improved physical functioning. These approaches offer a nonpharmacological, nonsurgical intervention for chronic pain management for military personnel. Future studies should optimize interventions to improve depressive symptoms in military populations experiencing chronic pain. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
Learn More >The mechanosensitive Piezo1 and Piezo2 channels convert mechanical force into cation permeation. However, their precise mechanogating and regulatory mechanisms remain elusive. Here, we report that Piezo1 utilizes three lateral ion-conducting portals equipped with physical gates for cooperative gating and splicing regulation. Mutating residues lining the portal converts Piezo1 into an anion-selective channel, demonstrating the portal-based cation-permeating pathway. Intriguingly, the portal is physically blocked with a plug domain, which undergoes alternative splicing in both Piezo1 and Piezo2. The Piezo1 isoform has local openings of the portals, enlarged single-channel conductance and sensitized mechanosensitivity. Remarkably, the three plugs are strategically latched onto the central axis for coordinated gating of the three portals. Disrupting the latching induces three quantal sub-conductance states in Piezo1, but not in the isoform. Together, we propose that Piezo utilizes an elegant plug-and-latch mechanism to physically and coordinately gate the lateral portals through the spliceable plug gates.
Learn More >Platinum-based chemotherapy-induced peripheral neuropathy is one of the most common causes of dose reduction and discontinuation of life-saving chemotherapy in cancer treatment; it often causes permanent impairment of quality of life in cancer patients. The mechanisms that underlie this neuropathy are not defined, and effective treatment and prevention measures are not available. Here, we demonstrate that SIRT2 protected mice against cisplatin-induced peripheral neuropathy (CIPN). SIRT2 accumulated in the nuclei of dorsal root ganglion sensory neurons and prevented neuronal cell death following cisplatin treatment. Mechanistically, SIRT2, an NAD+-dependent deacetylase, protected neurons from cisplatin cytotoxicity by promoting transcription-coupled nucleotide excision repair (TC-NER) of cisplatin-induced DNA crosslinks. Consistent with this mechanism, pharmacological inhibition of NER using spironolactone abolished SIRT2-mediated TC-NER activity in differentiated neuronal cells and protection of neurons from cisplatin-induced cytotoxicity and CIPN in mice. Importantly, SIRT2's protective effects were not evident in lung cancer cells in vitro or in tumors in vivo. Taken together, our results identified SIRT2's function in the NER pathway as a key underlying mechanism of preventing CIPN, warranting future investigation of SIRT2 activation-mediated neuroprotection during platinum-based cancer treatment.
Learn More >Unrelieved pain is a widespread condition that fuels the opioid crisis. Molecules that initiate painful sensations are intensively sought as therapeutic targets for improved pain interventions. In this issue of Cell, Beaulieu-Laroche et al. (2020) describe TACAN, a putative ion channel that mediates mechanical pain in mice.
Learn More >The activation of the AMP activated protein kinase (AMPK) exerts antinociceptive effects in acute and neuropathic pain models. Mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c), a mitochondrial-derived peptide, regulates many biological activities via activating AMPK. However, the role of MOTS-c in the formalin-induced inflammatory nociception remains unclear. In this study, we investigated the role of MOTS-c in the formalin-induced inflammatory nociception. The antinociceptive effect of MOTS-c was assessed by recording the time spent licking paw. The anti-inflammatory effect of MOTS-c was evaluated by detecting the inflammatory cytokine level changes in the mouse serum. Western blot was used to detect the changes of protein phosphorylation levels in the mouse spinal cord. Changes of c-fos expression in the spinal cord were assessed by immunohistochemistry. Our results showed that the intraperitoneal administration of MOTS-c reduced the time spent on licking in phase 2 in a dose-dependent manner in the formalin test. The antinociceptive effects of MOTS-c (50 mg/kg, i.p.) were attenuated by the AMPK antagonist compound C (10 mg/kg, i.p.). MOTS-c (50 mg/kg, i.p.) significantly reduced pro-inflammatory cytokine levels and elevated the level of anti-inflammatory cytokine in mouse serum. In addition, MOTS-c treatment significantly increased AMPKα phosphorylation level and suppressed formalin-induced extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinases (JNK), and P38 activation and c-fos expression in the mouse spinal cord. These results suggest that systemic administration of MOTS-c exerts antinociceptive and anti-inflammatory effects, at least partially, through activating AMPK pathway and inhibiting MAP kinases-c-fos signaling pathway in the mouse formalin test.
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