Browse by Audience
The kappa opioid receptor (κOR) is an important target for pain therapeutics to reduce depression and other harmful side effects of existing medications. The analgesic activity is mediated by κOR signaling through the adenylyl cyclase-inhibitory family of Gi protein. Here, we report the three-dimensional (3D) structure for the active state of human κOR complexed with both heterotrimeric Gi protein and MP1104 agonist. This structure resulted from long molecular dynamics (MD) and metadynamics (metaMD) simulations starting from the 3.1-Å X-ray structure of κOR-MP1104 after replacing the nanobody with the activated Gi protein and from the 3.5-Å cryo-EM structure of μOR-Gi complex after replacing the 168 missing residues. Using MD and metaMD we discovered interactions to the Gi protein with strong anchors to two intracellular loops and transmembrane helix 6 of the κOR. These anchors strengthen the binding, contributing to a contraction in the binding pocket but an expansion in the cytoplasmic region of κOR to accommodate G protein. These remarkable changes in κOR structure reveal that the anchors are essential for activation.
Learn More >Sleep and opioid medications used to treat insomnia and chronic pain are associated with adverse side effects (falls and cognitive disturbance). Although behavioural treatments such as cognitive behavioral therapy for insomnia (CBT-I) and pain (CBT-P) improve sleep and clinical pain, their effects on sleep and opioid medication use are unclear. In this secondary analysis of published trial data, we investigated whether CBT-I and CBT-P reduced reliance on sleep/opioid medication in patients with fibromyalgia and insomnia (FMI). Patients with FMI (n = 113, M = 53.0, SD = 10.9) completed 8 weeks of CBT-I (n = 39), CBT-P (n = 37) or waitlist control (WLC; n = 37). Participants completed 14 daily diaries at baseline, post-treatment and 6-month follow-up, assessing sleep and opioid medication usage. Multilevel modelling examined group by time effects on days of medication use. A significant interaction revealed CBT-P reduced the number of days of sleep medication use at post-treatment, but usage returned to baseline levels at follow-up. There were no other significant within- or between-group effects. CBT-P led to immediate reductions in sleep medication usage, despite lack of explicit content regarding sleep medication. CBT-I and CBT-P may be ineffective as stand-alone treatments for altering opioid use in FMI. Future work should explore CBT as an adjunct to other behavioural techniques for opioid reduction.
Learn More >Neuropathic pain is an unfavorable pathological pain, often persistent over time, thus leading to significant impairment of quality of life and public health burden. Notably, microRNAs (miRNAs) have been implicated in the pathophysiological process of neuropathic pain. The potential mechanism by which miR-34c-5p functions in neuropathic pain remains unclear. This study aimed to test the hypothesis that miR-34c-5p can modulate neuropathic pain in rat models with chronic constriction injury (CCI) of sciatic nerve, via interaction with the SIRT1/STAT3 signaling pathway Firstly, SIRT1 was validated as a target gene of miR-34c-5p and could be negatively regulated by miR-34c-5p. We induced miR-34c-5p overexpression/inhibition, SIRT1 knockdown, and STAT3 knockdown in the model rats to assess pain behavior patterns. Meanwhile, dorsal root ganglion (DRG) was transduced with overexpression or knockdown of miR-34c-5p or lipopolysaccharide to induce the production of inflammatory factors. It was observed that miR-34c-5p was up-regulated, and SIRT1 was under-expressed in the DRG neurons of dorsal spinal cords of the CCI rats. Furthermore, the ectopic expression of miR-34c-5p and knockdown of SIRT1 in CCI rats resulted in increased hyperalgesia and inflammation, corresponding to reduced paw withdrawal threshold and paw withdrawal latency, and elevated levels of IL-6, IL-1β and TNF-α. More importantly, miR-34c-5p inhibition reduced the hyperalgesia and inflammation by blocking the STAT3 signaling pathway through up-regulation of SIRT1. Conjointly, our results indicated that the down-regulation of miR-34c-5p could potentially provide sustained relief in neuropathic pain by promoting SIRT1 expression through STAT3 signaling pathway inactivation.
Learn More >Clinically, chronic postsurgical pain (CPSP) is very common. Many CPSP patients may experience depression. Thus far, little is known about the mechanism of the comorbidity of CPSP and depression. Ketamine has been confirmed to possess analgesic and rapid antidepressant effects, but it is unclear whether ketamine can relieve the comorbidity of CPSP and depression.
Learn More >To assess the supraspinal working mechanisms of the Burst spinal cord stimulation (SCS)-mode we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge Burst SCS would induce a more profound BOLD signal increase in areas associated with cognitive-emotional aspects of pain, as compared to Tonic SCS.
Learn More >Migraine has many presumed comorbidities which have rarely been compared between samples with and without migraine. Examining the association between headache pain intensity and monthly headache day (MHD) frequency with migraine comorbidities is novel and adds to our understanding of migraine comorbidity.
Learn More >In response to the national opioid public health crisis, there is an urgent need to develop nonopioid solutions for effective pain management. Neurosteroids are endogenous molecules with pleotropic actions that show promise for safe and effective treatment of chronic low back pain.
Learn More >A comprehensive overview and safety evaluation of fremanezumab as a preventive therapy for migraine.
: Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP mAb), is a migraine-specific treatment for migraine prevention.: This review will briefly discuss other available and emerging CGRP mAbs and the neurophysiology of fremanezumab. The review will focus on phase III trials of the efficacy of fremanezumab for episodic and chronic trials, and a recent pooled safety and tolerability analysis of its use.: Continued efficacy and safety data collection will help guide long-term risk and efficacy counseling in the general population.
Learn More >The physical therapy profession has recently begun to address its role in preventing and managing opioid use disorder (OUD). This topic calls for discussion of the scope of physical therapy practice, and the profession's role, in the prevention and treatment of complex chronic illnesses, such as OUD. OUD is not just an individual-level problem. Abundant scientific literature indicates OUD is a problem that warrants interventions at the societal level. This upstream orientation is supported in the American Physical Therapy Association's vision statement compelling societal transformation and its mission of building communities. Applying a population health framework to these efforts may provide physical therapists with a useful viewpoint that can inform clinical practice and research, as well as develop new cross-disciplinary partnerships. This Perspective discusses the intersection of OUD and persistent pain using the disease prevention model. Primordial, primary, secondary, and tertiary preventive strategies are defined and discussed. This Perspective then explains the potential contributions of this model to current practices in physical therapy, as well as provide actionable suggestions for physical therapists to help develop and implement upstream interventions that may reduce the impact of OUD in their communities.
Learn More >The objectives of this study were to obtain patient evaluations of the content, structure, and delivery modality of Meaning-Centered Pain Coping Skills Training (MCPC), a novel psychosocial intervention for patients with advanced cancer and pain. MCPC aims to help patients connect with valued sources of meaning in their lives (e.g., family relationships), while providing training in evidence-based cognitive and behavioral skills (e.g., guided imagery) to reduce pain.
Learn More >