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Sigma receptor is a transmembrane non-GPCR protein expressed mainly in the endoplasmic reticulum (ER) membrane associated with mitochondria. It is classified into two types; Sigma-1 (S1R) and Sigma-2 (S2R) based on their biological functions. S1R has been implicated in many neurological disorders such as anxiety, schizophrenia, and depression. Therefore, S1R ligands possess a variety of potential clinical applications with a great interest in the treatment of neuropathic pain. In this study, we report the discovery of a novel lead compound for S1R binding, based on the thiazolidine-2,4-dione nucleus. We have explored hydrophobic groups of different sizes on both sides of the five-membered ring scaffold guided by the crystal structure of S1R. Six compounds showed more than 50% displacement of the radioligand at 10 µM concentration with compound 6c resulting in 100% displacement and a K of 95.5 nM. Moreover, compounds 6c and 6e showed a significant selectivity over S2R. In addition, molecular docking predicted that all the compounds showed the critical salt bridge with Glu172 with variable degrees of π-stacking interaction with Tyr103. Upon optimization, this series of compounds could represent potential clinically useful S1R ligands for pain management.
Learn More >Pediatric inflammatory bowel disease (p-IBD) is a chronic relapsing gastrointestinal disorder of childhood with long-term morbidity. Several extraintestinal manifestations are described, the most common being joint pain and/or inflammation. However, patient and disease characteristics, treatments, and outcomes of p-IBD-associated musculoskeletal disease are not well established. Our study aims to summarize the recent literature on the epidemiology of musculoskeletal manifestations in p-IBD in the era of biologics.
Learn More >Chronic migraine (CM) diagnosis is nowadays based on the threshold of 15 headache days/month for three consecutive months, of which at least eight have migraine headache features. In recent years, proposals for reducing the threshold to 8 days/month have been proposed. The sole frequency parameter, however, is partial considering the variability in frequency, pain severity, associated symptoms, such as nausea, osmophobia, and photophobia, and presence of aura, but also the variable response to treatment and the association with several comorbidities. Therefore, in our opinion, a multiparameter perspective has to be taken into account that considers the underlying pathophysiology, in particular the presence of tension-type-like pain, cutaneous allodynia, and reduced pain threshold. A paradigm change in the definition of chronic migraine moves far beyond the mere 8 vs. 15 days/month, but has ethical and practical implications for treatment: should patients be treated with the most effective prophylactic drugs, i.e., monoclonal antibodies (MABs), if they enter into a new definition of CM? How should clinicians deal with treatment escalation towards MABs? What is the role of associated conditions, response to treatments, lifestyle issues, and psychological factors? And, finally, which endpoint should we use to define effectiveness? Is improvement in headache frequency enough, or should we move towards disability, quality of life, or workplace productivity?
Learn More >This systematic review was conducted to evaluate the best available evidence regarding the use of non-invasive neuromodulation techniques for managing chemotherapy-induced peripheral neuropathy (CIPN).
Learn More >A recent phase 3 study demonstrated that treatment with tanezumab, a nerve growth factor inhibitor, or nonsteroidal anti-inflammatory drugs (NSAIDs) improves pain and physical function in participants with moderate-to-severe osteoarthritis (OA) of the hip or knee. Here, we evaluated the time course and clinical importance of these initial efficacy findings using a mixture of primary, secondary, and post hoc endpoints.
Learn More >Formyl peptide receptor type 2 (FPR2/ALX) belongs to the formyl peptide receptors (FPRs) family clustered on chromosome 19 and encodes a family of three Class A of G protein-coupled receptors (GPCRs). A short N-terminal region, an NPXXY motif in transmembrane (TM) region 7 and an E/DRY motif that bridges TM3 and TM6 stabilizing inactive receptor conformations characterize this class of receptors. In recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), FPRs play a crucial role in innate immune responses. FPR2/ALX is highly expressed in myeloid cells, as well as in chondrocytes, fibroblasts, endothelial, epithelial and smooth muscle cells. FPR2/ALX mRNA expression was recently reported in the rat brainstem, spinal cord, thalamus/hypothalamus, cerebral neocortex, hippocampus, cerebellum and striatum. The central nervous system (CNS) distribution of FPR2/ALX suggests important functions in nociception. Thus, the present study was carried out to investigate the possible role of FPR2/ALX in nociception in mice. Intrathecal administration of the formyl peptide receptor type 1 (FPR1) agonist fMLF and the FPR2/ALX agonist BML-111 relieved nociception and these effects were reduced by contemporary administration of the FPR2/ALX antagonist WRW. Furthermore, measurement of cytokines and brain-derived neurotrophic factor (BDNF) in the spinal cord of neuropathic mice demonstrated that the antinociceptive effects of BML-111 might depend on the reduction in cytokine release and BDNF in the spinal cord. These results suggest a possible role of FPR2/ALX for pain control in the spinal cord.
Learn More >Knee osteoarthritis (OA) is among the most common and disabling persistent pain conditions, with increasing prevalence and impact around the globe. In the U.S., the rising prevalence of knee OA has been paralleled by an increase in annual rates of total knee arthroplasty (TKA), a surgical treatment option for late-stage knee OA. While TKA outcomes are generally good, post-operative trajectories of pain and functional status vary substantially; a significant minority of patients report ongoing pain and impaired function following TKA. A number of studies have identified sets of biopsychosocial risk factors for poor post-TKA outcomes (e.g., comorbidities, negative affect, sensory sensitivity), but few prospective studies have systematically evaluated the unique and combined influence of a broad array of factors.
Learn More >Virtual reality (VR) is a developing technology that has recently attracted the attention of healthcare practitioners. Recently, VR systems have been used to treat pain symptoms. The present study aims to evaluate the VR effectiveness on chronic pain management. A systematic literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Keywords were used to discover the potentially eligible studies. The primary focus of the present investigation was to evaluate the possible effect of VR-assisted treatments on chronic pain, especially in the commonly occurring low back and neck pain. Nine studies reporting randomized controlled trials were included in the present study. VR-mediated interventions demonstrated significant improvement for pain symptoms in patients experiencing chronic pain. In addition, VR-mediated therapy decreased pain intensity and disability in the case of chronic neck pain compared to control conditions. However, the VR interventions showed a statistically non-significant improvement in chronic low back pain when experimental groups were compared with controls. VR therapy positive effect on chronic pain did not differ from the one reported for other types of interventions for pain management, as physical exercise and laser therapy. Taken together, these findings showed that currently available lines of evidence on the effect of VR-mediated therapy in chronic pain management, despite pointing towards possible therapeutical benefits of the VR-based intervention, are overall inconclusive and that more research on VR-assisted therapy for chronic pain is needed.
Learn More >Restless legs syndrome is a highly prevalent comorbidity of migraine; however, its genetic contributions remain unclear.
Learn More >Human peripheral neuropathies are poorly understood, and the availability of experimental models limits further research. The PeriTox test uses immature dorsal root ganglia (DRG)-like neurons, derived from induced pluripotent stem cells (iPSC), to assess cell death and neurite damage. Here, we explored the suitability of matured peripheral neuron cultures for the detection of sub-cytotoxic endpoints, such as altered responses of pain-related P2X receptors. A two-step differentiation protocol, involving the transient expression of ectopic neurogenin-1 (NGN1) allowed for the generation of homogeneous cultures of sensory neurons. After >38 days of differentiation, they showed a robust response (Ca-signaling) to the P2X3 ligand α,β-methylene ATP. The clinical proteasome inhibitor bortezomib abolished the P2X3 signal at ≥5 nM, while 50-200 nM was required in the PeriTox test to identify neurite damage and cell death. A 24 h treatment with low nM concentrations of bortezomib led to moderate increases in resting cell intracellular Ca concentration but signaling through transient receptor potential V1 (TRPV1) receptors or depolarization-triggered Ca influx remained unaffected. We interpreted the specific attenuation of purinergic signaling as a functional cell stress response. A reorganization of tubulin to form dense structures around the cell somata confirmed a mild, non-cytotoxic stress triggered by low concentrations of bortezomib. The proteasome inhibitors carfilzomib, delanzomib, epoxomicin, and MG-132 showed similar stress responses. Thus, the model presented here may be used for the profiling of new proteasome inhibitors in regard to their side effect (neuropathy) potential, or for pharmacological studies on the attenuation of their neurotoxicity. P2X3 signaling proved useful as endpoint to assess potential neurotoxicants in peripheral neurons.
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