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Migraine is the most common neurological disorder and one of the major causes of years lived with disability. Its treatment (especially of chronic forms) is often challenging and accompanied with adverse effects. Although new therapeutic approaches have recently emerged (eg, calcitonin gene-related peptide antibodies), these are linked to strict prescribing guidelines and therefore limited to only a minority of patients. Recently, randomised controlled trials have demonstrated that open-label placebo treatments can lead to significant and clinically relevant improvements of chronic pain conditions.
Learn More >Chronic pain affects about 20 % of the Canadian population and can lead to physical, psychological and social vulnerabilities. However, this condition remains poorly recognized and undertreated. During 2020, as the COVID-19 pandemic disrupted daily living and health care systems, the situation of people with chronic pain has drawn little public attention.
Learn More >Previous studies have shown that persistent limb immobilization using a cast increases nociceptive behavior to somatic stimuli in rats. However, the peripheral neural mechanisms of nociception remain unclear. Using single-fiber electrophysiological recordings in vitro, we examined the general characteristics of cutaneous C-fiber afferents in the saphenous nerve and their responsiveness to mechanical and heat stimuli in a rat model of immobilization-induced pain by subjecting the rats to hindlimb cast immobilization for 4 weeks. The mechanical response of C-fibers appeared to increase in the model; however, statistical analysis revealed that neither the response threshold nor the response magnitude was altered. The general characteristics and heat responses of the C-fibers were not altered. The number of microglia and cell diameters significantly increased in the superficial dorsal horn of the lumbar spinal cord. Thus, activated microglia-mediated spinal mechanisms are associated with the induction of nociceptive hypersensitivity in rats after persistent cast immobilization.
Learn More >To explore the prevalence of poor social support and loneliness among people with chronic headache, and how these might be effect modifiers in the relationships between chronic headache and stress, medication overuse, and self-rated health.
Learn More >The transition from childhood to adolescence and from adolescence to adulthood are vulnerable phases in life. In these phases, late or insufficient treatment of diseases may lead to chronification and favor development of additional disorders. In adolescents, migraine often has a highly negative impact on school performance and everyday life. The hypothesis of the present study was that adolescents with migraine have a higher risk for developing additional disorders such as psychiatric disorders or other pain syndromes in the course of the disease.
Learn More >The rising opioid crisis has become a worldwide societal and public health burden, resulting from the abuse of prescription opioids. Targeting the κ-opioid receptor (KOR) in the periphery has emerged as a powerful approach to develop novel pain medications without central side effects. Inspired by the traditional use of sunflower () preparations for analgesic purposes, we developed novel stabilized KOR ligands (termed as helianorphins) by incorporating different dynorphin A sequence fragments into a cyclic sunflower peptide scaffold. As a result, helianorphin-19 selectively bound to and fully activated the KOR with nanomolar potency. Importantly, helianorphin-19 exhibited strong KOR-specific peripheral analgesic activity in a mouse model of chronic visceral pain, without inducing unwanted central effects on motor coordination/sedation. Our study provides a proof of principle that cyclic peptides from plants may be used as templates to develop potent and stable peptide analgesics applicable via enteric administration by targeting the peripheral KOR for the treatment of chronic abdominal pain.
Learn More >Pruritus (itch) is a debilitating symptom in liver diseases with cholestasis, which severely affects patients' quality of life. Limited treatment options are available for cholestatic itch, largely due to the incomplete understanding of the underlying molecular mechanisms. Several factors have been proposed as pruritogens for cholestatic itch, such as bile acids, bilirubin, lysophosphatidic acid, and endogenous opioids. Recently, two research groups independently identified Mas-related G protein-coupled receptor X4 (MRGPRX4) as a receptor for bile acids and bilirubin and demonstrated its likely role in cholestatic itch. This discovery not only opens new avenues for understanding the molecular mechanisms in cholestatic itch but provides a promising target for developing novel anti-itch treatments. In this review, we summarize the current theories and knowledge of cholestatic itch, emphasizing MRGPRX4 as a bile acid and bilirubin receptor mediating cholestatic itch in humans. We also discuss some future perspectives in cholestatic itch research.
Learn More >To determine the acceptability and feasibility of acupuncture for the treatment of endometriosis-related chronic pelvic pain. A prospective, randomized controlled feasibility study. Outpatient setting in Sydney, Australia. Participants who were aged 18-45 years, had a confirmed laparoscopic diagnosis of endometriosis in the past 5 years, and had regular menstrual periods and mean pelvic pain scores ≥4/10. Sixteen acupuncture treatments delivered by registered acupuncturists using a standardized point protocol over 8 weeks, twice per week plus usual care compared with usual care alone. Primary outcome measures were feasibility, safety, and acceptability of the acupuncture intervention. Secondary outcomes were changes in self-reported pelvic pain scores, changes in quality of life as measured by the Endometriosis Health Profile (EHP-30), changes in descending pain modulation, and changes in systemic inflammation (plasma interleukin [IL-6] concentrations). Twenty-nine participants were eligible to participate, with 19 participants completing the trial. There was unequal withdrawals between groups; the acupuncture group had a withdrawal rate of 14% compared with 53% in usual care. Adverse events were uncommon (6.7%) and generally mild. A 1.9 point decrease in median nonmenstrual pain scores and a 2.0 decrease in median menstrual pain scores between baseline and end of trial were observed in the acupuncture group only. Improvements in all domains of the EHP-30 were seen in the acupuncture group, with no changes seen in usual care. There was no difference between baseline and end of treatment in IL-6 concentrations for either group. Acupuncture was an acceptable, well-tolerated treatment and it may reduce pelvic pain and improve quality of life; however, usual care was not an acceptable control group. anzctr.org.au: ACTRN12617000053325. Prospectively registered January 11, 2017.
Learn More >α9-Containing nicotinic acetylcholine receptors (nAChRs) are key targets for the treatment of neuropathic pain. α-Conotoxin RgIA4 is a peptide antagonist of human α9α10 nAChRs with high selectivity. However, structural rearrangement reveals a potential liability for clinical applications. We herein report our designer RgIA analogues stabilized by methylene thioacetal as nonopioid analgesic agents. We demonstrate that replacing disulfide loop I [Cys-Cys] with methylene thioacetal in the RgIA skeleton results in activity loss, whereas substitution of loop II [Cys-Cys] can be accommodated. The lead molecule, RgIA-5524, exhibits highly selective inhibition of α9α10 nAChRs with an IC of 0.9 nM and much reduced degradation in human serum. studies showed that RgIA-5524 relieves chemotherapy-induced neuropathic pain in wild type but not α9 knockout mouse models, demonstrating that α9-containing nAChRs are necessary for the therapeutic effects. This work highlights the application of methylene thioacetal as a disulfide surrogate in conotoxin-based, disulfide-rich peptide drugs.
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