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Local anesthetics with long-lasting effects and selectivity for nociceptors have been sought over the past decades. In this study, we investigated whether amiodarone, a multiple channel blocker, provides long-lasting local anesthesia and whether adding a TRPV1 channel activator selectively prolongs sensory anesthetic effects without prolonging motor blockade. Additionally, we examined whether amiodarone provides long-lasting analgesic effects against inflammatory pain without TRPV1 channel activator co-administration. In the sciatic nerve block model, 32 adult C57BL/6J mice received either bupivacaine, amiodarone with or without capsaicin (a TRPV1 agonist), or vehicle peri-sciatic nerve injection. Sensory and motor blockade were assessed either by pinprick and toe spread tests, respectively. In another set of 16 mice, inflammatory pain was induced in the hind paw by zymosan injection, followed by administration of either amiodarone or vehicle. Mechanical and thermal sensitivity and paw thickness were assessed using the von Frey and Hargreaves tests, respectively. The possible cardiovascular and neurological side effects of local amiodarone injection were assessed in another set of 12 mice. In the sciatic nerve block model, amiodarone produced robust anesthesia, and the co-administration of TRPV1 agonist capsaicin prolonged the duration of sensory blockade, but not that of motor blockade [complete sensory block duration: 195.0 ± 9.8 min vs. 28.8 ± 1.3 min, F (2, 21) = 317.6, < 0.01, complete motor block duration: 27.5 ± 1.6 min vs. 21.3 ± 2.3 min, F (2, 22) = 11.1, = 0.0695]. In the zymosan-induced inflammatory pain model, low-dose amiodarone was effective in reversing the mechanical and thermal hypersensitivity not requiring capsaicin co-administration [50% withdrawal threshold at 8 h (g): 0.85 ± 0.09 vs. 0.25 ± 0.08, < 0.01, withdrawal latency at 4 h (s) 8.5 ± 0.5 vs. 5.7 ± 1.4, < 0.05]. Low-dose amiodarone did not affect zymosan-induced paw inflammation. Local amiodarone did not cause cardiovascular or central nervous system side effects. Amiodarone may have the potential to be a long-acting and nociceptor-selective local anesthetic and analgesic method acting over open-state large-pore channels.
Learn More >The role of the Slack (also known as Slo2.2, K1.1, or KCNT1) channel in pain-sensing is still in debate on which kind of pain it regulates. In the present study, we found that the Slack mice exhibited decreased mechanical pain threshold but normal heat and cold pain sensitivity. Subsequently, X-gal staining, hybridization, and immunofluorescence staining revealed high expression of the Slack channel in Isolectin B4 positive (IB4) neurons in the dorsal root ganglion (DRG) and somatostatin-positive (SOM) neurons in the spinal cord. Patch-clamp recordings indicated the firing frequency was increased in both small neurons in DRG and spinal SOM neurons in the Slack mice whereas no obvious slow afterhyperpolarization was observed in both WT mice and Slack mice. Furthermore, we found gene expression in spinal SOM neurons in Slack mice partially relieved the mechanical pain hypersensitivity of Slack mice and decreased AP firing rates of the spinal SOM neurons. Finally, deletion of the Slack channel in spinal SOM neurons is sufficient to result in mechanical pain hypersensitivity in mice. In summary, our results suggest the important role of the Slack channel in the regulation of mechanical pain-sensing both in small neurons in DRG and SOM neurons in the spinal dorsal horn.
Learn More >The activation of mast cells (MCs) and mediator release are closely related to the pathophysiology of irritable bowel syndrome (IBS). However, the exact underlying mechanisms are still not completely understood. The nuclear receptor subfamily 4a (Nr4a) is a family of orphan nuclear receptors implicated in regulating MC activation, degranulation, cytokine/chemokine synthesis and release. Acute and chronic stress trigger hypothalamic-pituitaryadrenal axis (HPA) activation to induce the release of corticotropin-releasing hormone (CRH), resulting in MC activation and induction of the Nr4a family. Our newest data showed that Nr4a members were specially over-expressed in colonic MCs of the chronic water-avoidance stress (WAS)-induced visceral hyperalgesia mice, suggesting that Nr4a members might be involved in the pathophysiology of visceral hypersensitivity. In this review, we highlight the present knowledge on roles of Nr4a members in the activation of MCs and the pathophysiology of IBS, and discuss signaling pathways that modulate the activation of Nr4a family members. We propose that a better understanding of Nr4a members and their modulators may facilitate the development of more selective and effective therapies to treat IBS patients.
Learn More >Morphine and its substitutes are frequently used in the clinical treatment of acute severe pain and advanced cancer patients. Long-term irregular use of morphine will lead to severe dependence. However, the genes behind the analgesic and addictive effects of morphine still need to be revealed.
Learn More >Elimination or blocking of astrocytes could ameliorate neuropathic pain in animal models. MiR-125a-5p, expressed in astrocyte derived extracellular vesicles, could mediate astrocyte function to regulate neuron communication. However, the role of miR-125a-5p in DPN (diabetic peripheral neuropathy) remains elusive.
Learn More >A gap remains in understanding the association among the symptoms of distal sensory peripheral neuropathy (DSPN) (pain, aching, burning, pins and needles, numbness), comorbidities, and medication use among persons living with People Living with HIV/AIDS (PLWH) with DSPN. This report describes the symptom characteristics associated with prescribed treatment regimens (HIV and non-HIV medications) and comorbidities from a cohort of PLWH experiencing symptoms of DSPN who reside in New York City.
Learn More >Computerized migraine diagnostic tools have been developed and validated since 1960. We conducted a systematic review to summarize and critically appraise the quality of all published studies involving computerized migraine diagnostic tools.
Learn More >National strategies from North America call for substantive improvements in entry-level pain management education to help reduce the burden of chronic pain. Past work has generated a valuable set of interprofessional pain management competencies to guide the education of future health professionals. However, there has been very limited work that has explored the development of such competencies for individual professions in different regions. Developing profession-specific competencies tailored to the local context is a necessary first step to integrate them within local regulatory systems. Our group is working toward this goal within the context of entry-level physiotherapy (PT) programs across Canada.
Learn More >Knee osteoarthritis (KOA) showed synovial fibrosis and hyperalgesia, although the correlation between the two is unclear. Besides, the specific changes of sensory innervation in animal models are still controversial, which makes it difficult to choose the modeling methods for KOA pain research.
Learn More >Acupuncture has a long history of being used in Chinese medicine for the treatment of migraine. However, molecular biomarkers for diagnosis and prognosis of migraine and its treatment are lacking. This study aimed to explore whether acupuncture could regulate differentially expressed exosomal miRNAs between patients with migraine without aura (MWoA) and healthy controls (HCs) and to identify diagnostic biomarkers that helped differentiate MWoA patients from HCs and identify prognostic biomarkers that helped to predict the effect of acupuncture.
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