Sigma‐1 receptor modulates neuroinflammation associated with mechanical hypersensitivity and opioid tolerance in a mouse model of osteoarthritis pain
| Autor: | Rafael Maldonado, Anthony H. Dickenson, Mireia Carcolé, Leonor Gonçalves, Sami Kummer, Begoña Fernández-Pastor, Manuel Merlos, David Cabañero, Daniel Zamanillo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist Male medicine.drug_class Morpholines Analgesic Pain Pharmacology Injections Intra-Articular 03 medical and health sciences Mice 0302 clinical medicine Drug tolerance Osteoarthritis medicine Animals Receptors sigma Sensitization Inflammation Sigma-1 receptor Dose-Response Relationship Drug Morphine business.industry Chronic pain Drug Tolerance medicine.disease Research Papers Iodoacetic Acid Analgesics Opioid Disease Models Animal 030104 developmental biology medicine.anatomical_structure Opioid Hyperalgesia Pyrazoles business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Br J Pharmacol |
| Popis: | Background and purpose Osteoarthritic pain is a chronic disabling condition lacking effective treatment. Continuous use of opioid drugs during osteoarthritic pain induces tolerance and may result in dose escalation and abuse. Sigma-1 (σ1) receptors, a chaperone expressed in key areas for pain control, modulates μ-opioid receptor activity and represents a promising target to tackle these problems. The present study investigates the efficacy of the σ1 receptor antagonist E-52862 to inhibit pain sensitization, morphine tolerance, and associated electrophysiological and molecular changes in a murine model of osteoarthritic pain. Experimental approach Mice received an intra-knee injection of monoiodoacetate followed by 14-day treatment with E-52862, morphine, or vehicle, and mechanical sensitivity was assessed before and after the daily doses. Key results Monoiodoacetate-injected mice developed persistent mechanical hypersensitivity, which was dose-dependently inhibited by E-52862. Mechanical thresholds assessed before the daily E-52862 dose showed gradual recovery, reaching complete restoration by the end of the treatment. When repeated treatment started 15 days after knee injury, E-52862 produced enhanced short-term analgesia, but recovery to baseline threshold was slower. Both a σ1 receptor agonist and a μ receptor antagonist blocked the analgesic effects of E-52862. An acute, sub-effective dose of E-52862 restored morphine analgesia in opioid-tolerant mice. Moreover, E-52862 abolished spinal sensitization in osteoarthritic mice and inhibited pain-related molecular changes. Conclusion and implications These findings show dual effects of σ1 receptor antagonism alleviating both short- and long-lasting antinociception during chronic osteoarthritis pain. They identify E-52862 as a promising pharmacological agent to treat chronic pain and avoid opioid tolerance. |
| Databáze: | OpenAIRE |
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