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Sigma‐1 receptor modulates neuroinflammation associated with mechanical hypersensitivity and opioid tolerance in a mouse model of osteoarthritis pain
Author(s) -
Carcolé Mireia,
Kummer Sami,
Gonçalves Leonor,
Zamanillo Daniel,
Merlos Manuel,
Dickenson Anthony H.,
FernándezPastor Begoña,
Cabañero David,
Maldonado Rafael
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14794
Subject(s) - sigma 1 receptor , medicine , neuroinflammation , osteoarthritis , opioid , hyperalgesia , neuroscience , receptor , threshold of pain , anesthesia , pharmacology , nociception , psychology , inflammation , pathology , agonist , alternative medicine
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.