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Sigma-1 receptor modulates neuroinflammation associated with mechanical hypersensitivity and opioid tolerance in a mouse model of osteoarthritis pain

Carcolé, M; Kummer, S; Gonçalves, L; Zamanillo, D; Merlos, M; Dickenson, AH; Fernández-Pastor, B; ... Maldonado, R; + view all (2019) Sigma-1 receptor modulates neuroinflammation associated with mechanical hypersensitivity and opioid tolerance in a mouse model of osteoarthritis pain. British Journal of Pharmacology , 176 (20) pp. 3939-3955. 10.1111/bph.14794. Green open access

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Abstract

BACKGROUND AND PURPOSE: Osteoarthritis pain is a chronic disabling condition lacking effective treatment. Continuous use of opioid drugs during osteoarthritis pain induces tolerance and may result in dose escalation and abuse. Sigma-1 receptor (σ1R), a chaperone expressed in key areas for pain control, modulates mu-opioid receptor (MOR) activity and represents a promising target to tackle these problems. The present study investigates the efficacy of σ1R antagonist E-52862 to inhibit pain sensitization, morphine tolerance and associated electrophysiological and molecular changes in a murine model of osteoarthritis 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. Interestingly, 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 the recovery to baseline thresholds was slower. Interestingly, both a σ1R agonist and a MOR antagonist inhibited E-52862 analgesic effect, and an acute sub-effective E-52862 dose 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 σ1R antagonism alleviating both short- and long-lasting antinociception during chronic osteoarthritis pain and identify E-52862 as a promising pharmacological agent to treat chronic pain and elude opioid tolerance.

Type: Article
Title: Sigma-1 receptor modulates neuroinflammation associated with mechanical hypersensitivity and opioid tolerance in a mouse model of osteoarthritis pain
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bph.14794
Publisher version: https://doi.org/10.1111/bph.14794
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Sigma-1 receptor, central sensitization, mechanical allodynia, neuroinflammation, opioid tolerance, osteoarthritis pain, spinal cord neurons
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10080453
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