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.
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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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