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

Abstract

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.

Molecular mechanisms of mechanical load-induced osteoarthritis

“…NGF inhibitors can effectively alleviate OA pain [78]. A report by Carcolé et al [79] indicated that sigma-1 receptors perceived and modulated mechanical pain in osteoarthritis. Furthermore, OA patients usually have peripheral nociceptors, a phenomenon in which the sensitivity of receptors increases and the excitability threshold of pain nerves decreases, which is clinically manifested as hyperalgesia (physiological stimulation can also cause pain).…”

Long-Lasting Nociplastic Pain Modulation by Repeated Administration of Sigma-1 Receptor Antagonist BD1063 in Fibromyalgia-like Mouse Models

“…The results also show that the efficacy of BD1063 is in the range of 25 to 60 mg/kg, the dose of 40 mg/kg being the one exerting maximal antihyperalgesic effects in both animal models. These results are consistent with previous studies using this range of σ1R antagonist administration to reveal antiallodynic and/or antihyperalgesic effects in a variety of rodent models, including spinal cord injury-induced neuropathic pain [ 22 , 23 ], paclitaxel-induced neuropathic pain [ 24 , 30 ], oxaliplatin-induced neuropathic pain [ 27 ], partial sciatic nerve ligation-induced neuropathic pain [ 26 ], spared nerve injury-induced neuropathic pain [ 31 , 32 , 33 ], infraorbital nerve constriction injury-induced trigeminal neuralgia [ 27 ], carrageenan-induced inflammatory pain [ 25 ], and MIA-induced osteoarthritis pain [ 34 ].…”

Anti-Inflammatory Effects Induced by a Polyphenolic Granular Complex from Olive (Olea europaea, Mainly Cultivar coratina): Results from In Vivo and Ex Vivo Studies in a Model of Inflammation and MIA-Induced Osteoarthritis

“…Chronic treatment with MOMAST ® GR25 fully prevented the development of mechanical hyperalgesia and spontaneous pain at both 7 and 14 days. Interestingly, the repeated administration of MOMAST ® GR25 did not induce tolerance to the anti-nociceptive effects, in contrast to other drugs, such as morphine, that shows tolerance to the analgesic effects both in naïve [ 50 , 51 ] and in MIA-treated animals [ 52 ], which represents one of the most important side effects for the use of opioids in chronic persistent pain [ 53 ]. Furthermore, MOMAST ® GR25 did not significantly modify the pain threshold of the contralateral (control) paw, thus excluding central analgesic properties and highlighting a pure anti-hypersensitive profile.…”