Acute nociceptive stimulation induces long-lasting constitutive activity of spinal μ-opioid receptors that masks pain sensitization.

Authors

Ryota Kano, Kazuya Momokino, Takuya Yamane, Sho Muneta, George R Uhl, Ichiro Sora, Kazutaka Ikeda, Yuta Kohro, Makoto Tsuda

Published in

Biochemical pharmacology. Pages 118596. Nov 05, 2026. Epub Nov 05, 2026.

Abstract

Acute nociceptive stimuli evoke transient pain sensitization that normally resolves after the stimulus has ceased. However, whether this apparent recovery reflects restoration of the nociceptive system to its basal state or active suppression of persistent sensitization remains unclear. Here, we show that mechanical hypersensitivity induced by acute chemical or electrical stimulation of primary afferent C-fibers was transient in wild-type mice but persisted for 1-2 weeks in mice lacking spinal μ-opioid receptors (MORs). Furthermore, intrathecal pretreatment with naloxone, naltrexone, or CTOP, all of which act as MOR inverse agonists, prevented recovery from C-fiber-induced mechanical hypersensitivity, whereas the neutral antagonist 6β-naltrexol had no effect. The naltrexone-induced reinstatement of mechanical hypersensitivity was prevented by 6β-naltrexol, consistent with induction of constitutively active spinal MORs. C-fiber stimulation also increased phosphorylation of spinal MORs, a biochemical marker of receptor activation, and this increase was abolished by naltrexone but not by 6β-naltrexol. Although mice had fully recovered behaviorally by 3, 6, and 24 hr after C-fiber stimulation, pharmacological inhibition of constitutively active MORs at each time-point consistently reinstated mechanical hypersensitivity. Together, these findings support a model in which acute nociceptive stimulation induces two parallel forms of long-term spinal plasticity: persistent pain sensitization and constitutive activation of MORs, the latter continuously masking the former to maintain an apparently resolved pain state. Our findings reveal a previously unrecognized homeostatic mechanism underlying pain resolution after acute nociceptive stimulation, and the C-fiber-mediated mechanisms for inducing MOR constitutive activity may provide a clue to develop a therapeutic strategy for sustained analgesia.

PMID:
42988337
Bibliographic data and abstract were imported from PubMed on 06 Nov 2026.

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