An Anterior Cingulate Cortex Neuronal Ensemble Controls Contextual Opioid Analgesic Tolerance.

ABSTRACT: Despite well-established cellular and molecular adaptations, opioid analgesic tolerance can be rapidly reversed in settings where these drugs are not expected. The specific neuronal populations that orchestrate this expectation-based tolerance remain poorly defined. In this study, we used a contextual tolerance training method alongside whole-brain clearing and immunostaining to identify brain regions involved in contextual tolerance and to pinpoint a specific neuronal ensemble in the ACC activated by this process. We observed that calcium activity in principal neurons of the ACC is suppressed by fentanyl in opioid-naïve mice or during contextual reversal but not during contextual tolerance. Chemogenetic silencing of the ACC induced tolerance reversal in the opioid-associated context without affecting thermal nociception in opioid-free mice. Furthermore, chemogenetic activation of the ACC contextual tolerance-active neuronal ensemble triggered analgesic tolerance in an unassociated context. This research highlights a role for ACC neuronal ensembles in mediating expectation-driven, contextual opioid analgesic tolerance without affecting basal nociception. Therefore, modulating the ACC could provide a promising strategy to improve pain relief while maintaining the essential ability to detect harmful stimuli.

Significance statement

Opioids are first-line treatments for pain, but tolerance leads to decreased efficacy and escalated dosing, increasing opioid use disorder and overdose risk. Remarkably, after repeated administration, tolerance can be rapidly reversed when the drug is administered in a context where it is not expected. However, the neuronal mechanisms underlying tolerance based on contextual expectation are still not well understood. Here, we demonstrate that an anterior cingulate cortex neuronal ensemble is necessary and sufficient to orchestrate expectation-driven tolerance, suggesting that targeted inhibition of this ensemble could prevent tolerance and improve analgesic treatment.

SUBMITTER: Perez RE 

PROVIDER: S-EPMC12393370 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature