An Anterior Cingulate Cortex Neuronal Ensemble Controls Contextual Opioid Analgesic Tolerance

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.