{"doi":"10.1101/2025.08.16.670663","title":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558816,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":235360,"name":"Yann S. Mineur","orcid":"0000-0002-8030-6776","position":1,"is_corresponding":false},{"id":225139,"name":"Chia‐Hui Chen","orcid":"0000-0001-9927-6215","position":2,"is_corresponding":false},{"id":863186,"name":"Wen‐Liang Zhou","orcid":"0000-0001-7792-1201","position":3,"is_corresponding":false},{"id":1460051,"name":"Julian Lee Thompsom","orcid":null,"position":4,"is_corresponding":false},{"id":1459620,"name":"Saagar S Motupally","orcid":"0000-0001-7584-4927","position":5,"is_corresponding":false},{"id":931819,"name":"Angélica Minier-Toribio","orcid":"0000-0002-8860-5973","position":6,"is_corresponding":false},{"id":235365,"name":"Marina R. Picciotto","orcid":"0000-0002-4404-1280","position":7,"is_corresponding":false},{"id":1459619,"name":"Rafael E. Perez","orcid":"0000-0001-7788-4631","position":0,"is_corresponding":true}],"reference_count":23,"raw_metadata":null,"created_at":"2026-07-19T02:55:30.312295Z","pmid":"40894796","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}