Perez Rafael E, Mineur Yann S, Chen Cheryl, Zhou Wen-Liang, Thompson Julian L, Motupally Saagar S, Minier-Toribio Angélica, Picciotto Marina R
Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
bioRxiv. 2025 Aug 19:2025.08.16.670663. doi: 10.1101/2025.08.16.670663.
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.
尽管存在既定的细胞和分子适应性变化，但在未预期使用这些药物的情况下，阿片类镇痛耐受性可迅速逆转。协调这种基于预期的耐受性的特定神经元群体仍未明确界定。在本研究中，我们使用了情境耐受性训练方法，结合全脑透明化和免疫染色，以确定参与情境耐受性的脑区，并找出在此过程中被激活的前扣带回皮质（ACC）中的特定神经元集群。我们观察到，在未接触过阿片类药物的小鼠中，或在情境逆转期间，芬太尼会抑制ACC主要神经元的钙活性，但在情境耐受性期间则不会。对ACC进行化学遗传学沉默可在阿片类相关情境中诱导耐受性逆转，而不影响未使用阿片类药物小鼠的热痛觉。此外，对ACC情境耐受性激活的神经元集群进行化学遗传学激活会在无关情境中引发镇痛耐受性。这项研究突出了ACC神经元集群在介导预期驱动的情境性阿片类镇痛耐受性而不影响基础痛觉感受方面的作用。因此，调节ACC可能提供一种有前景的策略，既能改善疼痛缓解，又能维持检测有害刺激的基本能力。
