Coordinated activity of a central pathway drives associative opioid analgesic tolerance

• DOI: 10.1126/sciadv.abo5627
• Publication Date: 2023-02-08T18:57:26Z
• Authors: Yiwen Hou; Guichang Zou; Xianglian Wang; Hui Guo; Xiao Ma; Xingyu Cheng; Zhiyong Xie; Xin Zuo; Jing Xia; Huanhuan Mao; Man Yuan; Qi Chen; Peng Cao; Yupeng Yang; Li Zhang; Wei Xiong
• Keywords: Basolateral amygdala

Opioid analgesic tolerance, a root cause of opioid overdose and misuse, can develop through an associative learning. Despite intensive research, the locus central pathway subserving tolerance (AOAT) remains unclear. Using combination chemo/optogenetic manipulation with calcium imaging slice physiology, here we identify neuronal ensembles in hierarchically organized essential for AOAT. The association morphine-induced analgesia environmental condition drives glutamatergic signaling from ventral hippocampus (vHPC) to dorsomedial prefrontal cortex (dmPFC) cholecystokininergic (CCKergic) neurons. Excitation CCKergic neurons, which project release CCK basolateral amygdala (BLA) relays AOAT signal inhibition BLA μ-opioid receptor function, thereby leading further loss morphine efficacy. This work provides evidence circuit across different brain regions distinct tolerance. components this are potential targets treat abuse.