A neural circuit for alcohol withdrawal-induced hyperalgesia in a nondependent state.

Alcohol use disorder is highly prevalent worldwide, with characteristically severe pain sensitivity during withdrawal. Here, we established a mouse model of hyperalgesia during ethanol withdrawal (EW) before addiction to investigate the window for onset and underlying mechanisms. Viral tracing with in vivo microendoscopic and two-photon calcium imaging identified a circuit pathway from dorsal hippocampal CA1 glutamatergic neurons (dCA1Glu) to anterior cingulate cortex glutamatergic neurons (ACCGlu) activated in EW mice with hyperalgesia. Chemogenetic inhibition of this pathway can alleviate hyperalgesia in EW mice, whereas artificial activation recapitulates EW-induced hyperalgesia in naïve mice. These findings demonstrate that the dCA1Glu → ACCGlu neuronal pathway participates in driving EW-induced hyperalgesia before ethanol dependence in mice.