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 (dCA1^Glu) to anterior cingulate cortex glutamatergic neurons (ACC^Glu) 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 dCA1^Glu → ACC^Glu neuronal pathway participates in driving EW-induced hyperalgesia before ethanol dependence in mice.