Lateral septum GABAergic neurons mediate the effects of dexmedetomidine on allodynia and sleep in a male mouse model of neuropathic pain.

Chronic pain and sleep disorders frequently co-occur and exacerbate each other, yet the neural mechanisms underlying this comorbidity remain poorly understood. Here, we found that hyperactivity of GABAergic neurons in the dorsal division of the lateral septum (LSGABA) drives both pain-like behavior and sleep disruption induced by spared nerve injury (SNI) in male mice. We showed that systemic or local application of dexmedetomidine (DEX), with known sedative and analgesic properties, reduces LSGABA hyperactivity via α2A adrenergic receptor activation, alleviating pain-like behavior and sleep disruption. LSGABA can project onto the glutamatergic and GABAergic neurons in the lateral preoptic area (LPO), respectively. The LSGABA→LPOGlu circuit and the LSGABA → LPOGABA circuit contribute to mechanical allodynia and sleep disruption, respectively. Furthermore, LS α2A adrenergic receptor plays an important role in DEX-regulated activity of LPOGABA and LPOGlu. Taken together, these findings reveal a shared neural substrate for chronic pain and sleep disorders and establish DEX as a potential treatment for this comorbidity through selective modulation of LSGABA-driven circuits.