The subthalamic nucleus-ventral pallidum projection targeting cholinergic circuits modulates chronic pain

The cholinergic system shows promise for pain management. Although cholinergic neurons in the ventral pallidum (VP) are involved in neuropathic pain, the anatomical organization and pharmacology of the cholinergic circuit contributing to the processing of acute and chronic pain remain unknown. In the present study, we demonstrate that VP cholinergic neurons in mice received pain signals from and mediated pain modulation by glutamatergic (Glu) neurons in the subthalamic nucleus (STN) in both physiological and neuropathic pain conditions. VP cholinergic neurons were a major source of acetylcholine released in the VP upon pain stimulation, and α4 and α7 were major subunits comprising functional nicotinic acetylcholine receptors (nAChRs) in VP cholinergic, GABAergic, and Glu neurons. In neuropathic pain mouse models, VP cholinergic neurons became hyperactive and released more acetylcholine in the VP, and α4 and α7 nAChRs were differentially modified on VP GABAergic and Glu neurons. These modifications were accompanied by hyperexcitability in VP GABAergic neurons and hypoactivity in VP Glu neurons. Reversal of upregulated α4 nAChRs on VP GABAergic neurons, but not that of downregulated α4 and α7 nAChRs on VP Glu neurons, attenuated the severity of hyperalgesia in neuropathic pain. Therefore, the STNGlu-VPChAT pathway is implicated in neuropathic pain by enhancing VP cholinergic circuits, and α4 nAChRs on VP GABAergic neurons may be potential therapeutic targets for the treatment of neuropathic pain.