Enhanced substance P-NK1R signaling in the parabrachial–parasubthalamic pathway promotes hyperalgesia and affective aversion in neuropathic pain

Chronic neuropathic pain is sustained by nerve injury-induced central sensitization and is characterized by both sensory and affective manifestations. However, its underlying neural circuit mechanisms remain to be fully elucidated. Here, we revealed that CaMKII-expressing neurons in the parasubthalamic nucleus (PSTN) were recruited and exhibited hyperactivity in a neuropathic pain mouse model, established via spared nerve injury of the sciatic nerve (SNI). Optogenetic and chemogenetic inhibition of PSTN CaMKII neurons alleviated hyperalgesia and induced conditioned place preference (CPP) in SNI mice, without altering pain thresholds in sham mice. Mechanistically, we demonstrated that PSTN neurons received monosynaptic glutamatergic inputs from tachykinin precursor 1 (Tac1)-expressing neurons in the lateral parabrachial nucleus (LPB), and were excited by glutamate and substance P (SP) co-released from this projection. Inhibition of the LPB–PSTN projection recapitulated the analgesic and CPP-inducing effects of direct inhibition of PSTN neurons in SNI mice. Notably, these therapeutic effects were mimicked by local administration of a neurokinin receptor 1 (NK1R) antagonist, but were reversed by intra-PSTN injection of SP. Together, this study not only establishes the involvement of the LPB–PSTN circuit and local NK1R in the pathophysiology of neuropathic pain but also demonstrates their promise as therapeutic targets.