Remifentanil-induced hyperalgesia (RIH) is a severe but common postoperative clinical problem with elusive underlying neural mechanisms. Here, we discovered that glutamatergic neurons in the thalamic ventral posterolateral nucleus (VPL^Glu) exhibited significantly elevated burst firing accompanied by upregulation of Ca_v3.1 T-type calcium channel expression and function in RIH model mice. In addition, we identified a glutamatergic neuronal thalamocortical circuit in the VPL projecting to hindlimb primary somatosensory cortex glutamatergic neurons (S1HL^Glu) that mediated RIH. In vivo calcium imaging and multi-tetrode recordings revealed heightened S1HL^Glu neuronal activity during RIH. Moreover, preoperative suppression of Ca_v3.1-dependent burst firing in VPL^Glu neurons or chemogenetic inhibition of VPL^Glu neuronal terminals in the S1HL abolished the increased S1HL^Glu neuronal excitability while alleviating RIH. Our findings suggest that remifentanil induces postoperative hyperalgesia by upregulating T-type calcium channel-dependent burst firing in VPL^Glu neurons to activate S1HL^Glu neurons, thus revealing an ion channel–mediated neural circuit basis for RIH that can guide analgesic development.

1. Propofol Hypersensitivity in Valvular Disease: Valvular heart disease (VD) patients exhibited 34% lower propofol CeLOC (2.8 vs. 4.25 µg/mL