Thalamocortical circuits drive remifentanil-induced postoperative hyperalgesia

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(v)3.1 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(v)3.1-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.