Remifentanil is widely used to control intraoperative pain.However,its analgesic effect is limited by the generation of postoperative hyperalgesia.In this study,we investigated whether the impairment of trans-membrane protein 16C(TMEM16C)/Slack is required for a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic recep-tor(AMPAR)activation in remifentanil-induced postoper-ative hyperalgesia.Remifentanil anesthesia reduced the paw withdrawal threshold from 2 h to 48 h postoperatively,with a decrease in the expression of TMEM16C and Slack in the dorsal root ganglia(DRG)and spinal cord.Knockdown of TMEM16C in the DRG reduced the expression of Slack and elevated the basal peripheral sensitivity and AMPAR expression and function.Overex-pression of TMEM16C in the DRG impaired remifentanil-induced ERK1/2 phosphorylation and behavioral hyperal-gesia.AMPAR-mediated current and neuronal excitability were downregulated by TMEM16C overexpression in the spinal cord.Taken together,these findings suggest that TMEM16C/Slack regulation of excitatory synaptic plas-ticity via GluAl-containing AMPARs is critical in the pathogenesis of remifentanil-induced postoperative hyper-algesia in rats.