Contribution of thalamo-cortico-limbic circuits to remifentanil-induced hyperalgesia (RIH) and the analgesic effects of electroacupuncture on RIH

Remifentanil is an ultrashort-acting opioid receptor agonist that has the greatest advantage in clinical analgesia but often induces hyperalgesia. The underlying mechanisms of remifentanil-induced hyperalgesia (RIH) remain unclear. Here, we report that exposure of remifentanil to rats induces an elevation of spontaneous neuronal activity, innoxious and noxious stimuli-evoked neuronal hyperactivities, and enhanced theta band local field potential (LFP) oscillations across the ventral posterolateral nucleus of the thalamus (VPL), primary somatosensory cortex (S1), insular cortex (IC), and anterior cingulate cortex (ACC) brain regions. Either chemogenetic inhibition of glutamatergic neurons in the S1 cortex, or blockade of the S1→ACC projection by chemogenetic and optogenetic approaches, attenuates the remifentanil-induced mechanical and thermal hyperalgesia in RIH model rats. Besides, electroacupuncture (EA) intervention at 2-Hz frequency alleviates the animals’ mechanical and thermal hyperalgesia in remifentanil-treated rats. Also, 2 Hz-EA treatment inhibits the remifentanil-induced enhancement of spontaneous neuronal activity, the innoxious and noxious stimuli-evoked hyperactivities, and the increase of theta band LFP oscillations in the VPL, S1, IC, and ACC cortexes. These results indicate that the sensitized neuronal activity and the heightened theta band brain rhythmical oscillations in the VPL, S1, IC, and ACC cortexes contributes to the development of RIH, while 2 Hz-EA treatment exerts its analgesic effects on the RIH through inhibiting the aberrant neuronal activities of pain-related thalamo-cortico-limbic circuits including VPL, S1, IC, and ACC brain regions. Our findings identify a cortical circuit mechanism underlying the pathogenesis of RIH, and present potential therapeutic targets for the treatment of RIH by EA. Summary: Sensitized neuronal activity and elevated theta rhythms in pain-related thalamo-cortico-limbic circuits contributes to RIH and the analgesic effects of 2 Hz-EA treatment on RIH.