| Remifentanil,as a classic opioid analgesic drug,has been widely used in clinical anesthesia due to its advantages,such as rapid onset,short duration,quick elimination and metabolism independent of liver and kidney function.With the widespread use of remifentanil,remifentanil-induced hyperalgesia(RIH)has gradually been paid attention to and emphasized.Because acute postoperative pain which is not effectively controlled can develop into chronic pain and affect the long-term outcome of patients,it has the key significance of research to explore the mechanism of RIH.The thalamocortical circuit plays a key role in pain encoding and perception.Thalamus are convergent points of pain signals,and different subnuclei of the thalamus may have specific pain encoding.The thalamic ventral posterolateral nucleus(VPL)is the relay of pain signals,while the primary somatosensory cortex serves as one of the higher-order relays for pain perception.These two brain regions may participate in RIH.Because female mice are intrinsically more variable than male mice,so adult male mice were chosen as experimental subjects in this study.In vivo and in vitro electrophysiological recording,immunofluorescence staining,two-photon calcium imaging,optical fiber recording,photogenetic and chemogenetic treatments were used to explore the mechanism of the thalamocortical circuit in RIH.Based on the mouse model of left(ipsilateral)plantar incision,we found that infusion of remifentanil via the tail vein induced a significant decrease in postoperative mechanical threshold of the non-surgical(right,i.e.,contralateral)plantar in RIH mice.However,remifentanil did not change the pain threshold of normal mice,suggesting that the remifentanil induced secondary pain sensitization was the result of the combination of remifentanil and surgical incision.Immunofluorescence staining and in vivo optical fiber recording showed that the expression of immediate early gene(c-Fos)protein and neuronal calcium activity of ipsilateral VPLGlu(glutamatergic neurons in VPL)neurons of RIH mice were significantly increased,while in vivo multi-channel electrode and in vitro electrophysiological recording exhibited that the frequency of burst firing of ipsilateral VPLGlu neurons of RIH mice was significantly increased.In addition,in vitro electrophysiological recordings of VPL slices showed that yellow light pulse stimulation(589 nm,1 Hz,100 ms)evoked burst firing in VPLGlu neurons expressing the light-sensitive channel protein eNpHR3.0 in normal mouse and induced a lower pain threshold in the hindlimb.These results suggest that the enhanced burst firing of VPLGlu neurons may participate in RIH.The cortex receives the nociceptive information ascending from the thalamus and perceives pain.We found that VPLGlu neurons projected to S1HLGlu(glutamatergic neurons in the hindlimb primary somatosensory cortex)neurons,and identified functional monosynaptic excitatory glutamatergic projections in the VPLGlu→S1HLGlu pathway.Moreover,yellow light stimulation of VPLGlu neurons in mice expressing eNpHR3.0 significantly elevated S1HLGlu neuronal activity.C-Fos immunofluorescence staining and electrophysiological records showed the increased neuronal activity in ipsilateral S1HLGlu neurons of RIH mice.Pharmacological or chemogenetic inhibition of the VPLGlu→S1HLGlu pathway in RIH mice reversed the enhanced activity of S1HLGlu neurons and significantly improved mechanical threshold.These results suggest that remifentanil induces the overexcitation of burst firing in VPLGlu neurons,enhances the activity of S1HLGlu neurons and produces pain sensitization.The subtype 3.1(Cav3.1)ion channel of T-type calcium channel is one of the important ion channels mediating the burst firing of VPLGlu neurons,further studies showed that the expression of Cav3.1 channel and T-type calcium current density were significantly increased in the ipsilateral VPL of RIH mice.Moreover,pharmacological blocking of T-type calcium channel using a nonspecific blocker mibefradil or virusspecifically knockdown of Cav3.1 channel expression could significantly reverse the increase in burst firing of VPLGlu neurons and S1HLGlu neurons induced by remifentanil and alleviate hypersensitivity in the non-surgical hindpaws of RIH mice.These results suggest that the up-regulation of Cav3.1 channel induced by remifentanil mediates the overexcitation of VPLGlu→S1HLGlu pathway,thereby inducing RIH.In conclusion,this study demonstrates that intraoperative administration of remifentanil induces the overexcitation of burst firing in VPLGlu neurons caused by upregulation of Cav3.1 channels,results in the increased activity of VPLGlu→S1HLGlu pathway,leads to the increased excitability of S1HLGlu neurons,and eventually produces pain sensitization.Our findings not only provide a novel sight for pain,but also provides a novel idea for the prevention of postoperative hyperalgesia. |
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