Investigation Of Pathogenesis Of Neuropathic Pain Due To That Change Of The Electrical Synapses Function In The Anterior Cingulate Cortex

Objectives: Neuropathic pain seriously affects the quality of life of patients.Conventional painkillers such as opioids and nsaids were not effective.Even with the latest neuropathic pain-specific indications,only some patients have pain relief.The cause of neuropathic pain is not fully understood.Synaptic plasticity is believed to be one of the important factors in the formation of neuropathic pain.Many studies have also highlighted the important role of electrical synapses in synaptic plasticity and neuronal oscillations.Thus,electrical synapses may contribute to the production of neuropathic pain.However,previous studies have focused on the role of chemical synapses and neglected the role of electrical synapses in the production of neuropathic pain.Methods:In this study,we constructed a model of chronic constriction injury of the sciatic nerve and a model ofspared nerve injury,and used microinjection,RNA interference technology and behavioral test to verify whether connexion 36(Cx36)is involved in the formation of neuropathic pain.Furthermore,the effect of Cx36 selective blocker mefloquine on neuropathic pain was further studied.Behavioral results were validated by in vivo and in vitro electrophysiological recording of synaptic plasticity to explore the relevant mechanisms of electrical synapses involved in neuropathic pain.Results:The authors found that Cx36,which constitutes the neuron–neuron electrical synapses,was up-regulated in theanterior cingulate cortex after nerve injury.Meanwhile,Cx36-mediated neuronal oscillations in the Gamma frequencyrange(30 to 80 Hz)and the neuronal synaptic transmission were also enhanced.Neuropathic painwas relieved by disrupting Cx36 function or expression in the anterior cingulate cortex.They also found that mefloquine,which are clinically used for treating malaria,affected Gamma oscillations and synaptic plasticity,leading to a sustained painrelief in chronic constriction injury and spared nerve injury models.Conclusions: The electrical synapses blocker mefloquine could affect Gamma oscillations and synaptic plasticity in theanterior cingulate cortex and relieve neuropathic pain.Cx36 may be a new therapeutic target for treating chronic pain.