title: Attenuation of Neuropathic Pain by Inhibiting Electrical Synapses in the Anterior Cingulate Cortex.
abstract: BACKGROUND
  Synaptic mechanisms and neuronal oscillations have been proposed to be responsible for neuropathic pain formation. Many studies have also highlighted the important role of electrical synapses in synaptic plasticity and in neuronal oscillations. Thus, electrical synapses may contribute to neuropathic pain generation. However, previous studies have primarily focused on the role of chemical synapses, while ignoring the role of electrical synapses, in neuropathic pain generation.
  
  
  METHODS
  The authors adopted microinjection, RNA interference techniques, and behavioral tests to verify the link between connexin 36 (Cx36) and neuropathic pain. They also studied the selective Cx36 blocker mefloquine in rat chronic constriction injury and spared nerve injury model of neuropathic pain. Electrophysiologic recordings were used to further confirm the behavioral data.
  
  
  RESULTS
  The authors found that Cx36, which constitutes the neuron-neuron electrical synapses, was up-regulated in the anterior cingulate cortex after nerve injury (n = 5). Meanwhile, Cx36-mediated neuronal oscillations in the gamma frequency range (30 to 80 Hz) (n = 7 to 8) and the neuronal synaptic transmission (n = 13 to 19) were also enhanced. Neuropathic pain was 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 pain relief in chronic constriction injury and spared nerve injury models (n = 7 to 12).
  
  
  CONCLUSIONS
  The electrical synapses blocker mefloquine could affect gamma oscillations and synaptic plasticity in the anterior cingulate cortex and relieve neuropathic pain. Cx36 may be a new therapeutic target for treating chronic pain.
authors.affiliation: From the Department of Anesthesiology and Intensive Care Medicine, Xinhua Hospital, College of Medicine, Shanghai Jiaotong University, Shanghai, China (Z.-Y.C., F.-Y.S., L.J., X.Z., X.-L.S., Y.-W.W.); and Laboratory of Neural Circuit Plasticity & Memory, Institute of Brain Functional Genomics, East China Normal University, Shanghai, China (W.Z., S.L., Z.-R.W.).
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Chen
authors.forename: Feng-Yan
authors.initials: FY
authors.lastname: Shen
authors.forename: Lai
authors.initials: L
authors.lastname: Jiang
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhao
authors.forename: Xiao-Lu
authors.initials: XL
authors.lastname: Shen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.forename: Zhi-Ru
authors.initials: ZR
authors.lastname: Wang
authors.forename: Ying-Wei
authors.initials: YW
authors.lastname: Wang
mesh_terms: D000818:Animals; D017630:Connexins / Q000187:drug effects; D004195:Disease Models, Animal; D054351:Electrical Synapses / Q000187:drug effects*; D006179:Gyrus Cinguli / Q000187:drug effects* / Q000503:physiopathology; D015767:Mefloquine / Q000494:pharmacology*; D009437:Neuralgia / Q000517:prevention & control*; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects; D000097004:Gap Junction delta-2 Protein
chemical_list: D017630:Connexins; D015767:Mefloquine; D000097004:Gap Junction delta-2 Protein