A New Use Of An Anti-malaria Drug-mefloquine-in Preventing The Development Of Neuropathic Pain And The Underlying Mechanism

Neuropathic pain is a chronic disease that can be caused by nerve injury. A critical mechanism underlying this disorders is the long-term potentiation induced in the synaptic connections between neurons in anterior cingulate cortex (ACC). Blocking the induction of this synaptic potentiation immediately after nerve injury (e.g., with the use of blockers of NMD A receptors or cAMP) has been indicated to be capable of preventing the development of neuropathic pain. However, all these treatments rely on the use of toxic drugs, which are not suitable for clinical use. Seeking for a drug with mild side-effect to block the synaptic potentiation in ACC neurons appears to be a critical task for treating neuropathic pain. We noted a clinically used anti-malaria drug-mefloquine (Meflo), which has been found to be a selective blocker of connexin 36(Cx36). In addition, previous studies have demonstrated that electric synapses make significant contribution to the excitation and synchrony of neural networks, the events that are critical for the induction of neuronal plasticity. Thus, applying Meflo initially after nerve surgery could have the effect to block the ACC plasticity associated with the development of neuropathic pain.We found that administered Meflo or general gap junction blocker Carbenoxolone (Cbx) intraperitoneally (i.p.) immediately after never injury induced by chronic constrictive nerve injury (CCI) or spared nerve injury (SNI) could have persistent attenuation of thermal hyperalgesia and mechanical allodynia, an effect can that could last for the whole period (> 1 month) of our experiments. In addition, microinjection of Meflo or Cbx in the ACC exhibited an effect similar to (i.p.) administration. Down-regulation of the expression of Cx36 by local RNAi technique in ACC was also found to be able to prevent the development of neuropathic pain. We found that the mefloquine could effectively prevent the development of neuropathic pain by blocking electrical synapses. Our research may provide a new therapeutic strategy of preventing the development of this disease.