Pharmacological Preliminary Study Of Alleviating Of Neuropathic Pain By (-)-Mefloquine

Neuropathic pain, which affects approximately 3% of populations, is a devastating pain syndrome caused by various insults to the nervous system, resulting in chronic spontaneous pain, hyperalgesia and allodynia. No effective pharmacological treatment for neuropathic pain is currently available. More than two-thirds of neuropathic pain patients suffer from insufficient pain relief. This is partially due to the fact that the underlying mechanisms of neuropathic pain development remain poorly understood.Although many studies have confirmed that chemical synapses are crucial for the formation of neuropathic pain, little is known about the role of electrical synapses in the pathogenesis of neuropathic pain. Previous studies have reported that the function of electrical synapses is associated with synaptic plasticity. Synaptic plasticity is key mechanism for the formation of neuropathic pain. We discovered that connexin 36 (Cx36), which constituted the neuron-neuron electrical synapses, showed an upregulation in the anterior cingulate cortex (ACC) after nerve injury. We found that damaging the function of specific electrical synapses in ACC or reducing the expression of electrical synapses are able to relieve neuropathic pain. As a selective gap junction blocker, whether mefloquine can relieve neuropathic pain come to attention. Mefloquine is usually used clinically as a racemic mixture of erythro isomers. Mefloquine is composed of two isomers, (+)-(11S,12R)-Meflo and (-)-11(R, 12S)-Meflo.In present study, we explored the role of different doses of mefloquine, (-)-mefloquine and (+)-mefloquine for alleviating neuropathic pain through the neuropathic pain model of chronic constriction injury (CCI). At the same time, we conducted a preliminary study of the toxicity, pharmacokinetics and molecule mechanism of (-)-mefloquine which plays a significant role in relieving neuropathic pain. (-)-(11R,12S)-mefloquine may be a potential new drug for neuropathic pain.1 Efficacy of mefloquine, (-)-mefloquine and (+)-mefloquine alleviating neuropathic painWe explored the analgesic effect of mefloquine using a neuropathic pain model. After CCI, rats were randomized in to a solvent group, mefloquine group(10mg/kg, 20mg/kg,30mg/kg), (-)-mefloquine group (7.5mg/kg, 10mg/kg,15mg/kg) and (+)-mefloquine group (10mg/kg,15mg/kg). After intraperitoneal injection of solvent or mefloquine, we continuous injected for five days.In the postoperative 7,14 and 21, we tested the mechanical allodynia and thermal hyperalgesia.The results showed that, compared to the vehicle group, mefloquine with 20mg/kg and 30mg/kg had significant difference in mechanical allodynia and thermal hyperalgesia, while 10mg/kg mefloquine had no apparent effect, (-)-mefloquine had apparent effect on mechanical allodynia and thermal hyperalgesia. The (+)-mefloquine only had effect on the themal hyperalgesia and had no effect on the mechanical allodynia.2 The preliminary toxicity study of (-)-mefloquine(-)-mefloquine had effective role on relief neuropathic pain in SD rats with CCI. And as a potential new drug for alleviating neuropathic pain, the toxicity study is also important. Therefore, we studied the the acute toxicity of (-)-mefloquine and effect of (-)-mefloquine on food intake, body weight, level of activity, biochemical parameters and pain perception in the effective concentration. In acute toxicity, LD50 value of this drug was 55mg/kg. The results showed that (-)-mefloquine in effective concentration had no significant effect on food intake, body weight, level of activity and pain perception. Some biochemical parameters had changes in the group of (-)-mefloquine.3 The preliminary pharmacokinetics study of (-)-mefloquineApplication of high performance liquid chromatography method, we studied the pharmacokinetics of intraperitoneal injection of 15mg/kg (-)-mefloquine. The results showed, after injection, AUC (0-∞> was 186.3±6.2 mg-min/L, ti/2 was 654.1±22.6min, MRT was 211.9±1.8min, Vd was 30.6±1.1L/kg, tmax was 5min, Cmax was 0.71±0.03mg/L, CL was 0.032±0.002mL/min/kg o Intraperitoneal injection of (-)-mefloquine had a rapid absorption, a long half-life and extensive tissue distribution.4 The effect of (-)-mefloquine on molecular which is induced activation by CCI in ACCIn order to further explore the role of (-)-mefloquine in alleviating neuropathic pain, we investigated the effect of (-)-mefloquine on changes in protein level induced by CCI surgery. Rats were divided into three groups, including sham group, CCI group and (-)-mefloquine group. After surgery, rats were injected with 15mg/kg of solvents and (-)-mefloquine in group of CCI and (-)-mefloquine respectively. Rats in sham group were only separated from the sciatic nerve without ligation. Sham group were injected solvent. In postoperative 7 day, we extracted protein from cingulated cortex area of the brain and conducted western blotting. The results showed that CCI-induced activation of p-GluR1 in the ACC was suppressed by i.p. administration of (-)-mefloquine,. CCI-induced activation of p-Erk1/2 in the ACC had a downward trend in the group of (-)-mefloquine.