Mechanical allodynia and affective behavior are improved by INI-0602,a gap junction hemichannel inhibitor,in a rat model of neuropathic pain induced by sciatic nerve injury

OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sciatic nerve injury（SNI）or sham surgery.Rat received daily treatment with INI-0602 intrathecally,at a dose of 0.25μg/10μL.The response frequency to mechanical allodynia in animals was measured with von Frey hairs on day 1,3,5,7,14,21.Rats were evaluated in the forced swimming test（FST）test,tail suspension test（TST）,sucrose preference test（SPT）for depression-like behavior.We performed open field test（OFT）and elevated plus-maze test（EPM）to evaluate anxiety-associated behaviors.Besides,we investigated the alterations of NMDA receptor and the brain-derived neurotrophic factor（BDNF）and also the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.RESULTS The SNI procedure produced mechanical allodynia and accompanied with depressive-like and anxiety-like behavior.Treatment with INI-0602 produced a significant analgesic effect in SNI rats at day 7（model+NS:11.017±1.506 g;model+INI-0602:31.157±1.532 g,P＜0.01）,and still obviously on the 21th day（31.067±1.787,P＜0.01）.INI-0602 could also improve the performance of sciatic nerve injury rats among program behavior tests related to depression and anxiety.In parallel with relief of pain,the alterations of NMDA receptor and the brain-derived neurotrophic factor（BDNF）,involved in central sensitization and synaptic plasticity,were investigated.INI-0602 not only could inhibited spared nerve injury induced up-regulated of NR2B and phosphorylation NR2B in early and late neuropathic pain（early phase:Nr2b:2.897±0.228,P＜0.01;p-Nr2b:2.984±0.236,P＜0.01;late phase:Nr2b:2.594±0.187,P＜0.01;p-Nr2b:3.124±0.330,P＜0.01）,but also could inhibit the increased of BDNF in the early（model+NS:3.637±0.381,model+INI-0602:1.148±0.372,P＜0.01）and upregulate the BDNF in late stage（model+NS:0.438±0.103,model+INI-0602:1.222±0.092,P＜0.01）.Meanwhile,INI-0602 significantly decreased the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.CONCLUSION INI-0602 blocked behavioral changes induced by neuropathic pain,suggesting that it might be a promising pharmacological approach of painemotion diseases.