Analgesic Effect And Mechanisms Of ZL006

Pain is an extremely unpleasant feeling in human sensory system.It not only interferes with people’s daily lives,life interest,intepersonal relationships,but also reduces the standard of living,loses the labor force,and even causes disability.From economical point of view,chronic pain can decline the production efficiency;increase the medical care costs and workers’ compensation.At present,major pharmaceutical companies and medical research institutions are trying to do some research on the complex mechanisms of signal transduction of pain,such as damage of peripheral nervous system,central and peripheral hypersensitivity in painful states,balance between upstream activate signaling pathways and downstream inhibitory signaling pathways,as well as protein expression and other aspects.Pain research involves a lot of basic knowledge.It is a major challenge for basic and clinical researchers.Acute pain is an instinct precaution that protects us from external injuries;however,chronic pain differs from acute pain,not just in its onset and duration.More importantly,chronic pain doesn’t show persistent injury or inflammation.Among the available analgesic drugs,the effect of conventional non-steroidal antipyretic analgesic anti-inflammatory drugs(NSAIDs)and opioids is not ideal.So scientists are attempt to find the mechanisms of chronic pain,one of the mechanisms is that activation of NMDA receptors via glutamate is one of the most significant changes in the role of central sensitization in chronic pain.NMDA receptor,once can be regarded as the most potential target for the development of novel analgesic drugs,which can cause severe side effects,such as motor ataxia,learning and memory loss and etc.,largely because NMDA receptors are widely distributed in nervous system,and mediating varieties of physiological function.To-avoid the side effects of directly blocking NMDA receptors,scientists begin to focus on the downstream of NMDA receptors.When NMDA receptors are activated,there will be a lot of calcium influx,and binding with calmodulin(CaM),thus,activating downstream effect molecules including generating large amount of nitric oxide synthesized by neuronal nitric oxide(nNOS).Many articles have shown that over production of NO contributes to allodynia and hyperalgesia effect.Intrathecal injection of NMDA induced acute thermal hyperalgesia can be blocked by non-selective nitric oxide inhibitor L-NAME.Selective nNOS inhibitor 7-NI can reverse hyperalgesia caused by intrathecal injection of NMDA,CCI,and SNL model.PSD95 contains a PDZ domain which can bind with nNOS,which activate NOS to produce large amounts of toxic NO.Some articles demonstrate that mutant PSD95 mice can’t associate with NMDA receptor,thereby can not mediate pain hypersensitivity.It is known to all that PSD95 plays a key role in mediating NMDA-PSD95 pathway.In this paper,we try to explore whether novel nNOS-PSD95 uncoupling small molecular compound ZL006 can produce analgesic effect.To explore the analgesic effect of ZL006 and its mechanisms,we try to do some experiments as follows:Part 1:To examine whether ZL006 can cause analgesic effect induced by NMDA.Intrathecal injection of MK-801,7-NI and ZL006 on the NMDA-induced hyperalgesia models and detect the biting,scratching,and licking time changes in 15 minutes,also observe the latency time changes in tail flicking test.Part 2:To explore whether ZL006 can take effect through oral or intrathecal administration of ZL006 on the spinal nerve ligation-induced neuropathic pain and CFA-induced inflammatory pain models,detect which route can take effect via up-and-down method in 24 hours.In addition,visceral pain was induced by intraperitoneal injection of acetic acid,and detect whether ZL006 can attenuate the writhing response induced by acid stimulation.Conclusion:ZL006 can produce analgesic effect on neuropathic,inflammatory and visceral pain,its mechanisms are closely associated with uncoupling of PSD95-nNOS.