The Interaction Of Uncoupling PSD95/nNOS And GABAR Agonist In Central Sensitization Of Chronic Pain

The word ’pain’ and its synonyms commonly refer to conscious experiences associated with bodily injury or disease,but are also used to describe discomfort related to other unpleasant feelings.The ability to detect noxious stimuli(acute pain)is essential to an organism’s survival and wellbeing.More commonly,alterations of the pain pathway lead to hypersensitivity,such that pain outlives its usefulness as an acute warning system and instead becomes chronic pain.There are two types of chronic pain:inflammatory nociceptive pain and neuropathic pain.Neuropathic pain is a major public health problem,with epidemiological studies reporting about one fifth of the general population to be affected both in the USA and Europe.The condition is debilitating and causes not only considerable personal suffering but also enormous socioeconomic costs.In addition to these bleak statistics,pharmacological management of chronic pain conditions has seen only limited progress in the last decades.Opioids and nonsteroidal anti-inflammatory drugs(NSAIDs)are the primary drugs of choice for pain treatment.However,the many and often severe adverse effects related to opioid and NSAID use preclude adequate dosing and effective pain control in a large population of pain sufferers,which also serves as the main driving force in the development of alternative analgesics.To find better treatments,neuroscientists have focused on specific molecules involved in mediating chronic pain.Sensitization of the pain signaling system is a key process in chronic pain states.Such sensitization,and also tonic activation,can be induced by mediators generated and released at different levels of the neuroaxis.Central sensitization refers to the process through which a state of hyperexcitability is established in the central nervous system,leading to enhanced processing of nociceptive(pain)messages.Although numerous mechanisms have been implicated in central sensitization,recently researches focus on three:alteration in glutamatergic neurotransmission/NMDA receptor-mediated hypersensitivity,loss of tonic inhibitory controls(disinhibition),and glial-neuronal interactions.The hypothetic antinociceptive effect of ZL006 combined with(+)-Borneol targeted two signal pathways in central sensitization will be synergistic or antergic.In part one;we assessed the synergistic effect of ZL006 with(+)-Borneol in SNL model.Intrathecal administrating of ZL006 significantly inhibited mechanical allodynia and thermal pain induced by nerve SNL or CFA.There was no effect on nociceptive behaviours measured in the same animals by intragastric administration.The same antihyperalgesic effect of(+)-Borneol by intrathecal administrating was demonstrated in SNL model and CFA model cause we found(+)-Borneol have a highly efficacious positive modulating action at GABA receptors on neuron of rat’s hippocampus.ZL006 combined with(+)-Borneol shows synergistic effect on SNL induced neuropathic pain.In part two,ZL006-05 is designed base on ZL006,which has been proved to block the ischemia-induced nNOS-PSD-95 association selectively,and esterifies with(+)-2-borneol.The pharmacokinetic data of ZL006-05 by intragastric administration shows the stable metabolite of itself or glucuronic acid combination.We assessed whether the compound ZL006-05 is antihyperalgesic in the SNL model of neuropathic pain.Intragastric administration of ZL006-05 not only significantly inhibited mechanical allodynia but also thermal pain induced by nerve SNL on days 7.ZL006-05 dose-dependently inhibited hyperalgesia in SNL model.The same antihyperalgesic effect of ZL006-05 is demonstrated in CFA model of inflammatory pain and vincristine-induced mechanical pain.ZL006-05 also significantly inhibited the writhing times on acetic acid writhing reaction.Compared with Pregabalin,ZL006-05 is devoid of sedation and motor impairment,and showed no loss of analgesic activity during a 28-day treatment period(i.e.no tolerance development).In part three,we assessed the hypothetic target of ZL006-05 in two signal pathways.Coimmunoprecipitation of PSD-95 with nNOS shows intragastric administration of ZL006-05 significantly blocked the SNL-induced nNOS-PSD-95 association in the L5 spinal cord.ZL006-05 has a highly efficacious positive modulating action at GABA receptors on neuron of rat’s hippocampus.Thus ZL006-05 alleviated SNL-induced neuropathic pain on nNOS knock out mice.Both effects demonstrate the mechanism of ZL006-05.In conclusion,ZL006-05 is antihyperalgesic in models of inflammatory and neuropathic pain of rodents.The effect is dose dependent.ZL006-05 is devoid of sedation and motor impairment,and showed no tolerance development.Thus,this new drug may serve as a treatment for chronic pain,perhaps without side effects.