Studies On Pharmacodynamics Of α*-Conotoxin GeXIVA And TxIB

The cone snails capture prey and defense competitor by excreting ingerdient comples venom.Venom of various cone snails contains as many as 100,000 different pharmacological active compounds,conotoxins or conopeptide.The a-conotoxins are the first conotoxins discovered and represented one such family that characteristically targets nicotinic acetylcholine receptors(nAChRs).The nAChRs are ligand-gated cationic channels that mediate fast synaptic transmission within the peripheral and central nervous systems and highly conserved over a wide range of species,from insects to fishes through to humans.The nAChRs are involved in a number of diseases states,such as the αa9a10 nAChRs have been confirmed as important targets in chronic pain and cancer chemotherapy and α6*nAChRs play important roles in addiction and Parkinson’s disease.In this context,specific ligands of nAChRs subtypes such as conotoxins are important or effective in studying of the structure-activity on nAChRs,further studying of the mechanism of interaction between receptor and ligand and for developing potential drug leads.The present study was designed to determine the pain reliever effects of αO-conotoxin GeXIVA which is the potent antagonist of α9α10 nAChRs and the inhibit addiction effects of a-conotoxin TxIB which is selective for α6/α3β2β3 nAChRs.The pain reliever effects of GeXIVA isomers and analog are analyzed systematically by several pain models,such as physical pain models(hot plate test and tail flick test),chemical pain models(acetic acid writhing test),neuropathic pain models(chronic constriction injury model and sciatic nerve injury model).The results showed that the GeXIVA isomers and analog produced dose-dependently pain reliever effects in neuropathic pain models.Repeated i.m.injection of GeXIVA isomers for 7 or 14 days in CCI model,the pain reliever effect was very stable without tolerance.Especially,GeXIVA[1,2]has prolonged analgesic activity after cessation of treatment.In addition,GeXIVA isomers and analog had no effect on motor performance of rats in the accelerating rotarod test.This study investigated whether TxIB had an impact on morphine-induced conditioned place preference.The results showed that TxIB treatment affected the expression of morphine induced CPP.In summary,αO-conotoxin GeXIVA which has potent pain reliever activity and no tolerance,offer new strategies to the treatment of neuropathic pain by intramuscular administration.The a-conotoxin TxIB has the potential of candidate drugs for the new inhibitor of morphine dependence.