Analgesic Pharmacodynamics And Target Of Conotoxin Txd1

The genus Conus capture prey by excreting ingredient complex venom. Cone snails are generally divided into three groups according to their prey:vermivorous (worm-hunting) species, molluscivorous (snail-hunting) and piscivorous (fish-hunting) cone snails. Each of them contains-2000different peptides in the venom named conotoxin, conopeptide or CTx. The conotoxins consist of7-40amino acid residues and have construction of disulfide bonds with ric cysteine (Cys) residues. In terms of the signal sequences and patterns of disulfide linkages, conotoxins can be divided into some gene superfamily:O-, B-, M-, A-, S-, T-, P-, I-etc. The superfamily may be subdivided into several families with distinct pharmacological activities, for example A-superfamily (a-, aA-, aB-, κA-and p-conotoxins); M-superfamily (μ-and Ψ-conotoxins); O-superfamily (ω-, μO,δ-, and K-conotoxins); T-superfamily (τ-and x-conotoxins) and so on. Conotoxins selectively act on various kinds of receptors of neurotransmitters, ion channels and neurokinins. Due to their highly pharmacological potency and target selectivity, conotoxins are not only used as perfect drug design templates and probes for neurobiological research, but also are developded into drugs directly, and have good research value and application prospect.The main purpose of this research is to screen and evaluate new conotoxins with physiological and analgesic activities which were synthesized in our laboratory. Young mice and goldfish were used to screen various conopeptides with bioactivities based on their animal behaviour after these peptides’injections separately. Then the bioactive conotoxins were evaluated with several analgesic pharmacological tests. Among these conotoxins, there was a peptide a-conotoxin Txdl, which showed strong analgesic effect. Several animal pain models were established, such as hot plate test, tail flick test which are physiology pain models, and rat chronic constriction injury (CCI) model which is neuropathic pain model. Analgesic pharmacodynamics of a-conotoxin Txdl were investigated in these pain models systematicly. The target of Txdl was further confirmed to be α3β4nAChRs based on previous research groundwork in our lab. The results would provide a method and reference for screening analgesic candidate drugs or drug leads, and provide basis to develop new drugs for neurologic diseases.