反毒为药:精准控制河鲀毒素用作局部麻醉药的新进展

From Poison to Potion:New Progress in Precise Control of Tetrodotoxin as a Local Anesthetic

钠离子通道阻断剂河鲀毒素(TTX)是致命的毒素之一,却是极具价值的神经生物学和生理学等生命科学研究领域的工具药.近年来,越来越多的研究指出,TTX具有强大的局部麻醉潜能,有望成为替代氨基酯类和氨基酰胺类局部麻醉药、避免阿片类药物滥用的新型麻醉药物.本文综述TTX局部麻醉应用的辅助药物、TTX缓释及控释给药系统等相关研究,旨在为局部麻醉新药研发提供参考并探讨新的思路.

Tetrodotoxin(TTX),a highly specific voltage-gated sodium channel blocker,is a deadly toxin but a valuable tool for life science research such as neurobiology and physiology.It provides a long nerve blockade without cardiovascular toxicity and is unable to penetrate the blood-brain barrier,making it an attractive candidate for local anesthetics.At present,conventional amino amide and amino ester local anesthetics are the mainstay in clinical practices such as local anesthesia,postoperative analgesia and cancer pain treatment.However,conventional local anesthetics have a relatively short action time and may cause systemic side effects in cardiovascular and nervous systems.To overcome these limitations,it is necessary to develop local anesthetics with long-lasting effect and high safety.The efficacy of TTX has been confirmed by clinical trials for patients with neuropathic pain,cancer pain and drug withdrawal syndrome.However,TTX is still limited in clinical application due to its systemic toxicity and scarcity of sources.The overdose of TTX can lead to mild suppression of motor and sensory functions,blood pressure changes and even respiratory muscle paralysis.Fortunately,researches are increasingly dedicated to improving the safety and efficacy of TTX.TTX has the potential to be a new type of anesthetic to replace amino esters and amino amides,without the abusability of opioids.TTX might be converted into a“potion”when used in tandem with vasoconstrictors,local anesthetics,polymer-drug conjugate and chemical permeation enhancers or when encapsulated with microparticles,liposomes,nanoparticles and other microparticle drug delivery systems(MDDS).Better results can be obtained by combining MDDS-TTX and external trigger energy(such as near-infrared light and ultrasound).These combinations produce repeatable and adjustable on-demand anesthesia,enabling patients to control the timing,intensity and duration of nerve block in a safe and non-invasive manner.This review summarizes the research progress of TTX adjuvant drugs,TTX sustained-and controlled-delivery systems,TTX modification techniques,and aims to provide reference for the development of new local anesthetic drugs and exploration of new ideas.