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

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.