Tetrodotoxin, a Candidate Drug for Nav1.1-Induced Mechanical Pain?

César Mattei

doi:10.3390/md16020072

Abstract

Tetrodotoxin (TTX), the mode of action of which has been known since the 1960s, is widely used in pharmacology as a specific inhibitor of voltage-gated sodium channels (Nav channels). This toxin has contributed to the characterization of the allosteric model of the Nav channel, and to discriminating TTX-sensitive and TTX-resistant subtypes. In addition to its role as a pharmacological tool, TTX is now considered a therapeutic molecule, and its development should lead to its use in certain pathologies involving Nav channels, particularly in the field of pain. Specifically, the blockade of Nav channels expressed in nociceptive fibres is one strategy for alleviating pain and its deleterious consequences on health. Recent work has identified, in addition to the Nav1.7, 1.8 and 1.9 channels, the Nav1.1 subtype on dorsal root ganglion (DRG) neurons as a crucial player in mechanical and non-thermal pain. The sensitivity of Nav1.1 to TTX could be exploited at the therapeutic level, especially in chronic pain conditions.

Highlights

The mode of action of tetrodotoxin (TTX) was characterised in the early 1960s by the pioneering work of the Narahashi team, which made it clear that this non-peptidyl toxin inhibits voltage-gatedNa+ channels (Nav) at very low concentrations [1]
It is possible to target the nociceptors, i.e., neurons responsible for converting high-intensity thermal, chemical or mechanical information into an electrical message. The transmission of this message is ensured by the propagation of the action potential, which depends on the opening of certain Nav channels
It has been tested by intramuscular injection to reduce cancer-related pain with significant effects [22,23]. It has been challenged for its potential against drug addiction behaviours: TTX exhibits a reduction of cue-induced increases in heroin craving and drug-associated anxiety with no sign of cardiovascular side effects [24]. This use of TTX was based on its ability to block Nav channels, the expression of which is modified over time, implying these Nav channels—i.e., Nav 1.3, 1.7—to be therapeutic targets for chronic pain

Summary

Introduction

The mode of action of tetrodotoxin (TTX) was characterised in the early 1960s by the pioneering work of the Narahashi team, which made it clear that this non-peptidyl toxin inhibits voltage-gated. The interaction between this toxin and the Nav channels has been dissected at the cellular and molecular level, and TTX is used as a pharmacological tool for Nav-dependent mechanisms [2] In this respect, the blocking it exerts on these channels and its ability to inhibit the rise of the action potential of excitable cells are the cause of human intoxication after eating ‘fugu’ puffer fish. It is possible to target the nociceptors, i.e., neurons responsible for converting high-intensity thermal, chemical or mechanical information into an electrical message. The transmission of this message is ensured by the propagation of the action potential, which depends on the opening of certain Nav channels. TTX does not cross the blood brain barrier, or very poorly, reducing the probability of central system depression and any adverse effects [6]

Implication of Nav Channels in Nociception

Therapeutic of TTX

Therapeutic Use of TTX

Conclusions