Tetrodotoxin: a potential pain killer?

Tetrodotoxin (TTX) is a neurotoxin with no confirmed antidote. It is most commonly known to occur in puffer fish (the Tetraodontidae family) although it has been confirmed that it is not the puffer fish themselves that produce the toxin but rather a micro-organism that migrates and then grows inside of them after birth. The toxin causes paralysis in humans and other vertebrates by blocking voltage-gated sodium channels (VGSCs), which often leads to death.  Due to its ability to block VGSCs there has also been research into the possibility that TTX may be used as a pain killer.

VGSCs are large essential membrane proteins which initiate and propagate action potentials and are composed of an α-subunit as well as one or more supporting β-subunits. The α-subunit is the part of the protein which determines the biophysical properties of the channel, including ion selectivity, whereas the β-subunits can modify the kinetic and voltage dependence properties of the channel and are also involved in the interaction of the protein with cell adhesion molecules, extracellular matrix and intracellular cytoskeleton. There are nine known mammalian α-subunit isoforms, all with differing tissue localisations and sensitivity to TTX but similar structural properties. They are made up of four homologous domains, each of which contain six transmembrane α-helical segments, connected by both extracellular an intracellular loops (Figure one of the referenced paper depicts this (page 283)). Within the α-subunit there are also binding sites for neurotoxins that can alter channel function.

TTX binds to a receptor site on the α-subunit and blocks the influx of sodium ions by obstructing the outer pore of the channel, which in turn inhibits the propagation of action potentials causing paralysis. The effects of TTX vary depending on the α-subunit isoform; some isoforms need higher concentrations of TTX than others to become blocked. Some of the isoforms which are more greatly affected by TTX have been shown to also play a big part in the expression of pain and so low levels of TTX could potentially be used to selectively block these channels to alleviate pain.

The effects of TTX on acute pain have not been well documented although data has suggested that it may have a little impact on acute pain. The toxins effects on inflammatory and neuropathic pain however have been better documented. The toxins effects on neuropathic pain have been widely studied as evidence has suggested that TTX-sensitive VGSCs have a key role in neuropathic pain and the majority of these studies have suggested that TTX may be an inhibitor of neuropathic pain. There have been fewer studies on the effects of the toxin on inflammatory pain but the few studies that have been done have shown that TTX may also inhibit inflammatory pain.

Unfortunately the few case studies that have been done have not been particularly promising. The one with the most positive results showed that the chronic pain of cancer patients was alleviated in half of the participants but it is unknown why only 50% responded to the treatment. It is clear from current research that TTX is likely to have pain relieving however further research would be needed if the toxin were ever to be used medically.

Reference: Nieto, F. R., & et al. (2012). Tetrodotoxin (TTX) as a Therapeutic Agent for Pain. Marine Drugs, 10, 281-305.