Abstract
Tetrodotoxin (TTX) is a potent neurotoxin found mainly in puffer fish and other marine and terrestrial animals. TTX blocks voltage-gated sodium channels (VGSCs) which are typically classified as TTX-sensitive or TTX-resistant channels. VGSCs play a key role in pain signaling and some TTX-sensitive VGSCs are highly expressed by adult primary sensory neurons. During pathological pain conditions, such as neuropathic pain, upregulation of some TTX-sensitive VGSCs, including the massive re-expression of the embryonic VGSC subtype NaV1.3 in adult primary sensory neurons, contribute to painful hypersensitization. In addition, people with loss-of-function mutations in the VGSC subtype NaV1.7 present congenital insensitive to pain. TTX displays a prominent analgesic effect in several models of neuropathic pain in rodents. According to this promising preclinical evidence, TTX is currently under clinical development for chemo-therapy-induced neuropathic pain and cancer-related pain. This review focuses primarily on the preclinical and clinical evidence that support a potential analgesic role for TTX in these pain states. In addition, we also analyze the main toxic effects that this neurotoxin produces when it is administered at therapeutic doses, and the therapeutic potential to alleviate neuropathic pain of other natural toxins that selectively block TTX-sensitive VGSCs.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
As we have described in the previous section, some TTX-sensitive voltage-gated sodium channels (VGSCs) play a key role in neuropathic pain, and this probably explains why the effect of TTX has been more widely tested in preclinical models of neuropathic pain
STX has served as the basis for the design of some synthetic derivatives, such as ST2530, a selective very potent inhibitor of NaV 1.7 isoform which reduced mechanical allodynia induced by the spared nerve injury (SNI) model of neuropathic pain in mice [87]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The mechanism of action by which TTX exerts its analgesic effect is by binding to the α-subunit within the outer vestibule of the VGSC, blocking the entry of Na+ ions through the channel [16,18] In this manner, TTX reduces the Na+ ionic fluxes required for the initiation and conduction of nerve impulses. Ongoing abnormal activity originating in injured peripheral These processes are be responsible hyperexcitability of primary sensory nerves can the triggerfor of inducing central sensitization [19]. VGSCs play a role in persistent and chronicmodifications pain as it has of been reported that occur changes of injury, as well as posttranslational these channels, after nerve on VGSCinjury, expression in primary sensory neurons, their abnormal and lead to peripheral sensitization processes [20]accumulation (see Table 1).
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