Effects of Tetrodotoxin in Mouse Models of Visceral Pain

Abstract

Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis. The subcutaneous administration of TTX dose-dependently inhibited the number of pain-related behaviors in all evaluated pain models and reversed the referred mechanical hyperalgesia (examined by stimulation of the abdomen with von Frey filaments) induced by capsaicin and cyclophosphamide, but not that induced by mustard oil. Morphine inhibited both pain responses and the referred mechanical hyperalgesia in all tests. Conditional nociceptor‑specific Nav1.7 knockout mice treated with TTX showed the same responses as littermate controls after the administration of the algogens. No motor incoordination after the administration of TTX was observed. These results suggest that blockade of TTX-sensitive sodium channels, but not Nav1.7 subtype alone, by systemic administration of TTX might be a potential therapeutic strategy for the treatment of visceral pain.

Analgesia Effect of Enteric Sustained-Release Tetrodotoxin Pellets in the Rat

“…The effective dose of enteric sustained-release TTX pellets were 20, 40, 60, and80 µg•kg −1 , which was about 10 times of the effective doses of i.m. injection or s.c. injection (1, 3 or 6 µg•kg −1 ) [12,28]. Further, it is noted that the LD 50 of the TTX pellets (840.13 µg/kg, Table 2) was also about two times as that of oral TTX (400 µg/kg, which is an estimated LD 50 value for mammals) [29], indicating highly improved safety of the oral delivery of TTX by pelletizing.…”

The influence of voltage‐gated sodium channels on human gastrointestinal nociception

“…Subcutaneously injected TTX has shown efficacy for control of moderate–severe pain in the setting of cancer when other analgesics have failed . Subcutaneous TTX has also demonstrated promise for management of gastrointestinal pain associated with intracolonic instillation of capsaicin or mustard oil in murine models . Studies evaluating the impact of TTX on human visceral perception are lacking but careful administration of this agent could prove to be useful for this purpose.…”

“…104 Subcutaneous TTX has also demonstrated promise for management of gastrointestinal pain associated with intracolonic instillation of capsaicin or mustard oil in murine models. 21 Studies evaluating the impact of TTX on human visceral perception are lacking but careful administration of this agent could prove to be useful for this purpose. To this point, no other pharmacological agents targeting VGSCs have been scientifically evaluated as treatments for gastrointestinal pain.…”

Voltage‐gated sodium channels: (NaV)igating the field to determine their contribution to visceral nociception

“…; Gonzalez‐Cano et al . ). Similarly, intrarectal administration of lidocaine (lignocaine) in irritable bowel syndrome (IBS) patients reduces rectal sensitivity and abdominal pain, suggesting Na V channels and activation of peripheral afferent endings in the colon play key roles in the pathogenesis of chronic visceral pain in IBS patients (Verne et al .…”