Antihyperalgesic effect of tetrodotoxin in rat models of persistent muscle pain

Abstract

Persistent muscle pain is a common and disabling symptom for which available treatments have limited efficacy. Since tetrodotoxin (TTX) displays a marked antinociceptive effect in models of persistent cutaneous pain, we tested its local antinociceptive effect in rat models of muscle pain induced by inflammation, ergonomic injury and chemotherapy-induced neuropathy. While local injection of TTX (0.03-1 μg) into the gastrocnemius muscle did not affect mechanical nociceptive threshold in naïve rats, exposure to the inflammogen carrageenan produced a marked muscle mechanical hyperalgesia, which was dose-dependently inhibited by TTX. This antihyperalgesic effect was still significant at 24 hours. TTX also displayed a robust antinociceptive effect on eccentric exercise-induced mechanical hyperalgesia in the gastrocnemius muscle, a model of ergonomic pain. Finally, TTX produced a small but significant inhibition of neuropathic muscle pain induced by systemic administration of the cancer chemotherapeutic agent oxaliplatin. These results indicate that TTX-sensitive sodium currents in nociceptors play a central role in diverse states of skeletal muscle nociceptive sensitization, supporting the suggestion that therapeutic interventions based on TTX may prove useful in the treatment of muscle pain.

Effect of Tetrodotoxin Pellets in a Rat Model of Postherpetic Neuralgia

“…Patients who received 30 μg TTX twice daily for 4 consecutive days resulted in an analgesic response of 56.7 days, while the placebo only enabled 9.9 days [ 18 ]. There was still a significant anti-hyperalgesia effect at 24 h with topical injection of 0.03–1.0 μg /kg TTX [ 10 ]. TTX as an effective treatment at low doses has shown that 1.0–3.0 μg/kg TTX reduces the expression of mechanical allodynia.…”

“…Furthermore, no gross motor or behavioral side effects were reported after intramuscular (i.m.) administration of 1 μg TTX [ 10 ].…”

Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults

“…Pufferfish extracts were used for centuries to alleviate neuralgia in patients affected by leprosy, reduce tetanus-related muscle spasms, and relieve pain resulting from rheumatoid arthritis [31,32]. Today, modern pharmacological studies have supported the beneficial effects of TTX on pain [15,17,[33][34][35][36]. Despite the current need for effective, non-addictive analgesics, concern around toxicity and potential for cardiac arrythmias have limited wider clinical acceptance of TTX.…”

“…If successful, TTX will be one of a select few peripherally acting analgesics. To date, preclinical studies have shown TTX to be effective at inhibiting neuropathic [13,14] and inflammatory pain [15][16][17]. In patients with moderate to severe pain due to either cancer or chemotherapy-induced neuropathy who failed other treatments, TTX was seen to reduce pain by 30% below baseline levels in some patients [18][19][20][21].…”

Sodium channels and pain: from toxins to therapies

“…Extensive studies with TTX analogue have revealed a new metabolite 4,9 anhydro‐TTX with great selectivity for Na V 1.6 (Rosker et al ., ). Furthermore, TTX has shown in vivo efficacy in preclinical pain models of inflammatory and neuropathic pain (Beloeil et al ., ; Marcil et al ., ; Alvarez and Levine, ; Salas et al ., ) (Table ). These results suggest TTX is a potential lead for further development of Na V ‐specific blockers.…”