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. 2015 Dec 17:311:499-507.
doi: 10.1016/j.neuroscience.2015.10.059. Epub 2015 Nov 5.

Antihyperalgesic effect of tetrodotoxin in rat models of persistent muscle pain

P Alvarez  1 , J D Levine  2
Affiliations

Antihyperalgesic effect of tetrodotoxin in rat models of persistent muscle pain

P Alvarez et al. Neuroscience. .

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 the 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 24h. 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.

Keywords: clinical trials; delayed-onset muscle soreness; inflammation; mechanical hyperalgesia; neuropathic muscle pain; voltage-dependent sodium channels.

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Figures

Figure 1
Figure 1. Effect of intramuscular TTX on mechanical nociceptive threshold in naïve rats
(A) Sequentially increasing the i.m. doses of TTX, each cumulative dose one-half log unit greater than the previous dose, were injected at 45 min inter-injection intervals. Prior to each subsequent dose, the mechanical nociceptive threshold was again assessed. TTX failed to produce an increase in mechanical nociceptive threshold in normal control rats at any of the tested doses. Indeed, the doses of 0.1 and 0.3 μg produced a small, albeit significant, decrease in mechanical nociceptive threshold. (B) In a separate group of rats, the injection of the highest dose of TTX (1 μg) did not modify the mechanical nociceptive threshold up to 60 min after injection. *P < 0.05.
Figure 2
Figure 2. Effect of intramuscular TTX on inflammatory mechanical hyperalgesia
(A) The injection of λ-carrageenan (100 μg/10 μl) into the gastrocnemius muscle produced a decrease of mechanical nociceptive threshold (Carr) measured 24 h later. At this time point sequentially increasing doses of TTX, each one-half log unit greater than the previous dose, were injected at 45 min inter-injection intervals. Prior to the injection of each higher dose of TTX, the mechanical nociceptive threshold was again assessed, to determine the effect of that dose on the carrageenan-induced mechanical hyperalgesia. TTX produced a dose-dependent increase in mechanical nociceptive threshold, in the presence of carrageenan induced mechanical hyperalgesia. Of note, not even the highest dose elevated the mechanical nociceptive threshold above the pre-carrageenan baseline. (B) After the highest intramuscular dose of TTX, or vehicle, were injected the mechanical nociceptive threshold was monitored to evaluate time course of their antihyperalgesic effect. Compared to vehicle, TTX induced a significant increase in mechanical nociceptive threshold, reversal of hyperalgesia, up to twenty-four hours after the local injection of a 1 μg dose of TTX, in carrageenan-injected rats. *P < 0.05; ***P < 0.001.
Figure 3
Figure 3. Local effect of TTX on ergonomic injury-induced mechanical hyperalgesia
After assessment of the mechanical nociceptive threshold (Baseline), rats were submitted to an eccentric exercise protocol. Twenty-four hours later, rats exhibited significant mechanical hyperalgesia (Pre). The local treatment (Post) with a dose of 1 μg of TTX, but not of D-PBS (Vehicle), markedly attenuated the eccentric exercise-induced muscle mechanical hyperalgesia. ***P < 0.001.
Figure 4
Figure 4. Effect of intramuscular TTX on oxaliplatin-induced mechanical hyperalgesia
After assessment of the mechanical nociceptive threshold (Base), rats received an i.v. dose of oxaliplatin (2 mg/kg) and their mechanical nociceptive thresholds were assessed 4 and 15 days later (OXP). At these time points sequentially increasing doses of TTX, each one-half log unit greater than the previous dose, were injected at 45 min inter-injection intervals. Prior to each higher dose of TTX, the mechanical nociceptive threshold was again assessed, to determine the effect of that dose on the oxaliplatin-induced mechanical hyperalgesia. (A) Four days after oxaliplatin injection TTX produced a small, albeit statistically significant, increase in mechanical nociceptive threshold compared to D-PBS vehicle (Veh). (B) Also four days after oxaliplatin injection, the higher dose of TTX (1 μg) was injected i.m., and the mechanical nociceptive threshold was measured at four different time points. TTX induced a small, albeit statistically significant, increase in mechanical nociceptive threshold after the local injection. (C) Fifteen days after oxaliplatin, only the highest dose of TTX (1 μg) produced a small, yet significant, increase in mechanical nociceptive threshold compared to vehicle. (B) Fifteen days after oxaliplatin injection, the dose of TTX (1 μg) was devoid of statistically significant effect on muscle mechanical hyperalgesia, as revealed by readings taken at 30 min to 2 hours. *P < 0.05; **P < 0.01.
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