Subcutaneous tetrodotoxin and inflammatory pain
Madrid, Spain
* E-mail: laguacil{at}ceu.es
Peripheral tetrodotoxin (TTX) has been proposed for the treatment of several types of pain, and thus i.m. TTX is currently being evaluated in patients with severe cancer pain.1 In some animal studies, it appears that inflammatory pain may also be responsive to the antinociceptive effect of TTX, but the potency of the drug after systemic injection is not clear. Thus, the subcutaneous injection of TTX attenuated pain behaviour in the inflammatory phase of the rat formalin test,2 but one study reported lack of activity in the carrageenan model, where the drug only seemed effective when injected in the sciatic nerve.3
We have studied the potential anti-hyperalgesic effect of subcutaneous TTX in the rat carrageenan model by using an analgesiometer (Ugo-Basile, Italy) to determine the threshold pressure needed to elicit a paw withdrawal reaction (Randall–Selitto test). After baseline determinations, the rats (SD, male, 250–350 g) were injected with TTX (2.5 µg kg–1, s.c.) or vehicle and 1 h later with 0.1 ml of 1% lambda carrageenan into the surface of the right hind paw. The effects on withdrawal reaction were studied 3 h post-injection. TTX reduced hyperalgesia slightly but significantly in the animals treated with this drug (Fig. 1).
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This finding further supports the antinociceptive properties of systemic TTX in inflammatory hyperalgesia, which is in agreement with the prominent changes of TTX-sensitive channels associated with inflammation4 5 and the reported analgesic effect in the formalin test.2 The small decrease in pain that we have detected suggests that single doses of TTX would not be very effective in acute, severe inflammatory conditions like the one elicited in this study. However, we think that this activity is enough to suggest that the drug could provide significant relief in milder, chronic inflammation, but it must be tested accordingly. This is appropriate, as some reports have expressed concern about the safety of TTX. Thus, we have presented preliminary results showing that repeated subcutaneous injections of TTX are well tolerated in rodent models able to detect aversion/dysphoria associated with drug treatments.6 More recently, we have studied the effects of TTX on the viability and proliferation of HepG2 cells in vitro and did not find any sign of cytotoxicity after 24 h of incubation with concentrations as high as 400 µM, a result that suggests good safety of the drug in non-excitable cells.
In summary, our experiments suggest that subcutaneous TTX injections may be well tolerated and confirm the possible applications of the drug in the management of inflammatory hyperalgesia, even when the underlying inflammatory process itself could not be affected.
References
1 Hagen NA, Fisher KM, Lapointe B, et al. An open-label, multi-dose efficacy and safety study of intramuscular tetrodotoxin in patients with severe cancer-related pain. J Pain Symptom Manage (2007) 34:171–82.[CrossRef][Web of Science][Medline]
2 Marcil J, Walczak J-S, Guindon J, Ngoc AH, Lu S, Beaulieu P. Antinociceptive effects of tetrodotoxin (TTX) in rodents. Br J Anaesth (2006) 96:761–8.
3 Beloeil H, Ababneh Z, Chung R, Zurakowski D, Mulkern RV, Berde CB. Effects of bupivacaine and tetrodotoxin on carrageenan-induced hind paw inflammation in rats (Part 1): hyperalgesia, edema, and systemic cytokines. Anesthesiology (2006) 105:128–38.[CrossRef][Web of Science][Medline]
4 Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain (2004) 108:237–47.[CrossRef][Web of Science][Medline]
5 Nassar MA, Stirling LC, Forlani G, et al. Nociceptor-specific gene deletion reveals a major role for Na
1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci USA (2004) 101:12706–11.
6 Morales L, Pérez-García C, Díez-Fernández C, et al. Effects of peripheral tetrodotoxin injections on hyperalgesia, inflammation and place conditioning. Meth Find Exp Clin Pharmacol (2006) 28((Suppl. 2)):115.[CrossRef][Web of Science][Medline]
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