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Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice

Nieto, Francisco Rafaela,1; Entrena, José Manuela,1; Cendán, Cruz Miguela; Del Pozo, Esperanzaa; Vela, José Miguelb; Baeyens, José Manuela,*

doi: 10.1016/j.pain.2007.10.012
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We evaluated the effect of low doses of systemically administered tetrodotoxin (TTX) on the development and expression of neuropathic pain induced by paclitaxel in mice. Treatment with paclitaxel (2 mg/kg, i.p., once daily during 5 days) produced long-lasting (2–4 weeks) heat hyperalgesia (plantar test), mechanical allodynia (electronic Von Frey test) and cold allodynia (acetone drop method), with maximum effects observed on days 7, 10 and 10–14, respectively. Acute subcutaneous treatment with 1 or 3 μg/kg of TTX reduced the expression of mechanical allodynia, whereas higher doses (3 or 6 μg/kg) were required to reduce the expression of cold allodynia and heat hyperalgesia. In contrast, TTX (3 or 6 μg/kg, s.c.) did not affect the response to the same thermal and mechanical stimuli in control animals, which indicates that the antihyperalgesic and antiallodynic effects of TTX were not due to unspecific inhibition of the perception of these stimuli. Administration of TTX (6 μg/kg, s.c.) 30 min before each of the 5 doses of paclitaxel did not modify the development of heat hyperalgesia produced by the antineoplastic, but abolished the development of mechanical and cold allodynia. Coadministration of a lower dose of TTX (3 μg/kg) also prevented the development of mechanical allodynia. No signs of TTX-induced toxicity or motor incoordination were observed. These data suggest that low doses of TTX can be useful to prevent and treat paclitaxel-induced neuropathic pain, and that TTX-sensitive subtypes of sodium channels play a role in the pathogenesis of chemotherapy-induced neuropathic pain.

aDepartment of Pharmacology and Institute of Neuroscience, Faculty of Medicine, University of Granada, Avenida de Madrid 11, 18012 Granada, Spain

bLaboratorios Dr. Esteve S.A., Avenida Virgen de Montserrat 221, 08041 Barcelona, Spain

*Corresponding author. Tel.: +34 958 243538; fax: +34 958 243537.

E-mail: jbaeyens@ugr.es

1F.R. Nieto and J.M. Entrena contributed equally to the study.

E-mail: jbaeyens@ugr.es

Submitted January 17, 2007; received in revised form September 28, 2007; accepted October 8, 2007.

© 2008 Lippincott Williams & Wilkins, Inc.
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