Anti-nociceptive effect of kinin B-1 and B-2 receptor antagonists on peripheral neuropathy induced by paclitaxel in mice
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2011-09-01
Autores
Costa, Robson
Motta, Emerson M.
Dutra, Rafael C.
Manjavachi, Marianne N.
Bento, Allisson F.
Malinsky, Fernanda R. [UNIFESP]
Pesquero, João Bosco [UNIFESP]
Calixto, Joao B.
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BACKGROUND and PURPOSEIn the current study, we investigated the role of both kinin B-1 and B-2 receptors in peripheral neuropathy induced by the chronic treatment of mice with paclitaxel a widely used chemotherapeutic agent.EXPERIMENTAL APPROACHChemotherapy-evoked hyperalgesia was induced by i.p. injections of paclitaxel (2 mg.kg(-1)) over 5 consecutive days. Mechanical and thermal hyperalgesia were evaluated between 7 and 21 days after the first paclitaxel treatment.KEY RESULTSTreatment with paclitaxel increased both mechanical and thermal hyperalgesia in mice (C57BL/6 and CD1 strains). Kinin receptor deficient mice (B-1, or B-2 receptor knock-out and B1B2 receptor, double knock-out) presented a significant reduction in paclitaxel-induced hypernociceptive responses in comparison to wild-type animals. Treatment of CD1 mice with kinin receptor antagonists (DALBK for B-1 or Hoe 140 for B-2 receptors) significantly inhibited both mechanical and thermal hyperalgesia when tested at 7 and 14 days after the first paclitaxel injection. DALBK and Hoe 140 were also effective against paclitaxel-induced peripheral neuropathy when given intrathecally or i.c.v.. A marked increase in B-1 receptor mRNA was observed in the mouse thalamus, parietal and pre-frontal cortex from 7 days after the first paclitaxel treatment.CONCLUSIONS and IMPLICATIONSKinins acting on both B-1 and B-2 receptors, expressed in spinal and supra-spinal sites, played a crucial role in controlling the hypernociceptive state caused by chronic treatment with paclitaxel.
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British Journal of Pharmacology. Hoboken: Wiley-Blackwell, v. 164, n. 2B, p. 681-693, 2011.