Anti-nociceptive effect of kinin B₁ and B₂ receptor antagonists on peripheral neuropathy induced by paclitaxel in mice.

Abstract

BACKGROUND AND PURPOSE:

In the current study, we investigated the role of both kinin B₁ and B₂ receptors in peripheral neuropathy induced by the chronic treatment of mice with paclitaxel a widely used chemotherapeutic agent.

EXPERIMENTAL APPROACH:

Chemotherapy-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 RESULTS:

Treatment with paclitaxel increased both mechanical and thermal hyperalgesia in mice (C57BL/6 and CD1 strains). Kinin receptor deficient mice (B₁, or B₂ 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 B₁ or Hoe 140 for B₂ 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 B₁ receptor mRNA was observed in the mouse thalamus, parietal and pre-frontal cortex from 7 days after the first paclitaxel treatment.

CONCLUSIONS AND IMPLICATIONS:

Kinins acting on both B₁ and B₂ receptors, expressed in spinal and supra-spinal sites, played a crucial role in controlling the hypernociceptive state caused by chronic treatment with paclitaxel.

• Authors: Robson Costa, Emerson M Motta, Rafael C Dutra, Marianne N Manjavachi, Allisson F Bento, Fernanda R Malinsky, João B Pesquero, João B Calixto
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 164 Issue 2b Pg. 681-93 (Sep 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21470206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Analgesics
• Bradykinin B1 Receptor Antagonists
• Bradykinin B2 Receptor Antagonists
• Kinins
• RNA, Messenger
• Receptor, Bradykinin B1
• Receptor, Bradykinin B2
• bradykinin, Leu(8)-des-Arg(9)-
• icatibant
• Paclitaxel
• Bradykinin

Topics

• Analgesics (pharmacology)
• Animals
• Bradykinin (analogs & derivatives, pharmacology)
• Bradykinin B1 Receptor Antagonists
• Bradykinin B2 Receptor Antagonists
• Hyperalgesia (chemically induced, drug therapy, genetics, metabolism)
• Kinins (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Paclitaxel (toxicity)
• Peripheral Nervous System Diseases (chemically induced, drug therapy, genetics, metabolism)
• RNA, Messenger (genetics)
• Receptor, Bradykinin B1 (deficiency, genetics, metabolism)
• Receptor, Bradykinin B2 (deficiency, genetics, metabolism)