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.