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

Abstract

BACKGROUND AND PURPOSEIn 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 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 (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 IMPLICATIONSKinins 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.

Effects of repeated milnacipran and fluvoxamine treatment on mechanical allodynia in a mouse paclitaxel-induced neuropathic pain model

“…These observations are consistent with those of other reports showing paclitaxel to induce mechanical allodynia in mice (4,19). The present study further demonstrated a significant attenuation of paclitaxel-induced mechanical allodynia by repeated milnacipran or fluvoxamine treatment.…”

“…to mice at doses of 0.5-2 mg/ kg, once per day for 5 consecutive days. Paclitaxel dosing was determined based on previous reports that used mice (4,19). Milnacipran hydrochloride or fluvoxamine maleate (Sigma Chemical Co., St. Louis, MO) was administered i.p.…”

Resistance to visceral leishmaniasis is severely compromised in mice deficient of bradykinin B2-receptors

“…C57Bl/6 B 2 R −/− knock-out (KOB2) [24] and C57BL/6- B2R +/+ wild type control mice (C57) originated from breeding colonies kindly donated by Dr J.B. Pesquero (UNIFESP, São Paulo, Brazil) were maintained in our animal facilities (LAT- IBCCF, UFRJ). Deletion of the entire coding sequence of kinin B2 receptors was achieved according to the methodology previously described by Rupniak et al .…”

Effect of Xylopic Acid on Paclitaxel-induced Neuropathic pain in rats

“…Several reports indicate that paclitaxel evokes proinflammatory pain mediators and cytokines, including bradykinin and TNF-α as well as the activation of microglial and astroglial cells (Costa et al, 2011;Burkhart et al, 1994;Manthey et al, 1992;Zhang et al, 2012;Burgos et al, 2012). It has been reported that xylopic acid inhibits the nociceptive effects of bradykinin and glutamate (Woode et al, 2013).…”