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.

Figure 1

Paclitaxel-induced hyperalgesia in kinin receptor-deficient mice. Mechanical (A) and thermal (B) withdrawal threshold of vehicle-treated wild-type (WT vehicle) mice, paclitaxel-treated WT (WT PTX) mice, paclitaxel-treated B₁R^−/−, (B₁R^−/− PTX) B₂R^−/− (B₂R^−/− PTX) and B₁B₂R^−/− (B₁B₂R^−/− PTX) mice were evaluated at different time intervals after the first paclitaxel treatment. (C, D) Inhibition of the AUC 0–6 h (from day 0 to 21) of paclitaxel-induced mechanical (C) and thermal (D) hyperalgesia in kinin receptor-deficient mice. The inhibition is shown as the AUC of the test group (receptor knock-out PTX animals), as a percentage of the control AUC (WT PTX animals). Each group represents the mean of five to six animals, and the error bars indicate the SEM. *P < 0.05 significantly different from paclitaxel-treated WT mice (two-way anova followed by the Bonferroni post-test). BL, baseline withdrawal threshold. #P < 0.05, significantly different from B₁R^−/− or B₂R^−/− group (one-way anova followed by the Newman–Keuls post-test).

Figure 2

Effect of treatment with selective kinin B₁ or B₂ receptor antagonists, DALBK (100 nmol·kg⁻¹, i.p.) and Hoe 140 (50 nmol·kg⁻¹, i.p.), respectively, on the genesis of paclitaxel-induced mechanical (A) and thermal (B) hyperalgesia in CD1 mice. The drugs were given twice a day (every 12 h) for 6 days, starting at the time of the first paclitaxel treatment. Each group represents the mean of five to six animals, and the error bars indicate the SEM. *P < 0.05, significantly different from paclitaxel-treated mice (two-way anova followed by the Bonferroni post-test). BL, baseline withdrawal threshold.

Figure 3

Effect of treatment with selective kinin B₁R or B₂R antagonists, DALBK (100–300 nmol·kg⁻¹, i.p.) and Hoe 140 (30–100 nmol·kg⁻¹, i.p.), respectively, on established mechanical (A, B, C) and thermal (D, E) hyperalgesia induced by paclitaxel in CD1 mice. A single injection of the drugs was given 7 (A, B, D) and 14 (C, E) days after the first paclitaxel (PTX) injection. (F) Effect of the repeated treatment with DALBK (100 nmol·kg⁻¹, i.p.) or Hoe 140 (50 nmol·kg⁻¹, i.p.), every 12 h for 2 days, on the sustained mechanical hyperalgesia in CD1 mice. Each group represents the mean of five to six animals, and the error bars indicate the SEM. *P < 0.05, significantly different from paclitaxel-treated mice (two-way anova followed by the Bonferroni post-test). BL, baseline withdrawal threshold.

Figure 4

Effect of i.pl. treatment with selective kinin B₁ or B₂ receptor antagonists, DALBK (3 nmol per paw, i.pl.) and Hoe 140 (3 nmol per paw, i.pl.), respectively, on paclitaxel-induced mechanical hyperalgesia in CD1 mice. A single injection of the drugs was given 7 (A) and 14 (B) days after the first paclitaxel (PTX) injection. (C) Effect of the i.pl. injection of kinin B₁ or B₂ receptor agonists, DABK (20 nmol per paw, i.pl.) and BK (10 nmol per paw, i.pl.), respectively, on licking behaviour in vehicle- and paclitaxel-treated CD1 mice. Each group represents the mean of five to six animals, and the error bars indicate the SEM. (A, B) *P < 0.05, significantly different from paclitaxel-treated mice (two-way anova followed by Bonferroni post-test). BL, baseline withdrawal threshold. (C) *P < 0.05, significantly different from saline- (i.pl.) injected mice (one-way anova followed by the Newman–Keuls post-test).

Figure 5

Effect of i.t. (A, B) or i.c.v. (C, D) treatment with selective kinin B₁ or B₂ receptor antagonists, DALBK (10 pmol) and Hoe 140 (100 pmol), respectively, on paclitaxel-induced mechanical hyperalgesia in CD1 mice. A single injection of the drugs was given 7 (A, C) and 14 (B, D) days after the first paclitaxel (PTX) injection. Each group represents the mean of five to six animals, and the error bars indicate the SEM. *P < 0.05, significantly different from paclitaxel-treated mice (two-way anova followed by Bonferroni post-test). BL, baseline withdrawal threshold.

Figure 6

Levels of expression of kinin B₁R mRNA in mouse paw skin (A), DRG (L₄–L₆) (B), spinal cord (L₄–L₆) (C), hypothalamus (D), thalamus (E) and pre-frontal (PF) cortex (D), 7 and 14 days after the first paclitaxel (PTX) treatment in CD1 mice, assessed by real-time RT-PCR assay. All data have been normalized for levels of GAPDH expression within the same sample. Each bar represents the mean SEM of three to four mice. *P < 0.05, significantly different from vehicle-treated mice (Student's t-test).