Coadministration of indomethacin and minocycline attenuates established paclitaxel-induced neuropathic thermal hyperalgesia: Involvement of cannabinoid CB1 receptors.

Subramanian S Parvathy,Willias Masocha

doi:10.1038/srep10541

Abstract

Taxanes such as paclitaxel, which are chemotherapeutic drugs, cause dose-dependent painful neuropathy in some patients. We investigated whether coadministration of minocycline and indomethacin produces antinociceptive effects in mice with paclitaxel-induced neuropathic thermal hyperalgesia and if the cannabinoid system is involved. Previously, we reported that coadministration of these two drugs results in antinociception against inflammatory pain at doses where either drug alone lack significant activity. In the current study, we observed that treatment of female mice with indomethacin or minocycline alone did not affect established paclitaxel-induced thermal hyperalgesia, whereas coadministration of the two drugs attenuated it. In male mice indomethacin had some antihyperalgesic activity, whilst minocycline did not. Coadministration of the two drugs had supraadditive antihyperalgesic activity in male mice. Administration of a cannabinoid CB1 receptor antagonist AM 251 blocked the antihyperalgesic effects of the combination of minocycline and indomethacin in both male and female mice. In conclusion our results indicate that coadministration of minocycline and indomethacin abrogates established paclitaxel-induced neuropathic thermal hyperalgesia in mice, and the potentiation of the antinociceptive effects of this combination involves the cannabinoid system.

Highlights

Taxanes such as paclitaxel, which are chemotherapeutic drugs, cause dose-dependent painful neuropathy in some patients
Two-way repeated measures analysis of variance (ANOVA) showed that mice treated with paclitaxel had similar baseline values but lower reaction latency at day 7 post administration compared to vehicle-treated animals (p > 0.05 and p < 0.001, respectively; Fig. 1A and B)
Two-way repeated measures ANOVA showed that the administration of indomethacin (1 or 10 mg/kg) or minocycline (50 mg/kg) to female mice with established paclitaxel-induced thermal hyperalgesia did not produce significant changes compared to vehicle treated mice (p > 0.05; n = 8 for all groups; Fig. 2A and C)

Summary

Introduction

Taxanes such as paclitaxel, which are chemotherapeutic drugs, cause dose-dependent painful neuropathy in some patients. We investigated whether coadministration of minocycline and indomethacin produces antinociceptive effects in mice with paclitaxel-induced neuropathic thermal hyperalgesia and if the cannabinoid system is involved. In conclusion our results indicate that coadministration of minocycline and indomethacin abrogates established paclitaxel-induced neuropathic thermal hyperalgesia in mice, and the potentiation of the antinociceptive effects of this combination involves the cannabinoid system. We observed that the combination of minocycline with indomethacin had more antinociceptive effects against thermal pain and lipopolysaccharide-induced thermal hyperalgesia and arthritis than when either drug was used alone[5]. We evaluated the effects of the coadministration of minocycline and indomethacin in a mouse model of paclitaxel-induced neuropathic pain[17,18] and whether the CB1 receptors are involved in the activity of the combination

Methods

Results

Conclusion