Inhibition of paclitaxel-induced A-fiber hypersensitization by gabapentin

Misaki Matsumoto, Makoto Inoue, Andreas Hald, Weijiao Xie, Hiroshi Ueda

Research output: Contribution to journalArticlepeer-review

Abstract

Paclitaxel (Taxol) is a widely used chemotherapeutic agent in the treatment of several tumors. However, its use is often associated with the generation of peripheral neuropathic pain expressed as mechanical allodynia and thermal hyperalgesia. The molecular mechanism behind this debilitating side effect is obscure, and efficient drugs for its prevention are required. We sought to clarify the cellular changes in the involved nociceptor types underlying paclitaxel-induced neuropathic pain and to test for an alleviating effect of gabapentin treatment in a murine model of paclitaxel-induced neuropathic pain. We found that a single treatment with paclitaxel (4 mg/kg i.p.) led to a decrease in both thermal and mechanical nociceptive thresholds as well as a reduction in the thresholds for 250-Hz (Aδ-fiber) and 2000 Hz (Aβ-fiber) but not 5-Hz (C-fiber) sine wave electrical stimuli-induced paw withdrawal. The paclitaxel-induced neuropathic pain was completely abrogated by gabapentin (30 mg/kg i.p.) treatment. Furthermore, we found that mRNA and protein levels of the voltage-gated calcium channel α2δ-1 subunit (Caα2δ-1), one of the putative targets for gabapentin, was up-regulated in dorsal root ganglions (DRGs), as well as increased expression of Caα2δ-1 protein in medium/large-sized DRG neurons by immunohistochemistry, following paclitaxel treatment. This suggests that paclitaxel induces A-fiber-specific hypersensitization, which may contribute to the functional mechanical allodynia and hyperalgesia, and that gabapentin could be a potential therapeutic agent for paclitaxel-induced neuropathic pain.

Original languageEnglish (US)
Pages (from-to)735-740
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume318
Issue number2
DOIs
StatePublished - 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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