Nicotine prevents and reverses paclitaxel-induced mechanical allodynia in a mouse model of CIPN

S. Lauren Kyte, Wisam Toma, Deniz Bagdas, Julie A. Meade, Lesley D. Schurman, Aron H. Lichtman, Zhi Jian Chen, Egidio Del Fabbro, Xianjun Fang, John W. Bigbee, M. Imad Damaj, David A. Gewirtz

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration, continues to be a dose-limiting and debilitating side effect during and/or after cancer chemotherapy. Paclitaxel, a taxane commonly used to treat breast, lung, and ovarian cancers, causes CIPN in 59-78% of cancer patients. Novel interventions are needed due to the current lack of effective CIPN treatments. Our studies were designed to investigate whether nicotine can prevent and/or reverse paclitaxel-induced peripheral neuropathy in a mouse model of CIPN, while ensuring that nicotine will not stimulate lung tumor cell proliferation or interfere with the antitumor properties of paclitaxel. Male C57BL/6J mice received paclitaxel every other day for a total of four injections (8 mg/kg, i.p.). Acute (0.3-0.9 mg/kg, i.p.) and chronic (24 mg/kg per day, s.c.) administration of nicotine respectively reversed and prevented paclitaxel-induced mechanical allodynia. Blockade of the antinociceptive effect of nicotine with mecamylamine and methyllycaconitine suggests that the reversal of paclitaxel-induced mechanical allodynia is primarily mediated by the a7 nicotinic acetylcholine receptor subtype. Chronic nicotine treatment also prevented paclitaxelinduced intraepidermal nerve fiber loss. Notably, nicotine neither promoted proliferation of A549 and H460 non-small cell lung cancer cells nor interfered with paclitaxel-induced antitumor effects, including apoptosis. Most importantly, chronic nicotine administration did not enhance Lewis lung carcinoma tumor growth in C57BL/6J mice. These data suggest that the nicotinic acetylcholine receptor-mediated pathways may be promising drug targets for the prevention and treatment of CIPN.

Original languageEnglish (US)
Pages (from-to)110-119
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume364
Issue number1
DOIs
StatePublished - Jan 2018
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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