Nicotine Prevents and Reverses Paclitaxel-Induced Mechanical Allodynia in a Mouse Model of CIPN

• Published in: The Journal of pharmacology and experimental therapeutics 2018-01, Vol.364 (1), p.110-119
• Main Authors: Kyte, S. Lauren, Toma, Wisam, Bagdas, Deniz, Meade, Julie A., Schurman, Lesley D., Lichtman, Aron H., Chen, Zhi-Jian, Del Fabbro, Egidio, Fang, Xianjun, Bigbee, John W., Damaj, M. Imad, Gewirtz, David A.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - pharmacology; Bridged-Ring Compounds - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Chemotherapy, Antibiotics, and Gene Therapy; Disease Models, Animal; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - prevention & control; Lung Neoplasms - drug therapy; Male; Mice; Mice, Inbred C57BL; Nicotine - pharmacology; Paclitaxel - adverse effects; Paclitaxel - pharmacology; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - drug therapy; Peripheral Nervous System Diseases - prevention & control; Receptors, Cholinergic - metabolism; Taxoids - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.117.243972

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 α7 nicotinic acetylcholine receptor subtype. Chronic nicotine treatment also prevented paclitaxel-induced 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.