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

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 7 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.

Effect of nicotine and alpha‐7 nicotinic modulators on visceral pain‐induced conditioned place aversion in mice

“…pain (Damaj et al, 1998;Bagdas et al, 2015aKyte et al, 2018). In our current study, nicotine was found to be more potent (27-fold) in alleviating the aversive state than the stretching responses induced by AA injection.…”

“…injection of AA, to compare the potency of nicotine in blocking nociceptive reflex behaviour and place aversion. We have previously demonstrated that nicotine can be antinociceptive in several mouse models of pain (Damaj et al., ; Bagdas et al., , ; Kyte et al., ). In our current study, nicotine was found to be more potent (27‐fold) in alleviating the aversive state than the stretching responses induced by AA injection.…”

“…Each mouse was used for only one experiment. Nicotine (Freitas et al., ), PHA543613 (Freitas et al., ), PNU282987 (Freitas et al., ), PNU120596 (Freitas et al., ,c), mecamylamine (Kyte et al., ) and hexamethonium (Damaj et al., ; Jackson et al., ) doses were selected based on our previous studies.…”

The Influence of Nicotine on Lung Tumor Growth, Cancer Chemotherapy, and Chemotherapy-Induced Peripheral Neuropathy

“…In our recent publication establishing the antinociceptive actions of nicotine in a mouse model of paclitaxel-induced peripheral neuropathy (Kyte et al, 2018), we also reported that nicotine does not stimulate proliferation of nonsmall cell lung cancer (NSCLC) or ovarian cancer cells in vitro, nor enhance NSCLC tumor growth in vivo. This work also demonstrated that nicotine fails to interfere with the antiproliferative and cytotoxic actions of paclitaxel in NSCLC cells in culture, whereas our recent unpublished studies have reproduced these findings in tumor-bearing mice (manuscript in preparation).…”

“…In rats, Di Cesare Mannelli et al (2013) demonstrated that acute administration of nicotine can reverse trauma-induced neuropathic pain as well as oxaliplatin-induced cold and mechanical allodynia, both of which are characteristic of chemotherapy-induced peripheral neuropathy (CIPN). Our laboratory, in collaboration with the Damaj group, has also shown that nicotine can both prevent and reverse paclitaxel-induced mechanical allodynia in mice following chronic and acute administration, respectively (Kyte et al, 2018). These two reports are, to our knowledge, currently the only publications investigating the use of nicotine in CIPN animal models, indicating that there is a need to explore the antiallodynic property of nicotine with other classes of cancer chemotherapy drugs that cause CIPN, such as the vinca alkaloids and bortezomib.…”