Hyperalgesia and Neuropathic Pain Mechanism in Rodent Models of Cigarette Smoking- and Nicotine-Induced Precipitated Withdrawal Study.

Abstract

Introduction: Quitting smoking, or nicotine deprivation, is associated with withdrawal symptoms, including increased pain sensitivity and hyperalgesia through poorly managed current therapies, thus highlighting the need to improve our knowledge of pain mechanisms and their management during nicotine withdrawal, or smoking cessation states.

Methods: In this context, the present study investigates the role of brain-derived neurotrophic factor (BDNF), inflammation, and redox balance in the cerebral cortex of adult rats exposed to oral nicotine and passive cigarette smoking through a whole-body inhalation chamber for short- and long-term exposure, where doses closely mimic the human smoking scenario. A subset of the exposure group received a single dose of mecamylamine hydrochloride, a nicotine acetylcholine receptor blocker, to evaluate the precipitated withdrawal effects as contributors to hyperalgesia and neuropathic pain.

Results: The results reveal that nicotine/cigarette smoking induces hyperalgesia, lowers pain tolerance, and upregulates BDNF expression in adult rats as compared to the unexposed healthy controls. Mecamylamine mitigates the negative effects of nicotine by modulating neural circuits of the cerebral cortex involved in pain and inflammation. Specifically, mecamylamine changes cytokine dynamics by upregulating interleukin-6 (IL-6) expression, restoring redox balance, and downregulating BDNF and its receptor, Trk-β, in the cerebral cortex, thereby exacerbating pain sensitivity and ameliorating pain tolerance.

Conclusion: The BDNF-Trk-β/IL-6 cascade in the cerebral cortex may prevent nicotine relapse by alleviating hyperalgesia and neuropathic pain during smoking cessation/nicotine withdrawal.

Implications: Tobacco use is almost double in chronic pain patients, where opioid-based drugs cause more addiction burden. The study provides an insight into potential non-opioid therapeutic strategies targeting the BDNF-Trk-β/IL-6 cascade in the cerebral cortex, the higher center of behavioral activities, using adult rodent models where nicotine doses closely mimic the human smoking situation, including passive cigarette smoking and oral nicotine use. The data of the study may be useful for neuropathic pain management during nicotine withdrawal/smoking cessation and quitting efforts.