Effects of kappa opioid receptor agonist and antagonist on the aversive effects of nicotine
Authors: DSouza Manoranjan S , Ward Melissa , Norman Haval 
Published: November 2023

Nicotine is a major psychoactive component of tobacco smoke. The rewarding effects of nicotine play an important role in the initiation and maintenance of tobacco smoke. However, nicotine also produces aversive effects. Interestingly, the aversive effects of nicotine largely determine the rate of development and intensity of nicotine dependence. We hypothesize that increasing the aversive effects of nicotine will help to promote smoking cessation. However, neural targets mediating the aversive effects of nicotine have not been fully identified. Nicotine binds to excitatory nicotinic receptors located on dynorphin‐releasing neurons and induces dynorphin release. Dynorphin is associated with stress‐like aversive states and is an endogenous ligand for the kappa opioid receptors (KORs). Therefore, in this study we evaluated the role of KORs in the aversive effects of nicotine using the nicotine‐induced conditioned taste aversion (CTA) model in rats. Nicotine‐induced CTA is a robust model to assess the aversive effects of nicotine and involves conditioning of two flavored solutions (e.g. grape and cherry Kool‐Aid solutions) with nicotine/saline in Wistar rats. First, a preferred flavored solution was determined by giving the animals simultaneous access to the two solutions during a PreTest. Subsequently, conditioning with nicotine and saline was carried out for eight days with four days of nicotine conditioning alternated with four days of saline conditioning. During conditioning, nicotine (0.4 mg/kg, base) was administered subcutaneously (s.c.) immediately after consumption of the preferred flavored solution and saline was administered after consumption of the other flavored solution on alternate days. The KORs were activated using the selective KOR agonist U50488 (0, 0.03, 0.15 & 0.3 mg/kg; s.c.) and inhibited using the KOR antagonist norBNI (0, 15 & 30 mg/kg; s.c.) in separate group of rats using a between‐subjects design. U50488 was administered 15 minutes prior to consumption of flavored solution on nicotine conditioning days. Because of the long‐acting nature of norBNI (3 weeks), norBNI was administered immediately after the PreTest but before conditioning with nicotine and saline. After, conditioning with nicotine and saline, preference of the animals to the two flavored solution was assessed again. When a solution is paired consistently with nicotine during conditioning, the aversive effects produced by nicotine will lead to avoidance of that flavored solution on the Test day in comparison to the other flavored solution associated with saline. In other words, control animals consumed less of the previously preferred solution on the Test day compared to PreTest day, suggesting development of nicotine‐induced aversive effects. We further report that administration of KOR agonist on nicotine conditioning days dose‐dependently increased nicotine‐induced aversive effects. In contrast, administration of norBNI prior to conditioning with nicotine attenuated nicotine‐induced aversive effects. Taken together, these data suggest that KORs mediate the aversive effects of nicotine and activation of KORs can possibly help in promoting smoking cessation.Support or Funding InformationSupported by Bower, Bennet, and Bennet Endowed Chair Research Award awarded to Dr. Manoranjan S. D'Souza by The Raabe College of Pharmacy, Ohio Northern University (ONU), Ada, Ohio.