Role of the kappa-opioid receptor system in stress-induced reinstatement of nicotine seeking in rats

Abstract

Rationale The correlation between stress and smoking is well established. The mechanisms that underlie this relationship are, however, unclear. Recent data suggest the kappa-opioid system is involved in the mediation of negative affective states associated with stress thereby promoting drug addiction and relapse. Pharmacological treatments targeting the kappa opioid system and this mechanism may prove to be useful therapeutics for nicotine addiction in the future. Objectives We sought to determine whether there was a stress-specific role of the kappa opioid system in nicotine seeking behavior. Method Groups of male Long Evans rats were trained to self-administer nicotine intravenously; their operant responding for nicotine was extinguished prior to tests of reinstatement. Pretreatment with systemic injections of the kappa opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was given prior to tests of stress (systemic injections of yohimbine (YOH)) or cue-induced reinstatement of nicotine seeking. Systemic injections of the KOR agonist U50,488 were also given in a test for reinstatement of nicotine seeking. Results Nor-BNI pretreatment at 1 hr and 24 hrs prior to testing was able to block YOH-induced, but not cue-induced reinstatement of nicotine seeking. U50,488 reinstated nicotine seeking behavior in a dose-dependent manner. Conclusions These findings support the hypothesis that the kappa opioid system is involved in relapse to nicotine seeking induced by stress, but not by conditioned cues. KOR antagonists such as nor-BNI may therefore be useful novel therapeutic agents for decreasing the risk of stress-induced drug relapse.

nor-BNI Antagonism of Kappa Opioid Agonist-Induced Reinstatement of Ethanol-Seeking Behavior

“…Previous work has shown that KOR antagonists block stress induced reinstatement of cocaine seeking and nicotine seeking in rats [2, 3]. The selective KOR antagonist norbinaltorphimine (nor-BNI) also reverses reinstatement of heroin seeking by the pharmacological stressor yohimbine [4].…”

Drug withdrawal conceptualized as a stressor

“…In general, KOR activation produces aversive states that, at least in laboratory animals, have characteristics of both withdrawal and stress (Bals-Kubik et al ., 1993; Newton et al ., 2002; McLaughlin et al ., 2003, 2006a; Bruchas et al ., 2010; Knoll and Carlezon, 2010; Muschamp et al ., 2011). Further, KOR activation is crucial in facilitating stress-induced reinstatement of operant responding in animals with substantial self-administration experience that have undergone extinction of operant responding for drug (Beardsley et al ., 2005; Land et al ., 2009; Bruchas et al ., 2010; Sun et al ., 2010; Schank et al ., 2012; Graziane et al ., 2013; Grella et al ., 2014; Sedki et al ., 2014) or reinstatement of drug-induced conditioned place preference (Carey et al ., 2007; Redila and Chavkin, 2008; Cordery et al ., 2012; Al-Hasani et al ., 2013; Jackson et al ., 2013; Aldrich et al ., 2014). An implicit assumption in these studies is that stress-induced dynorphin release produces negative affective states that drive reinstatement (Koob, 2008).…”

Neurobiological and Neurophysiological Mechanisms Underlying Nicotine Seeking and Smoking Relapse

“…Preclinical studies thus far revealed important roles for the norepinephrine, endocannabinoid, and neuropeptide systems (including opiate receptor and CRF mechanisms) in stress-primed reinstatement [142, 150, 160, 260]. Another critical consideration for ongoing research will be a closer examination of gender differences and their influence on stress-mediated relapse.…”

“…For example, dysregulation of dynorphin/kappa opioid receptor signaling in the brain may contribute to stress-induced reinstatement of drug seeking [158, 159]. A recent study showed that systemic administration of the selective kappa opioid receptor antagonist nor-binaltorphimine attenuates stress-, but not cue-, induced reinstatement of nicotine seeking [160]. Interestingly, systemic administration of the mixed mu/kappa opioid receptor antagonist naltrexone reduces cue-induced reinstatement of nicotine seeking [161].…”