Effect of the selective kappa-opioid receptor antagonist JDTic on nicotine antinociception, reward, and withdrawal in the mouse

Abstract

Rationale: Several lines of evidence support a role for the endogenous opioid system in mediating behaviors associated with drug dependence. Specifically, recent findings suggest that the kappa-opioid receptor (KOR) may play a role in aspects of nicotine dependence, which contribute to relapse and continued tobacco smoking.

Objective: The objective of this study is to determine the involvement of the KOR in the initial behavioral responses of nicotine, nicotine reward, and nicotine withdrawal using the highly selective KOR antagonist JDTic. JDTic doses of 1, 4, 8, or 16 mg/kg were administered subcutaneously (s.c.) 18 h prior to nicotine treatment.

Results: JDTic dose-dependently blocked acute nicotine-induced antinociception in the tail-flick but not the hot-plate test and did not significantly attenuate morphine's antinociceptive effect in either the tail-flick or hot-plate test. Furthermore, JDTic (8 and 16 mg/kg, s.c.) failed to block the expression of nicotine reward as measured by the conditioned place preference model. In contrast, JDTic and the KOR antagonist norBNI attenuated the expression of both the physical (somatic signs and hyperalgesia) and affective (anxiety-related behavior and conditioned place aversion) nicotine withdrawal signs.

Conclusions: Our findings clearly show that the KOR is involved in mediating the withdrawal aspects of nicotine dependence. The results from this study suggest that blockade of the KOR by selective KOR antagonists may be useful smoking cessation pharmacotherapies.

Fig. 1

Effects of JDTic on nicotine-induced hypothermia and antinociception. A single injection of nicotine (2.5 mg/kg, s.c.) induced a significant antinociception in the (a) tail-flick and (b) hot-plate tests, and (c) a decrease in body temperature in mice. a Nicotine-induced spinal antinociception measured using the tail-flick test was dose-dependently blocked by 18-h pretreatment with JDTic. JDTic had no significant effect in the hot-plate or body-temperature tests, and the highest dose used did not produce significant behavioral effects in saline treated mice. Each point represents the mean±SEM of six mice per group. Asterisk denotes p<0.05 vs. the saline and JDTic control groups and vs. nicotine-JDTic 16 mg/kg group for the tail-flick test (a)

Fig. 2

Effects of JDTic on the expression of nicotine reward in mice. Nicotine (0.5 mg/kg, s.c.) induced a significant conditioned place preference (CPP) in mice. Eighteen-hour pretreatment with JDTic (8 or 16 mg/kg) had no effect on expression of nicotine CPP in mice conditioned with 0.5 mg/kg nicotine. Each point represents the mean± SEM of eight mice per group. Asterisk denotes p<0.05 vs. the saline and JDTic control groups

Fig. 3

Physical and somatic nicotine withdrawal are blocked by pretreatment with JDTic. Mice chronically infused with nicotine for 7 days (36 mg/kg/day) were withdrawn from nicotine for 18–24 h. A significant (a) anxiety-related response, (b) increase in somatic withdrawal signs, and (c) hyperalgesia response were observed in nicotine-withdrawn mice. Eighteen-hour pretreatment with JDTic (8 mg/kg, s.c.) significantly attenuated expression of both the physical and affective nicotine withdrawal responses in mice. Each point represents the mean±SEM of six to eight mice per group. Asterisk denotes p<0.05 vs. the saline and JDTic control groups, and vs. nicotine-JDTic group. MP mini pump

Fig. 4

Physical and somatic nicotine withdrawal are blocked by pretreatment with norBNI. Mice were spontaneously withdrawn from nicotine (18–24 h) and treated with norBNI 18 h prior to testing. Results show that expression of (a) the anxiety-related response, (b) the increase in somatic signs, and (c) the hyperalgesia response were blocked by pretreatment with norBNI. Each point represents the mean±SEM of six to eight mice per group. Asterisk denotes p<0.05 vs. the saline and norBNI control groups, and vs. nicotine-norBNI group

Fig. 5

Expression of nicotine withdrawal aversion is blocked by kappa-opioid receptor antagonists. Mecamylamine (3.5 mg/kg, s.c.) precipitated a significant conditioned place aversion in chronic nicotine-infused mice. Expression of aversion was blocked by an 18-h pretreatment with the kappa-opioid antagonists, JDTic (16 mg/kg, s.c.), and norBNI (10 mg/kg, s.c.). Each point represents the mean±SEM of ten to 11 mice per group. Asterisk denotes p<0.05 vs. saline groups and nicotine-JDTic and nicotine-norBNI groups; sal saline, nic nicotine, mec mecamylamine