Antagonism of the kappa opioid receptor attenuates THC-induced place aversions in adult male Sprague-Dawley rats

Rationale: Prior research with transgenic mice in which the kappa opioid receptor (KOR) has been suppressed or activated suggests that the aversive effects of THC are mediated by activity of this receptor subtype. If the activity of the KOR system is responsible for mediating the THC's aversive effects, then selective antagonism of the KOR by norBNI should block such aversive effects. To test this hypothesis, rats were pretreated with norBNI 24 h prior to place conditioning with THC to assess its effect on the acquisition of THC-induced place aversions. Methods: In Experiment 1, rats pretreated with norBNI (0 or 15 mg/kg) were exposed 24 h later to one side of a place conditioning chamber and injected with THC (0, 0.56, 1 and 3.2 mg/kg). On the next day, they were injected with vehicle and placed on the opposite side of the chamber. This was repeated for a total of five cycles followed by a test of the animal's aversion to the THC-paired side. In Experiment 2, rats were pretreated with norBNI (0 or 30 mg/kg) prior to place conditioning 24 h later with THC (0 or 3.2 mg/kg). Results: In Experiment 1, THC produced dose-dependent place aversions that were unaffected by norBNI (15 mg/kg). In Experiment 2, THC induced significant place aversions that were fully attenuated by norBNI (30 mg/kg). Conclusions: Although 15 mg/kg norBNI was ineffective in antagonizing the aversive effects of THC, 30 mg/kg norBNI blocked the ability of THC to induce a place aversion. The results of the latter assessment are consistent with prior research with transgenic manipulations of the KOR and provide further evidence for the role of the KOR system in the aversive properties of THC.