Motivational effects of cannabinoids are mediated by μ-opioid and κ-opioid receptors

Repeated THC administration produces motivational and somatic adaptive changes leading to dependence in rodents. To investigate the molecular basis for cannabinoid dependence and its possible relationship with the endogenous opioid system, we explored Delta9-tetrahydrocannabinol (THC) activity in mice lacking mu-, delta- or kappa-opioid receptor genes. Acute THC-induced hypothermia, antinociception, and hypolocomotion remained unaffected in these mice, whereas THC tolerance and withdrawal were minimally modified in mutant animals. In contrast, profound phenotypic changes are observed in several place conditioning protocols that reveal both THC rewarding and aversive properties. Absence of mu receptors abolishes THC place preference. Deletion of kappa receptors ablates THC place aversion and furthermore unmasks THC place preference. Thus, an opposing activity of mu- and kappa-opioid receptors in modulating reward pathways forms the basis for the dual euphoric-dysphoric activity of THC.