Motivational Effects of Cannabinoids Are Mediated
by mu- Opioid and kappa -Opioid Receptors

Ghozland S, Matthes HW, Simonin F,
Filliol D, Kieffer BL, Maldonado R.
Laboratori de Neurofarmacologia, Facultat de Ciencies de la Salut i de la Vida,
Universitat Pompeu Fabra, 08003 Barcelona, Spain,
Centre National de la Recherche Scientifique Unite Propre de Recherche 9050,
Ecole Superieure de Biotechnologie de Strasbourg, 67400 Illkirch, France.
J Neurosci 2002 Feb 1;22(3):1146-1154


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 [Delta]9-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.

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