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Cannabinoid receptor and WIN 55 212‐2‐stimulated [35S]‐GTPγS binding in the brain of mu‐, delta‐ and kappa‐opioid receptor knockout mice

Numerous studies have shown the existence of functional links between the endogenous cannabinoid and opioid systems. However, extensive research is still needed to elucidate the biochemical mechanisms involved in this cannabinoid–opioid interaction. Mice lacking mu‐ (MOR), delta‐ (DOR) and kappa‐ (KOR) opioid receptors have been generated and some specific pharmacological effects induced by cannabinoids have been reported to be modified in these animals. In order to clarify further the possible mechanisms involved in this modification of cannabinoid responses we have now evaluated the expression and functional activity of cannabinoid receptors in different brain structures in these mutant animals. For this purpose, we have performed quantitative receptor autoradiography of CB1 cannabinoid receptors and activation of GTP‐binding proteins by CB1 agonists in the brain of wild‐type and homozygous MOR, DOR and KOR knockout mice. There were no significant differences in the levels of CB1 receptors in the brain of MOR mutant mice. In contrast, the efficacy of CB1 receptor activation by the cannabinoid agonist WIN 55 212‐2 was dramatically reduced in the caudate‐putamen of MOR knockout animals. The density of CB1 receptors as well as the stimulation of GTP‐binding proteins by WIN 55 212‐2 were significantly increased in the substantia nigra of mice deficient in DOR. Finally, there were no major changes in the levels and functional activity of CB1 cannabinoid receptors in any brain region in KOR knockout mice. Taken together, these results indicate that deletion of MOR and DOR causes alterations in cannabinoid receptor levels and functional activity in specific brain structures, which could explain some of the functional interactions observed between these two neuronal systems.