The cannabinoid receptor agonists, anandamide and WIN 55,212-2, do not directly affect mu opioid receptors expressed in Xenopus oocytes

A functional link between the cannabinoid and opioid receptor pathways has been proposed based on data showing that cannabinoid effects can be blocked by opioid receptor antagonists and that cannabinoids can bind to opioid receptors. To explore this link in more detail at the receptor level, we tested the hypothesis that cannabinoids directly activate or modulate mu opioid receptor function. The G-protein coupled mu opioid receptor, MOR-1, and its effector, the G-protein activated potassium channel, GIRK2 (Kir3.2), were expressed together in Xenopus oocytes and potassium currents measured using the two-electrode voltage clamp technique. The specific mu receptor agonist DAMGO activated potassium currents in oocytes expressing the mu receptor that were fully inhibited by the mu receptor antagonist, naloxone. The endogenous cannabinoid, anandamide, and the synthetic cannabinoid, WIN 55,212-2, had no direct effects on potassium currents in the oocytes expressing the mu receptor. The cannabinoids also had no effect on the magnitude of the potassium currents activated by DAMGO or on the desensitization kinetics of MOR-1 in the continued presence of DAMGO. Both WIN 55,212-2 and anandamide activated cannabinoid CB1 receptors when co-expressed with GIRK2 in the oocytes. We conclude that neither anandamide nor WIN 55,212-2 directly activate or modulate mu opioid receptor function in oocytes and that interactions of cannabinoids with mu opioid receptors are likely to be indirect.