RNA-injected Xenopus oocytes were used for studying homologous desensitization of opioid receptors to G-protein-coupled intracellular signaling pathways. In the oocytes expressing K opioid receptor, voltage-dependent Ca²⁺ channel α²⁺ and β subunits, the κ agonist U50488H (1 μM) inhibited Ca²⁺ channel current in a reversible manner, and the inhibition was diminished by sustained agonist exposure (homologous desensitization). More than 10 min was required to halve the inhibition of BI- or Q-type Ca²⁺ channels by the κ agonist, however, the t_½ for U50488H-induced inhibition of BIII- or N-type channels was only 6±1 min. Moreover, in the oocytes expressing κ opioid receptor, EP₄ prostaglandin receptor and CFTR channel, no apparent desensitization was observed in the κ receptor-mediated potentiation of the cyclic AMP production by prostaglandin E₂ even when the oocytes were treated with U50488H for 2 hours or more. The time-course of desensitization of μ opioid receptor was also different in the effector molecules. These observations suggest that rate of homologous desensitization of opioid receptor is not only dependent on the receptor molecule itself but also on its intracellular signaling systems.