Opioid receptor signalling mechanisms

1. Three pharmacological types of opioid receptors, mu, delta and kappa, and their corresponding genes have been identified. Although other types of opioid receptors have been suggested, their existence has not been established unequivocally. A fourth opioid receptor, ORL1, which is genetically closely related to the others, has also been isolated. ORL1 responds to the endogenous agonist nociceptin (orphanin FQ) and displays a pharmacological profile that differs greatly from mu, delta and kappa receptors. 2. All opioid receptors mediate many of their cellular effects via activation of heterotrimeric G-proteins. The mu, delta and kappa receptors are all capable of interacting with the pertussis toxin-sensitive G-protein alpha-subunits Gi1, Gi2, Gi3, Go1, Go2 and the pertussis toxin-insensitive Gz and G16. None of the opioid receptors interacts substantially with Gs and mu receptors do not activate Gq, G11, G12, G13, or G14. 3. Differential coupling of different opioid receptors to most types of G-proteins is marginal. The mu, delta and kappa receptors appear to preferentially activate Go and Gi2 over other pertussis toxin-sensitive G-proteins, although there is evidence that mu receptors show some preference for Gi3. delta Receptors couple more efficiently to G16 than do mu or kappa receptors. 4. There is some evidence that opioid receptors, particularly mu and ORL1 receptors, can also couple to cellular effectors in a G-protein-independent manner. 5. In general, the consequences of activation of any of the opioid receptors in a given cell type depend more on the profile (stoichiometry) of the G-proteins and effectors expressed than on the type of opioid receptor present in the cell. Notions that different types of opioid receptors intrinsically couple preferentially to one type of effector rather than another should, therefore, be discarded.