OPIOID RECEPTOR SIGNALLING MECHANISMS

Abstract

1. Three pharmacological types of opioid receptors, μ, δ and κ, 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 μ, δ and κ receptors. 2. All opioid receptors mediate many of their cellular effects via activation of heterotrimeric G‐proteins. The μ, δ and κ receptors are all capable of interacting with the pertussis toxin‐sensitive G‐protein α‐subunits G i1, G i2, G i3, G o1, G o2 and the pertussis toxin‐insensitive G z and G 16. None of the opioid receptors interacts substantially with G s and μ receptors do not activate G q, G 11, G 12, G 13 or G 14. 3. Differential coupling of different opioid receptors to most types of G‐proteins is marginal. The μ, δ and κ receptors appear to preferentially activate G o and G i2 over other pertussis toxin‐sensitive G‐proteins, although there is evidence that μ receptors show some preference for G i3. δ Receptors couple more efficiently to G 16 than do μ or κ receptors. 4. There is some evidence that opioid receptors, particularly μ 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.