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 op ioid receptors have been suggested, their existence has not been establishe d unequivocally. A fourth opioid receptor, ORL1, which is genetically close ly related to the others, has also been isolated. ORL1 responds to the endo genous agonist nociceptin (orphanin FQ) and displays a pharmacological prof ile that differs greatly from mu, delta and kappa receptors. 2. All opioid receptors mediate many of their cellular effects via activati on of heterotrimeric G-proteins. The mu, delta and kappa receptors are all capable of interacting with the pertussis toxin-sensitive G-protein alpha-s ubunits G(i1), G(i2), G(i3), G(o1), G(o2) and the pertussis toxin-insensiti ve G(z) and G(16) None of the opioid receptors interacts substantially with G(s) and mu 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-p roteins is marginal. The mu, delta and kappa receptors appear to preferenti ally activate G(o) and G(i2) over other pertussis toxin-sensitive G-protein s, although there is evidence that mu receptors show some preference for G( 13). delta Receptors couple more efficiently to G(16) than do mu or kappa r eceptors. 4. There is some evidence that opioid receptors, particularly mu and ORL1 r eceptors, can also couple to cellular effecters in a G-protein-independent manner. 5. In general, the consequences of activation of any of the opioid receptor s in a given cell type depend more on the profile (stoichiometry) of the G- proteins and effecters expressed than on the type of opioid receptor presen t in the cell. Notions that different types of opioid receptors intrinsical ly couple preferentially to one type of effector rather than another should , therefore, be discarded.