SENSITIVITY OF OPIOID RECEPTOR-LIKE RECEPTOR ORL1 FOR CHEMICAL MODIFICATION ON NOCICEPTIN, A NATURALLY-OCCURRING NOCICEPTIVE PEPTIDE

Nociceptin or orphanin FQ is a novel neuropeptide that activates an op ioid-like G protein-coupled receptor ORL1. This heptadecapeptide FGGFT GARKSARKLANQ resembles kappa-opioid peptide dynorphin A but exhibits a n opposite effect to make animals hyperreactive to nociceptive stimula tions (Meunier, J.-C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.-L., Guillemot, J.-C., Ferrara, P., Mons arrat, B., Mazarguil, H., Vassart, G., Parmentier, M., and Costentin, J. (1995) Nature 377, 532-535; Reinscheid, R.K., Nothacker, H.-P., Bou rson, A., Ardati, A., Henningsen, R.A., Bunzow, J.R., Grandy, D.K., La ngen, H., Monsma, F.J., Jr., and Civelli, O. (1995) Science 270, 792-7 94). In the present study, it was found that guinea pig brain contains receptors to which nociceptin binds much more strongly than to ORL1 r eceptors expressed in human 293 cells. Although the Tyr(1) --> Phe sub stitution for dynorphin A eliminates almost completely an ability to b ind to opioid receptors, the Phe(1) --> Tyr substitution in nociceptin was found to retain almost fully both receptor binding affinity and i n vivo hyperalgesic activity in tail-flick assay. Nociceptin was extre mely weak to bind to opioid receptors, while Tyr(1)-nociceptin exhibit ed 10-40 times increased affinity, especially for mu receptors, due to its N-terminal sequential identity to opioid peptides. Shortened anal ogs of dynorphin A are known to retain receptor binding ability and an algesic activity, whereas the removal of C-terminal hexa- or decapepti de from nociceptin totally abolished the affinity for the ORL1 recepto r. These results indicated that the mode of interaction between nocice ptin and ORL1 receptor is quite different from that between dynorphin and opioid receptor and that the C-terminal portion of nociceptin is c rucial for receptor recognition.