Sensitivity of Opioid Receptor-like Receptor ORL1 for Chemical Modification on Nociceptin, a Naturally Occurring Nociceptive Peptide

Abstract

Nociceptin or orphanin FQ is a novel neuropeptide that activates an opioid-like G protein-coupled receptor ORL1. This heptadecapeptide FGGFTGARKSARKLANQ resembles kappa-opioid peptide dynorphin A but exhibits an opposite effect to make animals hyperreactive to nociceptive stimulations (Meunier, J.-C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.-L., Guillemot, J.-C., Ferrara, P., Monsarrat, B., Mazarguil, H., Vassart, G., Parmentier, M., and Costentin, J. (1995) Nature 377, 532-535; Reinscheid, R. K., Nothacker, H.-P., Bourson, A., Ardati, A., Henningsen, R. A., Bunzow, J. R., Grandy, D. K., Langen, H., Monsma, F. J., Jr., and Civelli, O. (1995) Science 270, 792-794). In the present study, it was found that guinea pig brain contains receptors to which nociceptin binds much more strongly than to ORL1 receptors expressed in human 293 cells. Although the Tyr1 --> Phe substitution for dynorphin A eliminates almost completely an ability to bind to opioid receptors, the Phe1 --> Tyr substitution in nociceptin was found to retain almost fully both receptor binding affinity and in vivo hyperalgesic activity in tail-flick assay. Nociceptin was extremely weak to bind to opioid receptors, while Tyr1-nociceptin exhibited 10-40 times increased affinity, especially for mu receptors, due to its N-terminal sequential identity to opioid peptides. Shortened analogs of dynorphin A are known to retain receptor binding ability and analgesic activity, whereas the removal of C-terminal hexa- or decapeptide from nociceptin totally abolished the affinity for the ORL1 receptor. These results indicated that the mode of interaction between nociceptin and ORL1 receptor is quite different from that between dynorphin and opioid receptor and that the C-terminal portion of nociceptin is crucial for receptor recognition.

Further characterization of the ORL1 receptor‐mediated inhibition of noradrenaline release in the mouse brain in vitro

“…This view is further supported by our present ®nding that [Tyr 14 ]-nociceptin (identi®ed as a potent ORL 1 receptor ligand by Reinscheid et al, 1995;Berzetei-Gurske et al, 1996;Shimohigashi et al, 1996;Mathis et al, 1997) mimicked the e ect of nociceptin, in a manner sensitive to naloxone benzoylhydrazone. As expected, [des-Phe 1 ]-nociceptin, a degradation product of nociceptin (Montiel et al, 1997), failed to mimic the e ect of nociceptin.…”

Highly Potent Nociceptin Analog Containing the Arg-Lys Triple Repeat

“…Membranes were prepared from human embryonic kidney 293 cells expressing human ORL1, , ␦, and opioid receptors as described previously (25 Briefly, incubations were carried out at room temperature for 60 min in Tris-HCl buffer (pH 7.55) containing 0.1% bovine serum albumin. Bacitracin (100 g/ml) was added as an enzyme inhibitor.…”

“…A number of nociceptin analogs have been designed and synthesized to clarify the structural essentials for receptor interaction (18,19,(25)(26)(27)(28)(29). However, no analogs more potent than native nociceptin have yet been announced.…”

Hormones and the hippocampus

“…Although several brain molecules modulate nociception, including prostaglandins, several neuropeptides, interleukins, tumour necrosis factor, angiotensin, bombesin and CCK, attention has focused on an endogenous peptide, orphanin FQ (Reinscheid et al 1995), also termed nociceptin (Meunier 1997). This peptide is reported to mediate hyperalgesia by binding to the orphan receptor, ORL1 (Shimohigashi et al 1996, Meunier 1997. It is not known physiologically where nociceptin is produced and the nature of its principal target sites for action.…”