Orphan receptors and the concept of reverse physiology: discovery of the novel neuropeptide orphanin FQ/nociceptin.

The cloning of numerous orphan members from the supergene family of G protein-coupled receptors implies the existence of many as yet undiscovered neurotransmitters and neuropeptides. Recently, new technologies were developed to isolate natural ligands for orphan receptors, using the receptor as a biological sensor during the purification process. This manuscript will present the concept and technology of an approach which starts from a cloned receptor to ultimately describe the physiological functions of the transmitter system. This strategy inverts the classical order of biomedical research and was thus termed "reverse physiology". The first natural ligand isolated by this strategy is a peptide with significant similarity to the opioid peptides and has been named orphanin FQ or nociceptin (OFQ/NOC). Evidence for characterizing OFQ/NOC as a genuine neuropeptide will be reviewed. OFQ/NOC is biosynthetically derived from a larger precursor protein which may encode additional bioactive peptides. Since its discovery, a large number of studies have described numerous physiological functions of OFQ/NOC. Because of its relation to the opioid system, much attention has been focused on the involvement of OFQ/NOC in nociception, sometimes with controversial results. However, the pharmacological profile of the OFQ/NOC system suggests a clear separation from the opioids. The discovery of OFQ/NOC and the subsequent analyses of its physiological functions is an example which has already been followed by the identification of two other novel neuropeptides. The orphan receptor strategy holds a lot of promises for the postgenomic era, helping to fill the vast amount of sequence data with life.