[Fom orphan receptor to novel neuropeptide: an example of reverse pharmacology]

Nociceptin, a neuropeptide 17 amino acid residues in length, is the first novel bioactive substance to have been discovered by functional genomics. Nociceptin was isolated from a rat brain extract as the endogenous ligand to an orphan receptor, ORL1 (Opioid Receptor-Like 1), structurally akin to opioid receptors, whose cDNA had been cloned from a human brain stem library. The peptide is processed from a larger precursor polypeptide, prepro-nociceptin, which is widely distributed in the nervous system. Nociceptin is primarily an inhibitory neuropeptide that acts on neurons to depress synaptic transmission. Nociceptin's wide spectrum of pharmacological actions hints at several potential therapeutic applications for ORL1 receptor agonists and/or antagonists, particularly for treating pain states, stress and anxiety, cognitive defects, and drug addiction. A major challenge is now the discovery and pharmacological in vivo profiling of ORL1 receptor ligands that are active by medically practical routes of administration.