REVERSE PHYSIOLOGY - DISCOVERY OF THE NOVEL NEUROPEPTIDE, ORPHANIN FQNOCICEPTIN

The search for novel neurotransmitters and neuropeptides has been rece ntly revolutionized by the development of a purification strategy base d on orphan G protein-coupled receptors, cloned receptors for which no natural ligands are known. This strategy uses the orphan receptor as bait to identify its natural ligand. This article will review the disc overy of the first natural ligand isolated following this strategy. Th is ligand is a peptide that shares some striking sequence similarity t o the opioid peptides and has been named Orphanin FQ or Nociceptin (OF Q/NOC). The discovery of OFQ/NOC will be described as one example of t he use of orphan receptors in identifying novel neurotransmitters and neuropeptides, an example that has already been followed in the identi fication of other novel neuropeptides. After reviewing the conceptual and technological basis of the strategy and its successful first appli cation, we discuss the criteria used to validate OFQ/NOC as the natura l ligand of the orphan receptor and as a genuine neuropeptide. We also discuss the importance and implications of discovering OFQ/NOC mode o f synthesis, which is synthesized as expected in the form of a larger polypeptide precursor, which in turn raises the question of the existe nce of other OFQ/NOC-related peptides. We then present an overview of the numerous studies that have blossomed after the OFQ/NOC discovery a nd describe the numerous physiological roles that have already been at tributed to OFQ/NOC, and in particular the controversy regarding its i nvolvement in pain perception. Because of the similarities between the OFQ/NOC and opioid systems, we also discuss overlaps between these sy stems and present evidence favoring a pharmacological separation betwe en these systems. We finish by outlining the power of the orphan recep tor strategy and by discussing some of its pitfalls.