Results Probl Cell Differ (46) O. Civelli, Q.-Y. Zhou: Orphan G Protein-Coupled Receptors and Novel Neuropeptides DOI 10.1007/400_2007_057/Published online: 12 January 2008  Springer-Verlag Berlin Heidelberg 2008 The Orphanin FQ/Nociceptin (OFQ/N) System Olivier Civelli Department of Pharmacology, Department of Developmental and Cell Biology, University of California, Irvine, Med surge II, Room 369, Irvine, CA 92697-4625, USA ocivelli@uci.edu Abstract Orphanin FQ/nociceptin (OFQ/N) was the first novel neuropeptide discovered as the natural ligand of an orphan G protein-coupled receptor (GPCR). Orphan GPCRs are proteins classified as receptors on the basis of their sequence similarities to known GPCRs but that lack the ligands that activate them in vivo. One such orphan GPCR ex- hibited sequence similarities with the opioid receptors. OFQ/N was isolated as its natural ligand and shown to also share sequence similarities to the opioid peptides. This led to numerous studies attempting to find functional similarities and differences between the OFQ/N and opioid systems. This chapter will summarize our knowledge of the OFQ/N system and of its roles in the organism. Keywords Anxiety · Drug dependence · Memory · Neuropeptide · Orphan GPCR · Pain · Stress Abbreviations OFQ/N Orphanin FQ/nociceptin GPCR G protein-coupled receptor NOP OFQ/N receptor 1 Discovery of OFQ/N The G protein-coupled receptor (GPCR) ORL-1, also called XOR-1, ROR-C, LC132, Hyp8-1, and C (Bunzow et al. 1994; Chen et al. 1994; Fukuda et al. 1994; Lachowicz et al. 1995; Mollereau et al. 1994; Wang et al. 1994; Wick et al. 1995), had been found through its similarities to the opioid receptors and is known to bind none of the opioid peptides or synthetic opiates (Bunzow et al. 1994; Mollereau et al. 1994; Wang et al. 1994). Its natural ligand was therefore unknown, making it part of the orphan GPCRs. Purification of the natural ligand of the ORL-1 receptor was achieved sim- ultaneously in two different laboratories starting from either rat or porcine brain extracts (Meunier et al. 1995; Reinscheid et al. 1995). ORL-1 cDNA was transfected into cells that were exposed to the different extracts. Because of its similarities to the opioid receptors, it was assumed that ORL-1 might also bind a peptidergic ligand and share the same coupling mechanism to second