A Review of the NOP (ORL-1)-Nociceptin/Orphanin FQ System Covering Receptor Structure, Distribution, Role in Analgesia and Reward and Interactions with Other Receptors

The nociceptin/orphanin FQ receptor (NOP; also known as ORL-1, OP4) was first identified and cloned in the mid-90s using reverse pharmacology; shortly after the endogenous ligand nociceptin/orphanin FQ (N/OFQ) was identified. Since these initial discoveries there have been extensive investigations performed, all aimed toward gaining an understanding of NOP’s peripheral, spinal, and supraspinal roles in physiological and pathophysiological processes. This article reviews the molecular biology, in vitro and in vivo pharmacology of the nociceptin system, including the structure-activity relationships associated with the endogenous agonist, as well as the NOP receptor structure and binding-site elucidation studies. As the receptor and its endogenous ligand are widely expressed a cross-species comparison of the anatomical distribution pattern is presented focusing on CNS expression where most literature data is available. While the nociceptin system has been implicated in a wide range of biological actions, the similarities between NOP and the classical opioid receptors have ensured much of this work has centered on the role of NOP in pain transmission, substance abuse, and tolerance; as such this review includes advances from studies in these areas. Where appropriate comparison to the classic opioid system is included and, in addition, literature that is supportive of a central NOP-mediated, regulation of the MOP receptor is presented. Finally the status of the first generation of compounds with activity at NOP receptors to enter the clinic is provided.