Cellular mechanisms of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor regulation and heterologous regulation by N/OFQ

The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is the fourth and most recently discovered member of the opioid receptor superfamily that also includes m, d, and k opioid receptor subtypes (MOR, DOR, and KOR, respectively). The widespread anatomic distribution of the NOP receptor enables the modulation of several physiologic processes by its endogenous agonist, N/OFQ. Accordingly, the NOP receptor has gained a lot of attention as a potential target for the development of ligands with therapeutic use in several pathophysiological states. NOP receptor activation frequently results in effects opposing classic opioid receptor action; therefore, regulation of the NOP receptor and conditions affecting its modulatory tone are important to understand. Mounting evidence reveals a heterologous interaction of the NOP receptor with other G protein-coupled receptors, including MOR, DOR, and KOR, which may subsequently influence their function. Our focus in this review is to summarize and discuss the findings that delineate the cellular mechanisms of NOP receptor signaling and regulation and the regulation of other receptors by N/OFQ and the NOP receptor.