Cellular Mechanisms of Nociceptin/Orphanin FQ (N/OFQ) Peptide (NOP) Receptor Regulation and Heterologous Regulation by N/OFQ

Abstract

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.

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

“…This could be due to the fact that these were partial agonists or potentially due to an intrinsic difference in ligand-stimulated b-arrestin coupling and internalization, as has been demonstrated for mu receptors (Zaki et al, 2000;Bohn et al, 2004). It has been suggested that receptor regulation depends on the agonist examined and that peptide versus small molecule agonists at NOP receptors might influence their regulation via different mechanisms but this hypothesis requires further examination (Donica et al, 2013).…”

“…The receptor is rendered less responsive to repeated or continuous stimulation and exposure to agonist. Receptor desensitization is one of the underlying mechanisms for opioid tolerance, and NOP receptors have been shown to become desensitized after high agonist concentration or repeated sustained exposure to agonists in a number of contexts (Connor et al, 1996a;Mandyam et al, 2000;Thakker and Standifer, 2002a) in both acute and chronic treatment paradigms (for a thorough review on NOP receptor regulation see, Donica et al, 2013). In addition, receptor desensitization to the known NOP receptor downstream signaling cascades including ion channels, kinase signaling, and cAMP have been demonstrated by numerous groups.…”

“…GPCR internalization is mediated via recruitment of arrestin and typically via either a clathrin-dependent or -independent process. Numerous groups have investigated the many stages of NOP receptor trafficking (for a thorough review, see Donica et al, 2013). Early work in the NOP receptor field had difficulty in finding agonistinduced internalization (Dautzenberg et al, 2001); however, later reports showed that NOP receptors indeed internalized in response to N/OFQ treatment (Spampinato et al, 2001(Spampinato et al, , 2002.…”

“…The receptor undergoes a shift in conformation, allowing for arrestin docking to the receptor and subsequently the recruitment of the endocytosis machinery. The human, mouse and rat NOP receptors contain multiple serine, tyrosine, and threonine sites within their intracellular loops and C termini that are suitable for GRK or protein kinase A/C phosphorylation (Zhang et al, 2012a;Donica et al, 2013). GRK regulation of NOP receptors has been shown to act at multiple C-terminal sites (Mandyam et al, 2002).…”

Activation of the endogenous nociceptin system by selective nociceptin receptor agonist SCH 221510 produces antitransit and antinociceptive effect: a novel strategy for treatment of diarrhea‐predominant IBS

“…The antinociceptive effect of nociceptin was observed in animal models of visceral pain, what may be crucial for the resolution of IBS‐D. Moreover, studies on the interaction with several neurotransmitter systems, such as acetylcholine, glutamate, serotonin, and tachykinins through kinase activation and channel modulation may also be important for understanding of the GI tract pathophysiology and brain‐gut pain signaling …”