Chapter Eight - Central N/OFQ-NOP Receptor System in Pain Modulation
Introduction
After the cloning of delta- (Evans et al., 1992, Kieffer et al., 1992), kappa- (Yasuda et al., 1993), and mu- (Chen, Mestek, Liu, Hurley, & Yu, 1993) opioid receptors (DOP, KOP, and MOP receptors, respectively), several groups of scientists in 1994 identified a G-protein coupled receptor with high homology to opioid receptors and this receptor was named opioid receptor like 1 (ORL1) (Bunzow et al., 1994, Fukuda et al., 1994, Mollereau et al., 1994, Nishi et al., 1994, Wang et al., 1994). Subsequently, an endogenous haptadecapeptide (FGGFTGARKSARKLANQ) selective for ORL1 was discovered independently by two groups. This peptide was named “nociceptin” by one group based on its ability to elicit hyperalgesia following supraspinal administration in mice (Meunier et al., 1995). The other group named this same peptide as “orphanin FQ” based on the recognition of ORL1 and its first and last amino acid residues (Reinscheid et al., 1995). After the identification of nociceptin/orphanin FQ (N/OFQ), the ORL1 was renamed N/OFQ peptide (NOP) receptor based on the nomenclature guidelines recommended by the International Union of Basic and Clinical Pharmacology (Cox, Christie, Devi, Toll, & Traynor, 2015).
N/OFQ is derived from a precursor prepro-N/OFQ (ppN/OFQ), which is encoded on chromosome 8p21 in humans (Mollereau et al., 1996), and the sequence of ppN/OFQ gene has similar structural features to precursors of classical opioid peptides, such as prepro-enkephalin, -dynorphin, and -opiomelanocortin (Sundstrom, Dreborg, & Larhammar, 2010). The amino acid sequence of ppN/OFQ is highly conserved across several animal species, and ppN/OFQ and N/OFQ are widely distributed in the peripheral and central nervous system (CNS) of both rodents and primates. In particular, N/OFQ is provided by interneurons in numerous areas of the brain (Neal et al., 1999b, Peluso et al., 1998, Witta et al., 2004), suggesting its multiple effects on brain function. N/OFQ is also expressed in the dorsal horn and ventral horn of the spinal cord which integrate sensory processing (Neal et al., 1999b).
On the other hand, NOP receptor gene is encoded on chromosome 20 in humans (Lambert, 2008, Sundstrom et al., 2010), and its primary structure is also highly conserved across mammalians (Calo & Guerrini, 2013). According to several biochemical studies and three-dimensional crystal structure analysis, positions of amino acid residues configuring the binding pocket of NOP receptor differ from those of DOP, KOP, and MOP receptors (Granier et al., 2012, Manglik et al., 2012, Thompson et al., 2012, Wu et al., 2012). Consequentially, the hydrophobic and hydrophilic parts of the binding pockets of the NOP receptor and other opioid receptors are different. These atomic details of ligand–receptor recognition explain marked differences in the binding selectivity of corresponding ligands in spite of high sequence homology between the NOP receptor and classical opioid receptors (Calo and Guerrini, 2013, Calo et al., 2000, Schröder et al., 2014). Like N/OFQ, the NOP receptor is abundant in multiple brain areas and spinal cord (Berthele et al., 2003, Neal et al., 1999a), indicating that the N/OFQ-NOP receptor system plays a fundamental role in regulating several functions including pain.
Similar to classical opioid receptors (i.e., DOP, KOP, and MOP receptors), NOP receptor is coupled to pertussis toxin-sensitive Gi/o proteins, which inhibit adenylate cyclase and voltage-gated calcium channels and activate inward potassium channels (Hawes et al., 2000, Ma et al., 1997, Margas et al., 2008). These cellular events following NOP receptor activation reduce synaptic transmission, by either reducing neurotransmitter release via presynaptically located NOP receptors or inhibiting neuronal excitability via postsynaptically located NOP receptors (Connor, Vaughan, et al., 1996, Connor et al., 1996, Knoflach et al., 1996). Indeed, NOP receptor activation has been shown to inhibit the release of a variety of neurotransmitters (e.g., glutamate, gamma aminobutyric acid (GABA), substance P, and noradrenaline) in the CNS (Nicol et al., 1998, Nicol et al., 1996, Schlicker and Morari, 2000). Although NOP receptor activation induces a similar pattern of intracellular events as MOP, DOP, and KOP receptors, NOP receptor-mediated effects on pain modulation are more complicated than MOP receptor activation. Depending on the administration routes and animal species, NOP receptor activation could potentially lead to either pronociceptive or antinociceptive effect (Schröder et al., 2014). In this review, we highlight the functional evidence of central N/OFQ-NOP receptor system for regulating pain processing. In specific, we discuss the pharmacological evidence of spinal and supraspinal NOP receptor activation and integrated outcomes from systemic administration of NOP receptor-related ligands between rodents and nonhuman primates. Accumulated evidence strongly supports the therapeutic potential of NOP receptor-related agonists as effective and safe analgesics in primates.
Section snippets
Spinal Actions of NOP Receptor Agonists in Rodent Models of Acute Pain
Since the NOP receptor is present at central pain-processing pathways (Anton et al., 1996, Mollereau and Mouledous, 2000, Neal et al., 1999a), several groups of researchers have investigated the function of spinal N/OFQ-NOP receptor system in pain modulation. In rodents, several lines of evidence demonstrate that intrathecal administration of N/OFQ at nanomole doses produced antinociceptive effects in the rodent tail flick test (King et al., 1997, Xu et al., 1996). Intrathecal N/OFQ also had
Supraspinal Actions of NOP Receptor Agonists in Rodent Models of Acute Pain
The NOP receptor is abundant in supraspinal areas, such as thalamus, hypothalamus, locus coeruleus, periaqueductal gray (PAG), and rostral ventromedial medulla (RVM), which modulate ascending and descending pain pathways (Civelli, 2008, Heinricher et al., 1997, Mollereau and Mouledous, 2000, Neal et al., 1999a). Supraspinal actions of the N/OFQ-NOP receptor system are complicated, as supraspinal NOP receptor activation produces opposite effects on pain processing depending on the pain state and
Systemic Actions of NOP Receptor Agonists in Rodent Models of Acute Pain
As mentioned above, the involvement of N/OFQ-NOP receptor system in nociceptive processing is multimodal depending upon pain modalities and routes of administration in rodents. Effects of systemically administered NOP receptor agonists depend on the integration of peripheral, spinal, and supraspinal sties of action. Early studies show that systemic administration of a nonpeptidic NOP receptor agonist Ro64-6198 did not produce antinociceptive effects in the mouse and rat tail flick tests, nor in
Development of Bifunctional NOP/MOP Receptor Agonists
In the early stage of developing NOP receptor-related ligands as analgesics, the effort was mainly focused on NOP receptor antagonists due to central NOP receptor-mediated pronociception and antiopioid actions, and NOP receptor antagonist-induced antihyperalgesia in rodent pain models (Lutfy et al., 2003, Meunier et al., 1995, Mogil et al., 1996, Reinscheid et al., 1995). For example, pretreatment with a NOP receptor antagonist J-113397 potentiated antinociceptive effects of buprenorphine in
Conclusion
Taken together, functional profiles of central NOP receptor activation are different between rodents and primates. In rodents, antinociceptive and antihypersensitive actions of the N/OFQ-NOP receptor system in spinal and supraspinal areas are bidirectional depending on the doses, assays, and pain modalities. In stark contrast, NOP receptor-related ligands, i.e., both selective NOP receptor agonists and mixed NOP/MOP receptor agonists, produced only antinociception and antihypersensitivity in
Conflict of Interest
N.K. and H.D. declare that there is no conflict of interest. M.C.K. received research contracts from Grünenthal GmbH and Purdue Pharma L.P.
Acknowledgments
The U.S. National Institutes of Health, National Institute on Drug Abuse (DA032568, DA035359, and DA040104), National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR059193 and AR064456), and the U.S. Department of Defense (W81XWH-13-2-0045) supported this work.
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