Nociceptin receptor
The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 (opioid receptor-like 1) gene.[5] The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ).[6] This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors.[7] Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.
Although NOP shares high sequence identity (~60%) with the ‘classical’ opioid receptors μ-OP (MOP), κ-OP (KOP), and δ-OP (DOP), it possesses little or no affinity for opioid peptides or morphine-like compounds.[8] Likewise, classical opioid receptors possess little affinity towards NOP's endogenous ligand nociceptin, which is structurally related to dynorphin A.[8]
Discovery
In 1994, Mollereau et al. cloned a receptor that was highly homologous to the classical opioid receptors (OPs) μ-OR (MOP), κ-OR (KOP), and δ-OR (DOP) that came to be known as the Nociceptin Opioid Peptide receptor (NOP).[9] As these “classical” opioid receptors were identified 30 years earlier in the mid-1960s, the physiological and pharmacological characterization of NOP as well as therapeutic development targeting this receptor remain decades behind.[10][11] Although research on NOP has blossomed into its own sub-field, the lack of widespread knowledge of NOP's existence means that it is commonly omitted from studies that investigate the OP family, despite its promising role as a therapeutic target.
Mechanism and pharmacology
NOP cellular signalling partners
Like most
Neuroanatomy
Nociceptin controls a wide range of biological functions ranging from
Pain circuitry
The outcome of NOP activation on the brain's pain circuitry is site-specific. Within the central nervous system its action can be either similar or opposite to those of opioids depending on their location.[23] In animal models, activation of NOP in the brain stem and higher brain regions has mixed action, resulting in overall anti-opioid activity. NOP activation at the spinal cord and peripheral nervous system results in morphine-comparable analgesia in non-human primates.
Reward circuitry
NOP is highly expressed in every node of the mesocorticolimbic reward circuitry. Unlike MOP agonists such as codeine and morphine, NOP agonists do not have reinforcing effects. Nociceptin is thought to be an endogenous antagonist of dopamine transport that may act either directly on
Therapeutic potential
Analgesia and abuse liability
Recent studies indicate that targeting NOP is a promising alternative route to relieving pain without the deleterious side effects of traditional MOP-activating opioid therapies.[26][27][28][29][30][31] In primates, specifically activating NOP through systemic or intrathecal administration induces long-lasting, morphine-comparable analgesia without causing itch, respiratory depression, or the reinforcing effects that lead to addiction in an intravenous self-administration paradigm; thus eliminating all of the serious side-effects of current opioid therapies.[31]
Several commonly used opioid drugs including etorphine and buprenorphine have been demonstrated to bind to nociceptin receptors, but this binding is relatively insignificant compared to their activity at other opioid receptors in the acute setting (however the non-analgesic NOPr antagonist SB-612,111 was demonstrated to potentiate the therapeutic benefits of morphine). Chronic administration of nociceptin receptor agonists results in an attenuation of the analgesic and anti-allodynic effects of opiates; this mechanism inhibits the action of endogenous opioids as well, resulting in an increase in pain severity, depression, and both physical and psychological opiate dependence following chronic NOPr agonist administration.[32] Administration of the NOPr antagonist SB-612,111 has been shown to inhibit this process.[33] More recently a range of selective ligands for NOP have been developed, which show little or no affinity to other opioid receptors and so allow NOP-mediated responses to be studied in isolation.
Agonists
- AT-121 (Experimental agonist of both the µ-opioid and nociceptin receptors, showing promising results in non-human primates.)
- Buprenorphine (partial agonist, not selective for NOP, also partial agonist of µ-opioid receptors, and competitive antagonist of δ-opioid and κ-opioid receptors)
- BU08028 (Analogue of buprenorphine, partial agonist, agonist of µ-opioid receptor, has analgesic properties without physical dependence.)[34]
- Cebranopadol (full agonist at NOP, μ-opioid and δ-opioid receptors, partial agonist at κ-opioid receptor)
- Etorphine
- MCOPPB[35] (full agonist)
- MT-7716
- Nociceptin
- Norbuprenorphine (full agonist; non-selective (also full agonist at the MOR and DOR and partial agonist at the KOR); peripherally-selective)
- NNC 63-0532
- Ro64-6198
- Ro65-6570
- SCH-221,510
- SR-8993
- SR-16435 (mixed MOR / NOP partial agonist)
- TH-030418
Antagonists
- AT-076 (non-selective)
- JTC-801
- J-113,397
- LY-2940094
- SB-612,111
- SR-16430
- Thienorphine
Applications
NOP agonists are being studied as treatments for heart failure and migraine[36] while nociceptin antagonists such as JTC-801 may have analgesic[37] and antidepressant qualities.[38]
References
- ^ a b c ENSG00000125510 GRCh38: Ensembl release 89: ENSG00000277044, ENSG00000125510 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027584 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ "Entrez Gene: OPRL1 opiate receptor-like 1".
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Further reading
- Mollereau C, Mouledous L (July 2000). "Tissue distribution of the opioid receptor-like (ORL1) receptor". Peptides. 21 (7): 907–17. S2CID 13294560.
- New DC, Wong YH (2003). "The ORL1 receptor: molecular pharmacology and signalling mechanisms". Neuro-Signals. 11 (4): 197–212. PMID 12393946.
- Zaveri N (June 2003). "Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: research tools and potential therapeutic agents". Life Sciences. 73 (6): 663–78. PMID 12801588.
- Wick MJ, Minnerath SR, Roy S, Ramakrishnan S, PMID 7500847.
- Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, et al. (October 1995). "Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor". Nature. 377 (6549): 532–5. S2CID 4326860.
- Yung LY, Joshi SA, Chan RY, Chan JS, Pei G, Wong YH (January 1999). "GalphaL1 (Galpha14) couples the opioid receptor-like1 receptor to stimulation of phospholipase C". The Journal of Pharmacology and Experimental Therapeutics. 288 (1): 232–8. PMID 9862775.
- Feild JA, Foley JJ, Testa TT, Nuthulaganti P, Ellis C, Sarau HM, et al. (October 1999). "Cloning and characterization of a rabbit ortholog of human Galpha16 and mouse G(alpha)15". FEBS Letters. 460 (1): 53–6. S2CID 86483726.
- Mouledous L, Topham CM, Moisand C, Mollereau C, Meunier JC (March 2000). "Functional inactivation of the nociceptin receptor by alanine substitution of glutamine 286 at the C terminus of transmembrane segment VI: evidence from a site-directed mutagenesis study of the ORL1 receptor transmembrane-binding domain". Molecular Pharmacology. 57 (3): 495–502. PMID 10692489.
- Yung LY, Tsim KW, Pei G, Wong YH (2000). "Immunoglobulin G1 Fc fragment-tagged human opioid receptor-like receptor retains the ability to inhibit cAMP accumulation". Biological Signals and Receptors. 9 (5): 240–7. S2CID 32796564.
- Ito E, Xie G, Maruyama K, Palmer PP (December 2000). "A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP". Journal of Molecular Biology. 304 (3): 259–70. PMID 11090272.
- Okada K, Sujaku T, Chuman Y, Nakashima R, Nose T, Costa T, et al. (November 2000). "Highly potent nociceptin analog containing the Arg-Lys triple repeat". Biochemical and Biophysical Research Communications. 278 (2): 493–8. PMID 11097863.
- Serhan CN, Fierro IM, Chiang N, Pouliot M (March 2001). "Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4". Journal of Immunology. 166 (6): 3650–4. PMID 11238602.
- Mandyam CD, Thakker DR, Christensen JL, Standifer KM (August 2002). "Orphanin FQ/nociceptin-mediated desensitization of opioid receptor-like 1 receptor and mu opioid receptors involves protein kinase C: a molecular mechanism for heterologous cross-talk". The Journal of Pharmacology and Experimental Therapeutics. 302 (2): 502–9. S2CID 16475164.
- Thakker DR, Standifer KM (September 2002). "Orphanin FQ/nociceptin blocks chronic morphine-induced tyrosine hydroxylase upregulation". Brain Research. Molecular Brain Research. 105 (1–2): 38–46. PMID 12399106.
- Spampinato S, Di Toro R, Alessandri M, Murari G (December 2002). "Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells". Cellular and Molecular Life Sciences. 59 (12): 2172–83. S2CID 24462875.
External links
- "Opioid Receptors: NOP". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-09.
- nociceptin+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P41146 (Nociceptin receptor) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.