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Nociceptin receptor

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OPRL1
Available structures
PDBOrtholog search: A0A0G2JQE4 PDBe A0A0G2JQE4 RCSB
Identifiers
AliasesOPRL1, KOR-3, NOCIR, OOR, ORL1, NOP, NOPr, opioid related nociceptin receptor 1, KOR3, OPRL, PNOCR
External IDsOMIM: 602548; MGI: 97440; HomoloGene: 22609; GeneCards: OPRL1; OMA:OPRL1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4987

18389

Ensembl

ENSG00000277044
ENSG00000125510

ENSMUSG00000027584

UniProt

P41146

P35377

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr 20: 64.08 – 64.1 MbChr 2: 181.36 – 181.36 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

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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

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Nociceptin receptor vestibule complexed with nociceptin.[12] Upper part of TM helix 5 is hidden.

NOP cellular signalling partners

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Like most G-protein coupled receptors, NOP signals through canonical G proteins upon activation. G proteins are heterotrimeric complexes consisting of α, β, and γ subunits. NOP signals through a variety of Gα subtypes that trigger diverse downstream signaling cascades. NOP coupling to Gαi or Gαo subunits leads to an inhibition of adenylyl cyclase (AC) causing an intracellular decrease in cyclic adenosine monophosphate(cAMP) levels, an important second messenger for many signal transduction pathways.[13][14] NOP acting through Gαi/o pathways has also been shown to activate Phospholipase A2 (PLA2), thereby initiating Mitogen-activated protein kinase (MAPK) signaling cascades.[15] In contrast to classical OPs, NOP also couples to Pertussis toxin (PTX)-insensitive subtypes Gαz, Gα14, and Gα16, as well as potentially to Gα12 and Gαs.[16][17][18] Activation of NOP's canonical β-arrestin pathway causes receptor phosphorylation, internalization, and eventual downregulation and recycling.[19][20] NOP activation also causes indirect inhibition of opioid receptors MOP and KOP, resulting in anti-opioid activity in certain tissues. Additionally, NOP activation leads to the activation of potassium channels and inhibition of calcium channels which collectively inhibit neuronal firing.[21][22][23]

Neuroanatomy

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Nociceptin controls a wide range of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites.[24]

Pain circuitry

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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.[24] 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

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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 dopamine or by inhibiting GABA to affect dopamine levels.[25] In animal models, the result of NOP activation in the central nervous system has been shown to eliminate conditioned place preference induced by morphine, cocaine, alcohol, and methamphetamine.[26]

Therapeutic potential

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Analgesia and abuse liability

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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.[27][28][29][30][31][32] 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.[32]

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.[33] Administration of the NOPr antagonist SB-612,111 has been shown to inhibit this process.[34] 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

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  • 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.)[35]
  • Cebranopadol (full agonist at NOP, μ-opioid and δ-opioid receptors, partial agonist at κ-opioid receptor)
  • Etorphine
  • MCOPPB[36] (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

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Applications

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NOP agonists are being studied as treatments for heart failure and migraine[37] while nociceptin antagonists such as JTC-801 may have analgesic[38] and antidepressant qualities.[39]

References

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  1. ^ a b c ENSG00000125510 GRCh38: Ensembl release 89: ENSG00000277044, ENSG00000125510 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027584 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, et al. (March 1994). "ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization". FEBS Letters. 341 (1): 33–8. Bibcode:1994FEBSL.341...33M. doi:10.1016/0014-5793(94)80235-1. PMID 8137918. S2CID 25491521.
  6. ^ Henderson G, McKnight AT (August 1997). "The orphan opioid receptor and its endogenous ligand--nociceptin/orphanin FQ". Trends in Pharmacological Sciences. 18 (8): 293–300. doi:10.1016/S0165-6147(97)90645-3. PMID 9277133.
  7. ^ "Entrez Gene: OPRL1 opiate receptor-like 1".
  8. ^ a b Butour JL, Moisand C, Mazarguil H, Mollereau C, Meunier JC (February 1997). "Recognition and activation of the opioid receptor-like ORL 1 receptor by nociceptin, nociceptin analogs and opioids". European Journal of Pharmacology. 321 (1): 97–103. doi:10.1016/S0014-2999(96)00919-3. PMID 9083791.
  9. ^ Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, et al. (March 1994). "ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization". FEBS Letters. 341 (1): 33–8. Bibcode:1994FEBSL.341...33M. doi:10.1016/0014-5793(94)80235-1. PMID 8137918. S2CID 25491521.
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  11. ^ Goldstein A, Lowney LI, Pal BK (August 1971). "Stereospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain". Proceedings of the National Academy of Sciences of the United States of America. 68 (8): 1742–7. Bibcode:1971PNAS...68.1742G. doi:10.1073/pnas.68.8.1742. PMC 389284. PMID 5288759.
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  17. ^ Chan JS, Yung LY, Lee JW, Wu YL, Pei G, Wong YH (1998). "Pertussis toxin-insensitive signaling of the ORL1 receptor: coupling to Gz and G16 proteins". Journal of Neurochemistry. 71 (5): 2203–10. doi:10.1046/j.1471-4159.1998.71052203.x. PMID 9798948. S2CID 7978426.
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  19. ^ Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS, et al. (December 1996). "International Union of Pharmacology. XII. Classification of opioid receptors". Pharmacological Reviews. 48 (4): 567–92. PMID 8981566.
  20. ^ Donica CL, Awwad HO, Thakker DR, Standifer KM (May 2013). "Cellular mechanisms of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor regulation and heterologous regulation by N/OFQ". Molecular Pharmacology. 83 (5): 907–18. doi:10.1124/mol.112.084632. PMC 3629824. PMID 23395957.
  21. ^ Connor M, Yeo A, Henderson G (1996). "The effect of nociceptin on Ca2+ channel current and intracellular Ca2+ in the SH-SY5Y human neuroblastoma cell line". British Journal of Pharmacology. 118 (2): 205–7. doi:10.1111/j.1476-5381.1996.tb15387.x. PMC 1909632. PMID 8735615.
  22. ^ Connor M, Vaughan CW, Chieng B, Christie MJ (1996). "Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurones in vitro". British Journal of Pharmacology. 119 (8): 1614–8. doi:10.1111/j.1476-5381.1996.tb16080.x. PMC 1915781. PMID 8982509.
  23. ^ Ikeda K, Kobayashi T, Kumanishi T, Niki H, Yano R (2000). "Involvement of G-protein-activated inwardly rectifying K (GIRK) channels in opioid-induced analgesia". Neuroscience Research. 38 (1): 113–6. doi:10.1016/S0168-0102(00)00144-9. PMID 10997585. S2CID 29108127.
  24. ^ a b Calo' G, Guerrini R, Rizzi A, Salvadori S, Regoli D (April 2000). "Pharmacology of nociceptin and its receptor: a novel therapeutic target". British Journal of Pharmacology. 129 (7): 1261–83. doi:10.1038/sj.bjp.0703219. PMC 1571975. PMID 10742280.
  25. ^ Liu Z, Wang Y, Zhang J, Ding J, Guo L, Cui D, et al. (March 2001). "Orphanin FQ: an endogenous antagonist of rat brain dopamine transporter". NeuroReport. 12 (4): 699–702. doi:10.1097/00001756-200103260-00017. PMID 11277567. S2CID 27631391.
  26. ^ Toll L, Bruchas MR, Calo' G, Cox BM, Zaveri NT (April 2016). "Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems". Pharmacological Reviews. 68 (2): 419–57. doi:10.1124/pr.114.009209. PMC 4813427. PMID 26956246.
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Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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