Nociceptin receptor

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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.[1] 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).[2] This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors.[3] 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.[4] Likewise, classical opioid receptors possess little affinity towards NOP's endogenous ligand nociceptin, which is structurally related to dynorphin A.[4]

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).[5] 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.[6][7] 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 GPCRs, 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.[8][9] NOP acting through Gαi/o pathways has also been shown to activate Phospholipase A2 (PLA2), thereby initiating Mitogen-activated protein kinase (MAPK) signaling cascades.[10] 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.[11][12][13] Activation of NOP's canonical β-arrestin pathway causes receptor phosphorylation, internalization, and eventual downregulation and recycling.[14][15] 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.[16][17][18]

Neuroanatomy

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.[19]

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.[19] 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 dopamine or by inhibiting GABA to affect dopamine levels.[20] 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.[21]

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.[22][23][24][25][26][27] 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.[27]

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 attentuation 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.[28] Administration of the NOPr antagonist SB-612,111 has been shown to inhibit this process.[29] 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 and δ-opioid receptors, and competitive antagonist of κ-opioid receptors)
  • BU08028 (Analogue of buprenorphine, partial agonist, agonist of µ-opioid receptor, has analgesic properties without physical dependence.) [30]
  • Cebranopadol (full agonist at NOP, μ-opioid and δ-opioid receptors, partial agonist at κ-opioid receptor)
  • Etorphine
  • MCOPPB[31] (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

Applications

NOP agonists are being studied as treatments for heart failure and migraine[32] while nociceptin antagonists such as JTC-801 may have analgesic[33] and antidepressant qualities.[34]

References

  1. ↑ Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC (March 1994). "ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization". FEBS Letters. 341 (1): 33–8. doi:10.1016/0014-5793(94)80235-1. PMID 8137918.
  2. ↑ 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.
  3. ↑ "Entrez Gene: OPRL1 opiate receptor-like 1".
  4. ↑ 4.0 4.1 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.
  5. ↑ Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC (March 1994). "ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization". FEBS Letters. 341 (1): 33–8. doi:10.1016/0014-5793(94)80235-1. PMID 8137918.
  6. ↑ Martin WR (December 1967). "Opioid antagonists". Pharmacological Reviews. 19 (4): 463–521. PMID 4867058.
  7. ↑ 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. doi:10.1073/pnas.68.8.1742. PMC 389284. PMID 5288759.
  8. ↑ Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B (October 1995). "Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor". Nature. 377 (6549): 532–5. doi:10.1038/377532a0. PMID 7566152.
  9. ↑ Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ, Civelli O (1995). "Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor". Science. 270 (5237): 792–4. doi:10.1126/science.270.5237.792. PMID 7481766.
  10. ↑ Fukuda K, Shoda T, Morikawa H, Kato S, Mima H, Mori K (1998). "Activation of phospholipase A2 by the nociceptin receptor expressed in Chinese hamster ovary cells". Journal of Neurochemistry. 71 (5): 2186–92. doi:10.1046/j.1471-4159.1998.71052186.x. PMID 9798946.
  11. ↑ Childers SR, Snyder SH (1978). "Guanine nucleotides differentiate agonist and antagonist interactions with opiate receptors". Life Sciences. 23 (7): 759–61. doi:10.1016/0024-3205(78)90077-2. PMID 211364.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS, Hamon M (December 1996). "International Union of Pharmacology. XII. Classification of opioid receptors". Pharmacological Reviews. 48 (4): 567–92. PMID 8981566.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 19.0 19.1 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.
  20. ↑ Liu Z, Wang Y, Zhang J, Ding J, Guo L, Cui D, Fei J (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.
  21. ↑ 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.
  22. ↑ Lin AP, Ko MC (February 2013). "The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability". ACS Chemical Neuroscience. 4 (2): 214–24. doi:10.1021/cn300124f. PMC 3582300. PMID 23421672.
  23. ↑ Sukhtankar DD, Zaveri NT, Husbands SM, Ko MC (July 2013). "Effects of spinally administered bifunctional nociceptin/orphanin FQ peptide receptor/μ-opioid receptor ligands in mouse models of neuropathic and inflammatory pain". The Journal of Pharmacology and Experimental Therapeutics. 346 (1): 11–22. doi:10.1124/jpet.113.203984. PMC 3684842. PMID 23652222.
  24. ↑ Hu E, Calò G, Guerrini R, Ko MC (January 2010). "Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112". Pain. 148 (1): 107–13. doi:10.1016/j.pain.2009.10.026. PMC 2861283. PMID 19945794.
  25. ↑ Ko MC, Wei H, Woods JH, Kennedy RT (September 2006). "Effects of intrathecally administered nociceptin/orphanin FQ in monkeys: behavioral and mass spectrometric studies". The Journal of Pharmacology and Experimental Therapeutics. 318 (3): 1257–64. doi:10.1124/jpet.106.106120. PMC 1804255. PMID 16766718.
  26. ↑ Ko MC, Naughton NN (May 2009). "Antinociceptive effects of nociceptin/orphanin FQ administered intrathecally in monkeys". The Journal of Pain. 10 (5): 509–16. doi:10.1016/j.jpain.2008.11.006. PMC 2797530. PMID 19231294.
  27. ↑ 27.0 27.1 Ko MC, Woods JH, Fantegrossi WE, Galuska CM, Wichmann J, Prinssen EP (August 2009). "Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys". Neuropsychopharmacology. 34 (9): 2088–96. doi:10.1038/npp.2009.33. PMC 2804925. PMID 19279568.
  28. ↑ Khroyan TV, Polgar WE, Orduna J, Montenegro J, Jiang F, Zaveri NT, Toll L (November 2011). "Differential effects of nociceptin/orphanin FQ (NOP) receptor agonists in acute versus chronic pain: studies with bifunctional NOP/μ receptor agonists in the sciatic nerve ligation chronic pain model in mice". The Journal of Pharmacology and Experimental Therapeutics. 339 (2): 687–93. doi:10.1124/jpet.111.184663. PMC 3199991. PMID 21859931.
  29. ↑ Zaratin PF, Petrone G, Sbacchi M, Garnier M, Fossati C, Petrillo P, Ronzoni S, Giardina GA, Scheideler MA (February 2004). "Modification of nociception and morphine tolerance by the selective opiate receptor-like orphan receptor antagonist (-)-cis-1-methyl-7-[ [4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111)". The Journal of Pharmacology and Experimental Therapeutics. 308 (2): 454–61. doi:10.1124/jpet.103.055848. PMID 14593080.
  30. ↑ Huiping Ding, Paul W. Czoty, Norikazu Kiguchi, Gerta Cami-Kobeci, Devki D. Sukhtankar, Michael A. Nader, Stephen M. Husbands, and Mei-Chuan Ko, "A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates." Proc. Natl. Acad. Sci. USA August 29, 2016 0:1605295113v1-201605295 http://www.pnas.org/cgi/content/abstract/1605295113v1
  31. ↑ Hirao A, Imai A, Sugie Y, Yamada Y, Hayashi S, Toide K (March 2008). "Pharmacological characterization of the newly synthesized nociceptin/orphanin FQ-receptor agonist 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole as an anxiolytic agent". Journal of Pharmacological Sciences. 106 (3): 361–8. doi:10.1254/jphs.fp0071742. PMID 18319566.
  32. ↑ Mørk H, Hommel K, Uddman R, Edvinsson L, Jensen R (September 2002). "Does nociceptin play a role in pain disorders in man?". Peptides. 23 (9): 1581–7. doi:10.1016/S0196-9781(02)00101-8. PMID 12217418.
  33. ↑ Scoto GM, Aricò G, Ronsisvalle S, Parenti C (July 2007). "Blockade of the nociceptin/orphanin FQ/NOP receptor system in the rat ventrolateral periaqueductal gray potentiates DAMGO analgesia". Peptides. 28 (7): 1441–6. doi:10.1016/j.peptides.2007.05.013. PMID 17628212.
  34. ↑ Redrobe JP, Calo' G, Regoli D, Quirion R (February 2002). "Nociceptin receptor antagonists display antidepressant-like properties in the mouse forced swimming test". Naunyn-Schmiedeberg's Archives of Pharmacology. 365 (2): 164–7. doi:10.1007/s00210-001-0511-0. PMID 11819035.

Further reading

  • Mollereau C, Mouledous L (July 2000). "Tissue distribution of the opioid receptor-like (ORL1) receptor". Peptides. 21 (7): 907–17. doi:10.1016/S0196-9781(00)00227-8. PMID 10998524.
  • New DC, Wong YH (2003). "The ORL1 receptor: molecular pharmacology and signalling mechanisms". Neuro-Signals. 11 (4): 197–212. doi:10.1159/000065432. 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. doi:10.1016/S0024-3205(03)00387-4. PMC 3848886. PMID 12801588.
  • Wick MJ, Minnerath SR, Roy S, Ramakrishnan S, Loh HH (September 1995). "Expression of alternate forms of brain opioid 'orphan' receptor mRNA in activated human peripheral blood lymphocytes and lymphocytic cell lines". Brain Research. Molecular Brain Research. 32 (2): 342–7. doi:10.1016/0169-328X(95)00096-B. PMID 7500847.
  • Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B (October 1995). "Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor". Nature. 377 (6549): 532–5. doi:10.1038/377532a0. PMID 7566152.
  • 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, Ames RS (October 1999). "Cloning and characterization of a rabbit ortholog of human Galpha16 and mouse G(alpha)15". FEBS Letters. 460 (1): 53–6. doi:10.1016/S0014-5793(99)01317-4. PMID 10571060.
  • 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. doi:10.1159/000014645. PMID 10965058.
  • 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. doi:10.1006/jmbi.2000.4212. PMID 11090272.
  • Okada K, Sujaku T, Chuman Y, Nakashima R, Nose T, Costa T, Yamada Y, Yokoyama M, Nagahisa A, Shimohigashi Y (November 2000). "Highly potent nociceptin analog containing the Arg-Lys triple repeat". Biochemical and Biophysical Research Communications. 278 (2): 493–8. doi:10.1006/bbrc.2000.3822. 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. doi:10.4049/jimmunol.166.6.3650. 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. doi:10.1124/jpet.102.033159. PMID 12130708.
  • 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. doi:10.1016/S0169-328X(02)00390-X. 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. doi:10.1007/s000180200016. PMID 12568343.

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