Nociceptin receptor explained

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.

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 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 Gα_i or Gα_o 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 Gα_i/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 Gα_z, 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. 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 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.^[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 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.)^[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

• 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^[32] while nociceptin antagonists such as JTC-801 may have analgesic^[33] and antidepressant qualities.^[34]

Further reading

• Mollereau C, Mouledous L . Tissue distribution of the opioid receptor-like (ORL1) receptor . Peptides . 21 . 7 . 907–17 . July 2000 . 10998524 . 10.1016/S0196-9781(00)00227-8 . 13294560 .
• New DC, Wong YH . The ORL1 receptor: molecular pharmacology and signalling mechanisms . Neuro-Signals . 11 . 4 . 197–212 . 2003 . 12393946 . 10.1159/000065432 . free .
• Zaveri N . Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: research tools and potential therapeutic agents . Life Sciences . 73 . 6 . 663–78 . June 2003 . 12801588 . 10.1016/S0024-3205(03)00387-4 . 3848886 .
• Horace Loh . Wick MJ, Minnerath SR, Roy S, Ramakrishnan S, Loh HH . 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 . September 1995 . 7500847 . 10.1016/0169-328X(95)00096-B .
• Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B . Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor . Nature . 377 . 6549 . 532–5 . October 1995 . 7566152 . 10.1038/377532a0 . 1995Natur.377..532M . 4326860 . free .
• Yung LY, Joshi SA, Chan RY, Chan JS, Pei G, Wong YH . GalphaL1 (Galpha14) couples the opioid receptor-like1 receptor to stimulation of phospholipase C . The Journal of Pharmacology and Experimental Therapeutics . 288 . 1 . 232–8 . January 1999 . 9862775 .
• Feild JA, Foley JJ, Testa TT, Nuthulaganti P, Ellis C, Sarau HM, Ames RS . Cloning and characterization of a rabbit ortholog of human Galpha16 and mouse G(alpha)15 . FEBS Letters . 460 . 1 . 53–6 . October 1999 . 10571060 . 10.1016/S0014-5793(99)01317-4 . 86483726 . free . 1999FEBSL.460...53F .
• Mouledous L, Topham CM, Moisand C, Mollereau C, Meunier JC . 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 . March 2000 . 10692489 . 10.1124/mol.57.3.495.
• Yung LY, Tsim KW, Pei G, Wong YH . 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 . 2000 . 10965058 . 10.1159/000014645 . 2024-05-22 . 32796564 .
• Ito E, Xie G, Maruyama K, Palmer PP . 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 . December 2000 . 11090272 . 10.1006/jmbi.2000.4212 .
• Okada K, Sujaku T, Chuman Y, Nakashima R, Nose T, Costa T, Yamada Y, Yokoyama M, Nagahisa A, Shimohigashi Y . Highly potent nociceptin analog containing the Arg-Lys triple repeat . Biochemical and Biophysical Research Communications . 278 . 2 . 493–8 . November 2000 . 11097863 . 10.1006/bbrc.2000.3822 .
• Serhan CN, Fierro IM, Chiang N, Pouliot M . Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4 . Journal of Immunology . 166 . 6 . 3650–4 . March 2001 . 11238602 . 10.4049/jimmunol.166.6.3650 . free .
• Mandyam CD, Thakker DR, Christensen JL, Standifer KM . 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 . August 2002 . 12130708 . 10.1124/jpet.102.033159 . 16475164 .
• Thakker DR, Standifer KM . Orphanin FQ/nociceptin blocks chronic morphine-induced tyrosine hydroxylase upregulation . Brain Research. Molecular Brain Research . 105 . 1–2 . 38–46 . September 2002 . 12399106 . 10.1016/S0169-328X(02)00390-X .
• Spampinato S, Di Toro R, Alessandri M, Murari G . Agonist-induced internalization and desensitization of the human nociceptin receptor expressed in CHO cells . Cellular and Molecular Life Sciences . 59 . 12 . 2172–83 . December 2002 . 12568343 . 10.1007/s000180200016 . 24462875 . 11146108 .

External links

• Web site: Opioid Receptors: NOP . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-09 . 2016-03-03 . https://web.archive.org/web/20160303170531/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2411 . dead .

Notes and References

1. Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC . ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization . FEBS Letters . 341 . 1 . 33–8 . March 1994 . 8137918 . 10.1016/0014-5793(94)80235-1 . 25491521 . free . 1994FEBSL.341...33M .
2. Henderson G, McKnight AT . The orphan opioid receptor and its endogenous ligand--nociceptin/orphanin FQ . Trends in Pharmacological Sciences . 18 . 8 . 293–300 . August 1997 . 9277133 . 10.1016/S0165-6147(97)90645-3 .
3. Web site: Entrez Gene: OPRL1 opiate receptor-like 1.
4. Butour JL, Moisand C, Mazarguil H, Mollereau C, Meunier JC . 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 . February 1997 . 9083791 . 10.1016/S0014-2999(96)00919-3 .
5. Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC . ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization . FEBS Letters . 341 . 1 . 33–8 . March 1994 . 8137918 . 10.1016/0014-5793(94)80235-1. 25491521 . free . 1994FEBSL.341...33M .
6. Martin WR . Opioid antagonists . Pharmacological Reviews . 19 . 4 . 463–521 . December 1967 . 4867058 .
7. Goldstein A, Lowney LI, Pal BK . 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 . August 1971 . 5288759 . 10.1073/pnas.68.8.1742 . 389284. 1971PNAS...68.1742G . free .
8. Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B . Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor . Nature . 377 . 6549 . 532–5 . October 1995 . 7566152 . 10.1038/377532a0 . 1995Natur.377..532M . 4326860 . free .
9. Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ, Civelli O . Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor . Science . 270 . 5237 . 792–4 . 1995 . 7481766 . 10.1126/science.270.5237.792 . 1995Sci...270..792R . 38117854 .
10. Fukuda K, Shoda T, Morikawa H, Kato S, Mima H, Mori K . Activation of phospholipase A2 by the nociceptin receptor expressed in Chinese hamster ovary cells . Journal of Neurochemistry . 71 . 5 . 2186–92 . 1998 . 9798946 . 10.1046/j.1471-4159.1998.71052186.x . 22919153 . free .
11. Childers SR, Snyder SH . Guanine nucleotides differentiate agonist and antagonist interactions with opiate receptors . Life Sciences . 23 . 7 . 759–61 . 1978 . 211364 . 10.1016/0024-3205(78)90077-2 .
12. Chan JS, Yung LY, Lee JW, Wu YL, Pei G, Wong YH . Pertussis toxin-insensitive signaling of the ORL1 receptor: coupling to Gz and G16 proteins . Journal of Neurochemistry . 71 . 5 . 2203–10 . 1998 . 9798948 . 10.1046/j.1471-4159.1998.71052203.x . 7978426 . free .
13. Yung LY, Joshi SA, Chan RY, Chan JS, Pei G, Wong YH . GalphaL1 (Galpha14) couples the opioid receptor-like1 receptor to stimulation of phospholipase C . The Journal of Pharmacology and Experimental Therapeutics . 288 . 1 . 232–8 . January 1999 . 9862775 .
14. Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS, Hamon M . International Union of Pharmacology. XII. Classification of opioid receptors . Pharmacological Reviews . 48 . 4 . 567–92 . December 1996 . 8981566 .
15. Donica CL, Awwad HO, Thakker DR, Standifer KM . Cellular mechanisms of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor regulation and heterologous regulation by N/OFQ . Molecular Pharmacology . 83 . 5 . 907–18 . May 2013 . 23395957 . 10.1124/mol.112.084632 . 3629824.
16. Connor M, Yeo A, Henderson G . 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 . 1996 . 8735615 . 1909632 . 10.1111/j.1476-5381.1996.tb15387.x .
17. Connor M, Vaughan CW, Chieng B, Christie MJ . Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurones in vitro . British Journal of Pharmacology . 119 . 8 . 1614–8 . 1996 . 8982509 . 1915781 . 10.1111/j.1476-5381.1996.tb16080.x .
18. Ikeda K, Kobayashi T, Kumanishi T, Niki H, Yano R . Involvement of G-protein-activated inwardly rectifying K (GIRK) channels in opioid-induced analgesia . Neuroscience Research . 38 . 1 . 113–6 . 2000 . 10997585 . 10.1016/S0168-0102(00)00144-9 . 29108127 .
19. Calo' G, Guerrini R, Rizzi A, Salvadori S, Regoli D . Pharmacology of nociceptin and its receptor: a novel therapeutic target . British Journal of Pharmacology . 129 . 7 . 1261–83 . April 2000 . 10742280 . 1571975 . 10.1038/sj.bjp.0703219 .
20. Liu Z, Wang Y, Zhang J, Ding J, Guo L, Cui D, Fei J . Orphanin FQ: an endogenous antagonist of rat brain dopamine transporter . NeuroReport . 12 . 4 . 699–702 . March 2001 . 11277567 . 10.1097/00001756-200103260-00017 . 27631391 .
21. Toll L, Bruchas MR, Calo' G, Cox BM, Zaveri NT . Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems . Pharmacological Reviews . 68 . 2 . 419–57 . April 2016 . 26956246 . 10.1124/pr.114.009209 . 4813427.
22. Lin AP, Ko MC . The therapeutic potential of nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability . ACS Chemical Neuroscience . 4 . 2 . 214–24 . February 2013 . 23421672 . 10.1021/cn300124f . 3582300.
23. Sukhtankar DD, Zaveri NT, Husbands SM, Ko MC . 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 . July 2013 . 23652222 . 10.1124/jpet.113.203984 . 3684842.
24. Hu E, Calò G, Guerrini R, Ko MC . Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112 . Pain . 148 . 1 . 107–13 . January 2010 . 19945794 . 10.1016/j.pain.2009.10.026 . 2861283.
25. Ko MC, Wei H, Woods JH, Kennedy RT . 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 . September 2006 . 16766718 . 10.1124/jpet.106.106120 . 9537945 .
26. Ko MC, Naughton NN . Antinociceptive effects of nociceptin/orphanin FQ administered intrathecally in monkeys . The Journal of Pain . 10 . 5 . 509–16 . May 2009 . 19231294 . 10.1016/j.jpain.2008.11.006 . 2797530.
27. Ko MC, Woods JH, Fantegrossi WE, Galuska CM, Wichmann J, Prinssen EP . Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys . Neuropsychopharmacology . 34 . 9 . 2088–96 . August 2009 . 19279568 . 10.1038/npp.2009.33 . 2804925.
28. Khroyan TV, Polgar WE, Orduna J, Montenegro J, Jiang F, Zaveri NT, Toll L . 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 . November 2011 . 21859931 . 3199991 . 10.1124/jpet.111.184663 .
29. Zaratin PF, Petrone G, Sbacchi M, Garnier M, Fossati C, Petrillo P, Ronzoni S, Giardina GA, Scheideler MA . 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 . February 2004 . 14593080 . 10.1124/jpet.103.055848 . 8036750 .
30. Ding H, Czoty PW, Kiguchi N, Cami-Kobeci G, Sukhtankar DD, Nader MA, Husbands SM, Ko MC . A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates . Proceedings of the National Academy of Sciences of the United States of America . 113 . 37 . E5511–8 . September 2016 . 27573832 . 5027459 . 10.1073/pnas.1605295113 . 36624494 . free . 2016PNAS..113E5511D .
31. Hirao A, Imai A, Sugie Y, Yamada Y, Hayashi S, Toide K . 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 . March 2008 . 18319566 . 10.1254/jphs.fp0071742 . free .
32. Mørk H, Hommel K, Uddman R, Edvinsson L, Jensen R . Does nociceptin play a role in pain disorders in man? . Peptides . 23 . 9 . 1581–7 . September 2002 . 12217418 . 10.1016/S0196-9781(02)00101-8 . 22718102 .
33. Scoto GM, Aricò G, Ronsisvalle S, Parenti C . Blockade of the nociceptin/orphanin FQ/NOP receptor system in the rat ventrolateral periaqueductal gray potentiates DAMGO analgesia . Peptides . 28 . 7 . 1441–6 . July 2007 . 17628212 . 10.1016/j.peptides.2007.05.013 . 29027947 .
34. Redrobe JP, Calo' G, Regoli D, Quirion R . Nociceptin receptor antagonists display antidepressant-like properties in the mouse forced swimming test . Naunyn-Schmiedeberg's Archives of Pharmacology . 365 . 2 . 164–7 . February 2002 . 11819035 . 10.1007/s00210-001-0511-0 . 25596953 .