Nociceptin receptor

Last updated

OPRL1
Available structures
PDB Ortholog search: A0A0G2JQE4 PDBe A0A0G2JQE4 RCSB
Identifiers
Aliases OPRL1 , KOR-3, NOCIR, OOR, ORL1, NOP, NOPr, opioid related nociceptin receptor 1, KOR3, OPRL, PNOCR
External IDs OMIM: 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 Mb Chr 2: 181.36 – 181.36 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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.

Contents

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

Nociceptin receptor vestibule complexed with nociceptin. Upper part of TM helix 5 is hidden. 8F7X Nociceptin receptor.png
Nociceptin receptor vestibule complexed with nociceptin. Upper part of TM helix 5 is hidden.

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 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

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

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

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

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. [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

Antagonists

Applications

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]

Related Research Articles

<span class="mw-page-title-main">Agonist</span> Chemical which binds to and activates a biochemical receptor

An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.

<span class="mw-page-title-main">Opioid receptor</span> Group of biological receptors

Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.

Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor. Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. Functional selectivity, or biased signaling, is most extensively characterized at G protein coupled receptors (GPCRs). A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics or antiproliferative drugs, or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression. Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.

<span class="mw-page-title-main">Opioid peptide</span> Class of peptides that bind to opioid receptors

Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble those of opiates. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, control of food intake, and the rewarding effects of alcohol and nicotine.

<span class="mw-page-title-main">Nociceptin</span> Chemical compound

Nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor. Nociceptin acts as a potent anti-analgesic, effectively counteracting the effect of pain-relievers; its activation is associated with brain functions such as pain sensation and fear learning.

κ-opioid receptor Protein-coding gene in the species Homo sapiens, named for ketazocine

The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.

<span class="mw-page-title-main">Endomorphin</span> Chemical compound

Endomorphins are considered to be natural opioid neuropeptides central to pain relief. The two known endomorphins, endomorphin-1 and endomorphin-2, are tetrapeptides, consisting of Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Phe amino acid sequences respectively. These sequences fold into tertiary structures with high specificity and affinity for the μ-opioid receptor, binding it exclusively and strongly. Bound μ-opioid receptors typically induce inhibitory effects on neuronal activity. Endomorphin-like immunoreactivity exists within the central and peripheral nervous systems, where endomorphin-1 appears to be concentrated in the brain and upper brainstem, and endomorphin-2 in the spinal cord and lower brainstem. Because endomorphins activate the μ-opioid receptor, which is the target receptor of morphine and its derivatives, endomorphins possess significant potential as analgesics with reduced side effects and risk of addiction.

μ-opioid receptor Protein-coding gene in the species Homo sapiens, named for its ligand morphine

The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(mu)-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium and for which the receptor was named, with mu being the first letter of Morpheus, the compound's namesake in the original Greek. It is an inhibitory G-protein coupled receptor that activates the Gi alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.

δ-opioid receptor Opioid receptor

The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.

<span class="mw-page-title-main">JTC-801</span> Chemical compound

JTC-801 is an opioid analgesic drug used in scientific research.

<span class="mw-page-title-main">J-113,397</span> Chemical compound

J-113,397 is an opioid drug which was the first compound found to be a highly selective antagonist for the nociceptin receptor, also known as the ORL-1 receptor. It is several hundred times selective for the ORL-1 receptor over other opioid receptors, and its effects in animals include preventing the development of tolerance to morphine, the prevention of hyperalgesia induced by intracerebroventricular administration of nociceptin, as well as the stimulation of dopamine release in the striatum, which increases the rewarding effects of cocaine, but may have clinical application in the treatment of Parkinson's disease.

<span class="mw-page-title-main">SB-612,111</span> Chemical compound

SB-612,111 is an opioid receptor ligand which is a potent and selective antagonist for the nociceptin receptor (ORL-1), several times more potent than the older drug J-113,397. It does not have analgesic effects in its own right, but prevents the development of hyperalgesia, and also shows antidepressant effects in animal studies.

<span class="mw-page-title-main">Ro64-6198</span> Chemical compound

Ro64-6198 is an opioid drug used in scientific research. It acts as a potent and selective agonist for the nociceptin receptor, also known as the ORL-1 receptor, with over 100x selectivity over the other opioid receptors. It produces anxiolytic effects in animal studies equivalent to those of benzodiazepine drugs, but has no anticonvulsant effects and does not produce any overt effects on behaviour. However it does impair short-term memory, and counteracts stress-induced anorexia. It also has antitussive effects, and reduces the rewarding and analgesic effects of morphine, although it did not prevent the development of dependence. It has been shown to reduce alcohol self-administration in animals and suppressed relapses in animal models of alcoholism, and ORL-1 agonists may have application in the treatment of alcoholism.

<span class="mw-page-title-main">MCOPPB</span> Chemical compound

MCOPPB is a drug which acts as a potent and selective agonist for the nociceptin receptor, with a pKi of 10.07 and much weaker activity at other opioid receptors. It has only moderate affinity for the mu opioid receptor, weak affinity for the kappa opioid receptor and negligible binding at the delta opioid receptor. In animal studies, MCOPPB produces potent anxiolytic effects, with no inhibition of memory or motor function, and only slight sedative side effects which do not appear until much higher doses than the effective anxiolytic dose range.

<span class="mw-page-title-main">Buprenorphine/samidorphan</span> Combination drug formulation

Buprenorphine/samidorphan is a combination formulation of buprenorphine and samidorphan which is under development as an add on to antidepressants in treatment-resistant depression (TRD).

<span class="mw-page-title-main">Cebranopadol</span> Opioid analgesic drug

Cebranopadol is an opioid analgesic of the benzenoid class which is currently under development internationally by Grünenthal, a German pharmaceutical company, and its partner Depomed, a pharmaceutical company in the United States, for the treatment of a variety of different acute and chronic pain states. As of November 2014, it is in phase III clinical trials.

<span class="mw-page-title-main">SR-16435</span> Drug

SR-16435 is a drug which acts as a potent partial agonist at both the μ-opioid receptor and nociceptin receptor. In animal studies it was found to be a potent analgesic, with results suggestive of reduced development of tolerance and increased activity against neuropathic pain compared to classic μ-selective agonists.

<span class="mw-page-title-main">Sunobinop</span> Chemical compound

Sunobinop is a high affinity small molecule nociceptin receptor partial agonist.

<span class="mw-page-title-main">Ro65-6570</span> Nociceptin receptor agonist

Ro65-6570 is an opioid drug. It has a potential use in preventing the addiction to other opioids.

<span class="mw-page-title-main">SCH-221510</span> Nociceptin receptor agonist

SCH-221510 is an experimental opioid drug. It has potential as an analgesic and as a treatment to addiction of certain drugs.

References

  1. 1 2 3 ENSG00000125510 GRCh38: Ensembl release 89: ENSG00000277044, ENSG00000125510 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 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.
  10. ↑ Martin WR (December 1967). "Opioid antagonists". Pharmacological Reviews. 19 (4): 463–521. PMID   4867058.
  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.
  12. ↑ Wang Y, Zhuang Y, DiBerto JF, Zhou XE, Schmitz GP, Yuan Q, et al. (2023). "Structures of the entire human opioid receptor family". Cell. 186 (2): 413–427.e17. doi:10.1016/j.cell.2022.12.026. PMID   36638794.
  13. ↑ 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. Bibcode:1995Natur.377..532M. doi: 10.1038/377532a0 . PMID   7566152. S2CID   4326860.
  14. ↑ Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, et al. (1995). "Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor". Science. 270 (5237): 792–4. Bibcode:1995Sci...270..792R. doi:10.1126/science.270.5237.792. PMID   7481766. S2CID   38117854.
  15. ↑ 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. S2CID   22919153.
  16. ↑ 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.
  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.
  18. ↑ 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.
  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. 1 2 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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. PMID   16766718. S2CID   9537945.
  31. ↑ 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.
  32. 1 2 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.
  33. ↑ Khroyan TV, Polgar WE, Orduna J, Montenegro J, Jiang F, Zaveri NT, et al. (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.
  34. ↑ Zaratin PF, Petrone G, Sbacchi M, Garnier M, Fossati C, Petrillo P, et al. (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. S2CID   8036750.
  35. ↑ Ding H, Czoty PW, Kiguchi N, Cami-Kobeci G, Sukhtankar DD, Nader MA, et al. (September 2016). "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. Bibcode:2016PNAS..113E5511D. doi: 10.1073/pnas.1605295113 . PMC   5027459 . PMID   27573832. S2CID   36624494.
  36. ↑ 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.
  37. ↑ 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. S2CID   22718102.
  38. ↑ 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. S2CID   29027947.
  39. ↑ 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. S2CID   25596953.

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