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 i 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. 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

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]

Further reading

External links

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.
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  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 .