Advertisement

NOP Receptor Ligands and Parkinson’s Disease

  • Daniela Mercatelli
  • Clarissa Anna Pisanò
  • Salvatore Novello
  • Michele MorariEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 254)

Abstract

Nociceptin/Orphanin FQ (N/OFQ) and its NOP receptor are highly expressed in motor areas of the rodent, nonhuman, and human primate brain, such as primary motor cortex, thalamus, globus pallidus, striatum, and substantia nigra. Endogenous N/OFQ negatively regulates motor behavior and dopamine transmission through NOP receptors expressed by dopaminergic neurons of the substantia nigra compacta. Consistent with the existence of an N/OFQ tone over dopaminergic transmission, blockade of NOP receptor antagonists increases striatal dopamine release. In this chapter, we will review the evidence linking the N/OFQ-NOP receptor system to Parkinson’s disease (PD). We will first discuss data showing that the central N/OFQ-NOP receptor system undergoes plastic changes in different basal ganglia nuclei following dopamine depletion. Then we will show that NOP receptor antagonists relieve motor deficits in different rodent and nonhuman primate models of PD. Mechanistically, NOP receptor blockade in substantia nigra reticulata results in rebalancing of the inhibitory GABAergic and excitatory glutamatergic inputs impinging on nigro-thalamic GABAergic neurons, leading to thalamic disinhibition. We will also present data showing that, in addition to motor symptoms, N/OFQ also plays a role in the parkinsonian neurodegeneration. In fact, NOP receptor antagonists possess neuroprotective/neurorescue properties in in vitro and in vivo models of PD.

Keywords

Compound 24 J-113397 L-DOPA Nociceptin/Orphanin FQ NOP Parkinson’s Disease SB-612111 Trap-101 

References

  1. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366–375CrossRefGoogle Scholar
  2. Alexander GE, Crutcher MD, DeLong MR (1990) Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res 85:119–146CrossRefGoogle Scholar
  3. Arcuri L, Viaro R, Bido S, Longo F, Calcagno M, Fernagut PO, Zaveri NT, Calo G, Bezard E, Morari M (2016) Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson’s disease. Neurobiol Dis 89:55–64CrossRefGoogle Scholar
  4. Arcuri L, Mercatelli D, Morari M (2017) Parkinson’s disease: no NOP, new hope. Oncotarget 8:8995–8996CrossRefGoogle Scholar
  5. Arcuri L, Novello S, Frassineti M, Mercatelli D, Pisano CA, Morella I, Fasano S, Journigan BV, Meyer ME, Polgar WE, Brambilla R, Zaveri NT, Morari M (2018) Anti-Parkinsonian and anti-dyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists. Br J Pharmacol 175:782–796CrossRefGoogle Scholar
  6. Baik JH, Picetti R, Saiardi A, Thiriet G, Dierich A, Depaulis A, Le Meur M, Borrelli E (1995) Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377:424–428CrossRefGoogle Scholar
  7. Bastias-Candia S, di Benedetto M, D’Addario C, Candeletti S, Romualdi P (2015) Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: relevance to sporadic Parkinson’s disease. Environ Toxicol 30:656–663CrossRefGoogle Scholar
  8. Brown JM, Gouty S, Iyer V, Rosenberger J, Cox BM (2006) Differential protection against MPTP or methamphetamine toxicity in dopamine neurons by deletion of ppN/OFQ expression. J Neurochem 98:495–505CrossRefGoogle Scholar
  9. Cenci MA, Lee CS, Bjorklund A (1998) L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA. Eur J Neurosci 10:2694–2706CrossRefGoogle Scholar
  10. Collins LM, Dal Bo G, Calcagno M, Monzon-Sandoval J, Sullivan AM, Gutierrez H, Morari M, O’Keeffe GW (2015) Nociceptin/orphanin FQ inhibits the survival and axon growth of midbrain dopaminergic neurons through a p38-MAPK dependent mechanism. Mol Neurobiol 53:7284–7297CrossRefGoogle Scholar
  11. Cuenda A, Rousseau S (2007) p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 1773:1358–1375CrossRefGoogle Scholar
  12. di Benedetto M, Cavina C, D’Addario C, Leoni G, Candeletti S, Cox BM, Romualdi P (2009) Alterations of N/OFQ and NOP receptor gene expression in the substantia nigra and caudate putamen of MPP+ and 6-OHDA lesioned rats. Neuropharmacology 56:761–767CrossRefGoogle Scholar
  13. Gavioli EC, Calo G (2013) Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs. Pharmacol Ther 140:10–25CrossRefGoogle Scholar
  14. Gouty S, Brown JM, Rosenberger J, Cox BM (2010) MPTP treatment increases expression of pre-pro-nociceptin/orphanin FQ mRNA in a subset of substantia nigra reticulata neurons. Neuroscience 169:269–278CrossRefGoogle Scholar
  15. Karunakaran S, Saeed U, Mishra M, Valli RK, Joshi SD, Meka DP, Seth P, Ravindranath V (2008) Selective activation of p38 mitogen-activated protein kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. J Neurosci 28:12500–12509CrossRefGoogle Scholar
  16. Khan MS, Boileau I, Kolla N, Mizrahi R (2018) A systematic review of the role of the nociceptin receptor system in stress, cognition, and reward: relevance to schizophrenia. Transl Psychiatry 8:38CrossRefGoogle Scholar
  17. Laudenbach V, Calo G, Guerrini R, Lamboley G, Benoist JF, Evrard P, Gressens P (2001) Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain. J Clin Invest 107:457–466CrossRefGoogle Scholar
  18. Mabrouk OS, Marti M, Morari M (2010) Endogenous nociceptin/orphanin FQ (N/OFQ) contributes to haloperidol-induced changes of nigral amino acid transmission and parkinsonism: a combined microdialysis and behavioral study in naive and nociceptin/orphanin FQ receptor knockout mice. Neuroscience 166:40–48CrossRefGoogle Scholar
  19. Malinowska B, Godlewski G, Schlicker E (2002) Function of nociceptin and opioid OP4 receptors in the regulation of the cardiovascular system. J Physiol Pharmacol 53:301–324PubMedGoogle Scholar
  20. Mallimo EM, Kusnecov AW (2013) The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation. Front Cell Neurosci 7:173CrossRefGoogle Scholar
  21. Marti M, Guerrini R, Beani L, Bianchi C, Morari M (2002) Nociceptin/orphanin FQ receptors modulate glutamate extracellular levels in the substantia nigra pars reticulata. A microdialysis study in the awake freely moving rat. Neuroscience 112:153–160CrossRefGoogle Scholar
  22. Marti M, Mela F, Guerrini R, Calo G, Bianchi C, Morari M (2004a) Blockade of nociceptin/orphanin FQ transmission in rat substantia nigra reverses haloperidol-induced akinesia and normalizes nigral glutamate release. J Neurochem 91:1501–1504CrossRefGoogle Scholar
  23. Marti M, Mela F, Veronesi C, Guerrini R, Salvadori S, Federici M, Mercuri NB, Rizzi A, Franchi G, Beani L, Bianchi C, Morari M (2004b) Blockade of nociceptin/orphanin FQ receptor signaling in rat substantia nigra pars reticulata stimulates nigrostriatal dopaminergic transmission and motor behavior. J Neurosci 24:6659–6666CrossRefGoogle Scholar
  24. Marti M, Mela F, Fantin M, Zucchini S, Brown JM, Witta J, di Benedetto M, Buzas B, Reinscheid RK, Salvadori S, Guerrini R, Romualdi P, Candeletti S, Simonato M, Cox BM, Morari M (2005) Blockade of nociceptin/orphanin FQ transmission attenuates symptoms and neurodegeneration associated with Parkinson’s disease. J Neurosci 25:9591–9601CrossRefGoogle Scholar
  25. Marti M, Trapella C, Viaro R, Morari M (2007) The nociceptin/orphanin FQ receptor antagonist J-113397 and L-DOPA additively attenuate experimental parkinsonism through overinhibition of the nigrothalamic pathway. J Neurosci 27:1297–1307CrossRefGoogle Scholar
  26. Marti M, Trapella C, Morari M (2008) The novel nociceptin/orphanin FQ receptor antagonist Trap-101 alleviates experimental parkinsonism through inhibition of the nigro-thalamic pathway: positive interaction with L-DOPA. J Neurochem 107:1683–1696CrossRefGoogle Scholar
  27. Marti M, Sarubbo S, Latini F, Cavallo M, Eleopra R, Biguzzi S, Lettieri C, Conti C, Simonato M, Zucchini S, Quatrale R, Sensi M, Candeletti S, Romualdi P, Morari M (2010) Brain interstitial nociceptin/orphanin FQ levels are elevated in Parkinson’s disease. Mov Disord 25:1723–1732CrossRefGoogle Scholar
  28. Marti M, Rodi D, Li Q, Guerrini R, Fasano S, Morella I, Tozzi A, Brambilla R, Calabresi P, Simonato M, Bezard E, Morari M (2012) Nociceptin/orphanin FQ receptor agonists attenuate L-DOPA-induced dyskinesias. J Neurosci 32:16106–16119CrossRefGoogle Scholar
  29. Marti M, Mela F, Budri M, Volta M, Malfacini D, Molinari S, Zaveri NT, Ronzoni S, Petrillo P, Calo G, Morari M (2013) Acute and chronic antiparkinsonian effects of the novel nociceptin/orphanin FQ receptor antagonist NiK-21273 in comparison with SB-612111. Br J Pharmacol 168:863–879CrossRefGoogle Scholar
  30. Meredith GE, Rademacher DJ (2011) MPTP mouse models of Parkinson’s disease: an update. J Parkinson’s Dis 1:19–33Google Scholar
  31. Morari M, O’Connor WT, Darvelid M, Ungerstedt U, Bianchi C, Fuxe K (1996) Functional neuroanatomy of the nigrostriatal and striatonigral pathways as studied with dual probe microdialysis in the awake rat – I. Effects of perfusion with tetrodotoxin and low-calcium medium. Neuroscience 72:79–87CrossRefGoogle Scholar
  32. Nolan YM, Sullivan AM, Toulouse A (2013) Parkinson’s disease in the nuclear age of neuroinflammation. Trends Mol Med 19:187–196CrossRefGoogle Scholar
  33. Norton CS, Neal CR, Kumar S, Akil H, Watson SJ (2002) Nociceptin/orphanin FQ and opioid receptor-like receptor mRNA expression in dopamine systems. J Comp Neurol 444:358–368CrossRefGoogle Scholar
  34. Picetti R, Saiardi A, Abdel Samad T, Bozzi Y, Baik JH, Borrelli E (1997) Dopamine D2 receptors in signal transduction and behavior. Crit Rev Neurobiol 11:121–142CrossRefGoogle Scholar
  35. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease. Nat Rev Dis Prim 3:17013CrossRefGoogle Scholar
  36. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047CrossRefGoogle Scholar
  37. Post A, Smart TS, Krikke-Workel J, Dawson GR, Harmer CJ, Browning M, Jackson K, Kakar R, Mohs R, Statnick M, Wafford K, McCarthy A, Barth V, Witkin JM (2016) A selective nociceptin receptor antagonist to treat depression: evidence from preclinical and clinical studies. Neuropsychopharmacology 41:1803–1812CrossRefGoogle Scholar
  38. Redrobe JP, Calo G, Guerrini R, Regoli D, Quirion R (2000) [Nphe(1)]-Nociceptin (1-13)-NH(2), a nociceptin receptor antagonist, reverses nociceptin-induced spatial memory impairments in the Morris water maze task in rats. Br J Pharmacol 131:1379–1384CrossRefGoogle Scholar
  39. Scatton B, Claustre Y, Cudennec A, Oblin A, Perrault G, Sanger DJ, Schoemaker H (1997) Amisulpride: from animal pharmacology to therapeutic action. Int Clin Psychopharmacol 12(Suppl 2):S29–S36CrossRefGoogle Scholar
  40. Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B (1997) Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther 280:83–97PubMedGoogle Scholar
  41. Schwarting RK, Huston JP (1996a) The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Prog Neurobiol 50:275–331CrossRefGoogle Scholar
  42. Schwarting RK, Huston JP (1996b) Unilateral 6-hydroxydopamine lesions of meso-striatal dopamine neurons and their physiological sequelae. Prog Neurobiol 49:215–266CrossRefGoogle Scholar
  43. Sedelis M, Hofele K, Auburger GW, Morgan S, Huston JP, Schwarting RK (2000) MPTP susceptibility in the mouse: behavioral, neurochemical, and histological analysis of gender and strain differences. Behav Genet 30:171–182CrossRefGoogle Scholar
  44. Serra PA, Sciola L, Delogu MR, Spano A, Monaco G, Miele E, Rocchitta G, Miele M, Migheli R, Desole MS (2002) The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induces apoptosis in mouse nigrostriatal glia. Relevance to nigral neuronal death and striatal neurochemical changes. J Biol Chem 277:34451–34461CrossRefGoogle Scholar
  45. Sibaev A, Fichna J, Saur D, Yuece B, Timmermans JP, Storr M (2015) Nociceptin effect on intestinal motility depends on opioid-receptor like-1 receptors and nitric oxide synthase co-localization. World J Gastrointest Pharmacol Ther 6:73–83CrossRefGoogle Scholar
  46. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840CrossRefGoogle Scholar
  47. Toledo MA, Pedregal C, Lafuente C, Diaz N, Martinez-Grau MA, Jimenez A, Benito A, Torrado A, Mateos C, Joshi EM, Kahl SD, Rash KS, Mudra DR, Barth VN, Shaw DB, McKinzie D, Witkin JM, Statnick MA (2014) Discovery of a novel series of orally active nociceptin/orphanin FQ (NOP) receptor antagonists based on a dihydrospiro(piperidine-4,7′-thieno[2,3-c]pyran) scaffold. J Med Chem 57:3418–3429CrossRefGoogle Scholar
  48. Toll L, Bruchas MR, Calo G, Cox BM, Zaveri NT (2016) Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol Rev 68:419–457CrossRefGoogle Scholar
  49. Usiello A, Baik JH, Rouge-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E (2000) Distinct functions of the two isoforms of dopamine D2 receptors. Nature 408:199–203CrossRefGoogle Scholar
  50. Viaro R, Sanchez-Pernaute R, Marti M, Trapella C, Isacson O, Morari M (2008) Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism. Neurobiol Dis 30:430–438CrossRefGoogle Scholar
  51. Viaro R, Calcagno M, Marti M, Borrelli E, Morari M (2013) Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands. Neuropharmacology 72:126–138CrossRefGoogle Scholar
  52. Visanji NP, de Bie RM, Johnston TH, McCreary AC, Brotchie JM, Fox SH (2008) The nociceptin/orphanin FQ (NOP) receptor antagonist J-113397 enhances the effects of levodopa in the MPTP-lesioned nonhuman primate model of Parkinson’s disease. Mov Disord 23:1922–1925CrossRefGoogle Scholar
  53. Volta M, Mabrouk OS, Bido S, Marti M, Morari M (2010a) Further evidence for an involvement of nociceptin/orphanin FQ in the pathophysiology of Parkinson’s disease: a behavioral and neurochemical study in reserpinized mice. J Neurochem 115:1543–1555CrossRefGoogle Scholar
  54. Volta M, Marti M, McDonald J, Molinari S, Camarda V, Pela M, Trapella C, Morari M (2010b) Pharmacological profile and antiparkinsonian properties of the novel nociceptin/orphanin FQ receptor antagonist 1-[1-cyclooctylmethyl-5-(1-hydroxy-1-methyl-ethyl)-1,2,3,6-tetrahydro-pyri din-4-yl]-3-ethyl-1,3-dihydro-benzoimidazol-2-one (GF-4). Peptides 31:1194–1204CrossRefGoogle Scholar
  55. Volta M, Viaro R, Trapella C, Marti M, Morari M (2011) Dopamine-nociceptin/orphanin FQ interactions in the substantia nigra reticulata of hemiparkinsonian rats: involvement of D2/D3 receptors and impact on nigro-thalamic neurons and motor activity. Exp Neurol 228:126–137CrossRefGoogle Scholar
  56. Zarubin T, Han J (2005) Activation and signaling of the p38 MAP kinase pathway. Cell Res 15:11–18CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Daniela Mercatelli
    • 1
  • Clarissa Anna Pisanò
    • 1
  • Salvatore Novello
    • 1
  • Michele Morari
    • 1
    Email author
  1. 1.Department of Medical Sciences, Section of Pharmacology, and National Institute of NeuroscienceUniversity of FerraraFerraraItaly

Personalised recommendations