{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T10:28:24Z","timestamp":1770978504262,"version":"3.50.1"},"reference-count":122,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2017,10,8]],"date-time":"2017-10-08T00:00:00Z","timestamp":1507420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Orexins\/hypocretins are neuropeptides formed by proteolytic cleavage of a precursor peptide, which are produced by neurons found in the lateral hypothalamus. The G protein-coupled receptors (GPCRs) for these ligands, the OX1 and OX2 orexin receptors, are more widely expressed throughout the central nervous system. The orexin\/hypocretin system has been implicated in many pathways, and its dysregulation is under investigation in a number of diseases. Disorders in which orexinergic mechanisms are being investigated include narcolepsy, idiopathic sleep disorders, cluster headache and migraine. Human narcolepsy has been associated with orexin deficiency; however, it has only rarely been attributed to mutations in the gene encoding the precursor peptide. While gene variations within the canine OX2 gene hcrtr2 have been directly linked with narcolepsy, the majority of human orexin receptor variants are weakly associated with diseases (the idiopathic sleep disorders, cluster headache and polydipsia-hyponatremia in schizophrenia) or are of potential pharmacogenetic significance. Evidence for functional and\/or heterodimerization between wild-type variant orexin receptors and opioid and cannabinoid receptors is discussed in the context of its relevance to depression and epilepsy.<\/jats:p>","DOI":"10.3390\/ph10040079","type":"journal-article","created":{"date-parts":[[2017,10,9]],"date-time":"2017-10-09T11:25:35Z","timestamp":1507548335000},"page":"79","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Orexin Receptor Multimerization versus Functional Interactions: Neuropharmacological Implications for Opioid and Cannabinoid Signalling and Pharmacogenetics"],"prefix":"10.3390","volume":"10","author":[{"given":"Miles","family":"Thompson","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego 92093, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa 920-8620, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Innocenzo","family":"Rainero","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Turin, Torino 10124, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Maj","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Saint George\u2019s University, Saint George\u2019s 11739, Grenada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jyrki","family":"Kukkonen","sequence":"additional","affiliation":[{"name":"Biochemistry and Cell Biology, Department of Veterinary Biosciences, University of Helsinki, Helsinki 11739, Finland"},{"name":"Department of Physiology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki 00100, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1212\/WNL.56.1.115","article-title":"A prepro-orexin gene polymorphism is associated with narcolepsy","volume":"56","author":"Gencik","year":"2001","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3389\/fnins.2014.00057","article-title":"OX1 and OX2 orexin\/hypocretin receptor pharmacogenetics","volume":"8","author":"Thompson","year":"2014","journal-title":"Front. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/bph.12261","article-title":"Discovery and development of orexin receptor antagonists as therapeutics for insomnia","volume":"171","author":"Winrow","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/978-1-4939-0956-8_9","article-title":"Pharmacogenetics of the G protein-coupled receptors","volume":"1175","author":"Thompson","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/ajmg.b.30047","article-title":"Variants of the orexin2\/hcrt2 receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette\u2019s syndrome comorbidity","volume":"129","author":"Thompson","year":"2004","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/7854_2016_49","article-title":"Orexin\/hypocretin signalling","volume":"33","author":"Kukkonen","year":"2017","journal-title":"Curr. Top Behav. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1111\/bph.12324","article-title":"Orexin\/hypocretin receptor signalling cascades","volume":"171","author":"Kukkonen","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/bph.12296","article-title":"Orexin\/hypocretin receptor signalling: A functional perspective","volume":"171","author":"Leonard","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1212\/WNL.57.10.1896","article-title":"Polymorphisms in hypocretin\/orexin pathway genes and narcolepsy","volume":"57","author":"Olafsdottir","year":"2001","journal-title":"Neurology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/79690","article-title":"A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains","volume":"6","author":"Peyron","year":"2000","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s10194-011-0314-8","article-title":"Evidence for an association between migraine and the hypocretin receptor 1 gene","volume":"12","author":"Rainero","year":"2011","journal-title":"J. Headache Pain"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.jad.2010.10.033","article-title":"Association between major mood disorders and the hypocretin receptor 1 gene","volume":"130","author":"Rainero","year":"2011","journal-title":"J. Affect. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.biopsych.2005.04.015","article-title":"Association of an orexin 1 receptor 408Val variant with polydipsia-hyponatremia in schizophrenic subjects","volume":"58","author":"Meerabux","year":"2005","journal-title":"Biol. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1007\/s12017-007-8001-2","article-title":"The orexin 1 receptor (HCRTR1) gene as a susceptibility gene contributing to polydipsia-hyponatremia in schizophrenia","volume":"9","author":"Fukunaka","year":"2007","journal-title":"Neuromol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/YPG.0b013e328341a3db","article-title":"Panic disorder is associated with the Val308Iso polymorphism in the hypocretin receptor gene","volume":"21","author":"Annerbrink","year":"2011","journal-title":"Psychiatr. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1111\/j.1526-4610.2007.00863.x","article-title":"Association between migraine and the G1246A polymorphism in the hypocretin receptor 2 gene","volume":"47","author":"Schurks","year":"2007","journal-title":"Headache"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1212\/01.wnl.0000219765.95038.d7","article-title":"A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort","volume":"66","author":"Baumber","year":"2006","journal-title":"Neurology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1212\/01.wnl.0000215852.35329.34","article-title":"Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene","volume":"66","author":"Schurks","year":"2006","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1111\/j.1526-4610.2008.01080.x","article-title":"Haplotype analysis confirms the association between the HCRTR2 gene and cluster headache","volume":"48","author":"Rainero","year":"2008","journal-title":"Headache"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/j.1468-2982.2007.01287.x","article-title":"The G1246A polymorphism in the hypocretin receptor 2 gene is not associated with treatment response in cluster headache","volume":"27","author":"Schurks","year":"2007","journal-title":"Cephalalgia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0092-8674(00)80949-6","article-title":"Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior","volume":"92","author":"Sakurai","year":"1998","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1073\/pnas.95.1.322","article-title":"The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity","volume":"95","author":"Kilduff","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1152\/ajpcell.00227.2012","article-title":"Physiology of the orexinergic\/hypocretinergic system: A revisit in 2012","volume":"304","author":"Kukkonen","year":"2013","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0092-8674(00)81965-0","article-title":"The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene","volume":"98","author":"Lin","year":"1999","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1101\/gr.161001","article-title":"Identification and functional analysis of mutations in the hypocretin (orexin) genes of narcoleptic canines","volume":"11","author":"Hungs","year":"2001","journal-title":"Genome Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0092-8674(00)81973-X","article-title":"Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation","volume":"98","author":"Chemelli","year":"1999","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/S0896-6273(03)00330-1","article-title":"Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: Molecular genetic dissection of non-REM and REM sleep regulatory processes","volume":"38","author":"Willie","year":"2003","journal-title":"Neuron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0140-6736(99)05582-8","article-title":"Hypocretin (orexin) deficiency in human narcolepsy","volume":"355","author":"Nishino","year":"2000","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/S0006-8993(99)01131-2","article-title":"Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats","volume":"821","author":"Ida","year":"1999","journal-title":"Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1006\/bbrc.1998.9994","article-title":"Stimulation of gastric acid secretion by centrally administered orexin-A in conscious rats","volume":"254","author":"Takahashi","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E1089","DOI":"10.1152\/ajpendo.00351.2004","article-title":"Food deprivation differentially modulates orexin receptor expression and signalling in rat hypothalamus and adrenal cortex","volume":"288","author":"Karteris","year":"2005","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0960-0760(99)00110-7","article-title":"Orexins stimulate corticosterone secretion of rat adrenocortical cells, through the activation of the adenylate cyclase-dependent signalling cascade","volume":"70","author":"Malendowicz","year":"1999","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1006\/bbrc.1998.9750","article-title":"Independent feeding and metabolic actions of orexins in mice","volume":"253","author":"Lubkin","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0361-9230(99)00271-3","article-title":"Effects of food restriction on the hypothalamic prepro-orexin gene expression in genetically obese mice","volume":"51","author":"Yamamoto","year":"2000","journal-title":"Brain Res. Bull."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1124\/mol.110.064584","article-title":"Mapping the binding pocket of dual antagonist almorexant to human orexin 1 and orexin 2 receptors: Comparison with the selective OX1 antagonist SB-674042 and the selective OX2 antagonist N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA)","volume":"78","author":"Malherbe","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.neulet.2011.10.061","article-title":"Mapping of the binding sites for the OX1 orexin receptor antagonist, SB-334867, using orexin\/hypocretin receptor chimaeras","volume":"506","author":"Putula","year":"2012","journal-title":"Neurosci. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.ejphar.2011.05.074","article-title":"Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists","volume":"667","author":"Tran","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3178","DOI":"10.1021\/bi300136h","article-title":"Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site-directed mutagenesis","volume":"51","author":"Heifetz","year":"2012","journal-title":"Biochemistry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nsmb.3183","article-title":"Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors","volume":"23","author":"Yin","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nature14035","article-title":"Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant","volume":"519","author":"Yin","year":"2015","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Karhu, L., Turku, A., and Xhaard, H. (2015). Modeling of the OX1R-orexin-A complex suggests two alternative binding modes. BMC Struct. Biol., 15.","DOI":"10.1186\/s12900-015-0036-2"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1212\/01.WNL.0000142424.65251.DB","article-title":"A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache","volume":"63","author":"Rainero","year":"2004","journal-title":"Neurology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1515\/CCLM.2005.026","article-title":"Whole genome amplification of buccal cell DNA: Genotyping concordance before and after multiple displacement amplification","volume":"43","author":"Thompson","year":"2005","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/gm40","article-title":"New strategies and emerging technologies for massively parallel sequencing: Applications in medical research","volume":"1","author":"Mardis","year":"2009","journal-title":"Genome Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/ng.653","article-title":"Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome","volume":"42","author":"Krawitz","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1093\/protein\/6.1.37","article-title":"ALSCRIPT: A tool to format multiple sequence alignments","volume":"6","author":"Barton","year":"1993","journal-title":"Protein Eng."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1476-5381.2009.00169.x","article-title":"G protein-coupled receptor hetero-dimerization: Contribution to pharmacology and function","volume":"158","author":"Milligan","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/978-1-4939-0956-8_8","article-title":"G protein-coupled receptor mutations and human genetic disease","volume":"1175","author":"Thompson","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/978-1-4939-0956-8_7","article-title":"G protein-coupled receptor accessory proteins and signalling: Pharmacogenomic insights","volume":"1175","author":"Thompson","year":"2014","journal-title":"Methods Mol Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1042\/BJ20041745","article-title":"The sustainability of interactions between the orexin-1 receptor and beta-arrestin-2 is defined by a single C-terminal cluster of hydroxy amino acids and modulates the kinetics of ERK MAPK regulation","volume":"387","author":"Milasta","year":"2005","journal-title":"Biochem. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/bph.12481","article-title":"Molecular determinants of orexin receptor-arrestin-ubiquitin complex formation","volume":"171","author":"Jaeger","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Duguay, D., Belanger-Nelson, E., Mongrain, V., Beben, A., Khatchadourian, A., and Cermakian, N. (2011). Dynein light chain Tctex-Type 1 modulates orexin signalling through its interaction with orexin 1 receptor. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026430"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4069","DOI":"10.1096\/fj.09-131367","article-title":"Discovery of a functional immunoreceptor tyrosine-based switch motif in a 7-transmembrane-spanning receptor: Role in the orexin receptor OX1R-driven apoptosis","volume":"23","author":"Voisin","year":"2009","journal-title":"FASEB J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"16726","DOI":"10.1074\/jbc.M111.223537","article-title":"Temporal profiling of orexin receptor-arrestin-ubiquitin complexes reveals differences between receptor subtypes","volume":"286","author":"Dalrymple","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6570","DOI":"10.1074\/jbc.M407397200","article-title":"OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms","volume":"280","author":"Holmqvist","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.bcp.2005.12.021","article-title":"Agonist potency differentiates G protein activation and Ca2+ signalling by the orexin receptor type 1","volume":"71","author":"Magga","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.cellsig.2015.11.009","article-title":"OX2 orexin\/hypocretin receptor signal transduction in recombinant Chinese hamster ovary cells","volume":"28","author":"Kukkonen","year":"2016","journal-title":"Cell. Signal."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4808","DOI":"10.1210\/jcem.86.10.7921","article-title":"Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: Implications for adrenal function and energy homeostasis","volume":"86","author":"Randeva","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0163-7258(98)00030-8","article-title":"Molecular basis of receptor\/G-protein-coupling selectivity","volume":"80","author":"Wess","year":"1998","journal-title":"Pharmacol. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/mol.112.080523","article-title":"Autocrine endocannabinoid signalling through CB1 receptors potentiates OX1 orexin receptor signalling","volume":"83","author":"Jantti","year":"2013","journal-title":"Mol. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Milligan, G., Canals, M., Pediani, J.D., Ellis, J., and Lopez-Gimenez, J.F. (2006). The role of GPCR dimerisation\/oligomerisation in receptor signalling. GPCRs: From Deorphanization to Lead Structure Identification, Springer. Available online: https:\/\/link.springer.com\/chapter\/10.1007\/2789_2006_007.","DOI":"10.1007\/2789_2006_007"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1080\/10408360591001895","article-title":"The G protein-coupled receptors: Pharmacogenetics and disease","volume":"42","author":"Thompson","year":"2005","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/(SICI)1097-0134(20000501)39:2<112::AID-PROT2>3.0.CO;2-B","article-title":"A fast method to sample real protein conformational space","volume":"39","author":"Feldman","year":"2000","journal-title":"Proteins"},{"key":"ref_64","first-page":"543","article-title":"SEAVIEW and PHYLO_WIN: Two graphic tools for sequence alignment and molecular phylogeny","volume":"12","author":"Galtier","year":"1996","journal-title":"Comput. Appl. Biosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.tips.2005.01.004","article-title":"Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation","volume":"26","author":"Bulenger","year":"2005","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1042\/BJ20110230","article-title":"The orexin OX1 receptor exists predominantly as a homodimer in the basal state: Potential regulation of receptor organization by both agonist and antagonist ligands","volume":"439","author":"Xu","year":"2011","journal-title":"Biochem. J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"37414","DOI":"10.1074\/jbc.M111.287649","article-title":"Heteromultimerization of cannabinoid CB(1) receptor and orexin OX(1) receptor generates a unique complex in which both protomers are regulated by orexin A","volume":"286","author":"Ward","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.bbamcr.2013.12.010","article-title":"Heterodimerization of mouse orexin type 2 receptor variants and the effects on signal transduction","volume":"1843","author":"Wang","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.bbrc.2014.02.026","article-title":"Human orexin\/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors","volume":"445","author":"Jantti","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1097\/00008571-200310000-00008","article-title":"A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha","volume":"13","author":"Thompson","year":"2003","journal-title":"Pharmacogenetics"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1097\/FPC.0b013e328012d0bf","article-title":"A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate","volume":"17","author":"Thompson","year":"2007","journal-title":"Pharmacogenet. Genom."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/BF03256212","article-title":"G-protein-coupled receptors and asthma endophenotypes: The cysteinyl leukotriene system in perspective","volume":"10","author":"Thompson","year":"2006","journal-title":"Mol. Diagn. Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1002\/med.20071","article-title":"Cysteinyl-leukotrienes and their receptors in asthma and other inflammatory diseases: Critical update and emerging trends","volume":"27","author":"Capra","year":"2007","journal-title":"Med. Res. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3389\/fphar.2016.00299","article-title":"Cysteinyl leukotrienes pathway genes, atopic asthma and drug response: From population isolates to large genome-wide association studies","volume":"7","author":"Thompson","year":"2016","journal-title":"Front Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.regpep.2004.07.010","article-title":"Expression of orexin receptors in the brain and peripheral tissues of the male sheep","volume":"124","author":"Zhang","year":"2005","journal-title":"Regul. Pept."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.cellsig.2011.12.012","article-title":"Heterodimerization of human apelin and kappa opioid receptors: Roles in signal transduction","volume":"24","author":"Li","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1016\/j.cellsig.2015.03.027","article-title":"Heterodimerization of human orexin receptor 1 and kappa opioid receptor promotes protein kinase A\/cAMP-response element binding protein signalling via a Galphas-mediated mechanism","volume":"27","author":"Chen","year":"2015","journal-title":"Cell. Signal."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"4870","DOI":"10.1523\/JNEUROSCI.0732-07.2007","article-title":"Cannabinoids excite hypothalamic melanin-concentrating hormone but inhibit hypocretin\/orexin neurons: Implications for cannabinoid actions on food intake and cognitive arousal","volume":"27","author":"Huang","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Zheng, H., Pearsall, E.A., Hurst, D.P., Zhang, Y., Chu, J., Zhou, Y., Reggio, P.H., Loh, H.H., and Law, P.Y. (2012). Palmitoylation and membrane cholesterol stabilize mu-opioid receptor homodimerization and G protein coupling. BMC Cell Biol., 13.","DOI":"10.1186\/1471-2121-13-6"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ejphar.2015.05.012","article-title":"Opioid receptors: Structural and mechanistic insights into pharmacology and signalling","volume":"763","author":"Shang","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1523\/JNEUROSCI.3258-04.2005","article-title":"The wake-promoting peptide orexin-B inhibits glutamatergic transmission to dorsal raphe nucleus serotonin neurons through retrograde endocannabinoid signalling","volume":"25","author":"Shen","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1124\/mol.112.078063","article-title":"OX1 orexin\/hypocretin receptor signalling through arachidonic acid and endocannabinoid release","volume":"82","author":"Turunen","year":"2012","journal-title":"Mol. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"14600","DOI":"10.1523\/JNEUROSCI.2671-11.2011","article-title":"Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition","volume":"31","author":"Ho","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0009-3084(02)00151-2","article-title":"Dimerization of G protein-coupled receptors: CB1 cannabinoid receptors as an example","volume":"121","author":"Westenbroek","year":"2002","journal-title":"Chem. Phys. Lipids"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1124\/mol.104.006882","article-title":"Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors enhances heterodimer formation: A mechanism for receptor cross-talk?","volume":"67","author":"Kearn","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1073\/pnas.0907915107","article-title":"Formation and dissociation of M1 muscarinic receptor dimers seen by total internal reflection fluorescence imaging of single molecules","volume":"107","author":"Hern","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1111\/j.1742-4658.2005.04728.x","article-title":"Allosteric functioning of dimeric class C G-protein-coupled receptors","volume":"272","author":"Pin","year":"2005","journal-title":"FEBS J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/nmeth.1213","article-title":"Cell-surface protein-protein interaction analysis with time-resolved FRET and snap-tag technologies: Application to GPCR oligomerization","volume":"5","author":"Maurel","year":"2008","journal-title":"Nat. Methods"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1042\/BST20150285","article-title":"The use of fluorescence correlation spectroscopy to characterize the molecular mobility of fluorescently labelled G protein-coupled receptors","volume":"44","author":"Kilpatrick","year":"2016","journal-title":"Biochem. Soc. Trans."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"15541","DOI":"10.1074\/jbc.M314014200","article-title":"Cell surface expression of \u03b11D-adrenergic receptors is controlled by heterodimerization with \u03b11B-adrenergic receptors","volume":"279","author":"Hague","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1124\/jpet.106.106526","article-title":"\u03b12C-adrenergic receptors exhibit enhanced surface expression and signalling upon association with \u03b22-adrenergic receptors","volume":"318","author":"Prinster","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1210\/me.2004-0167","article-title":"Genomic organization of mouse orexin receptors: Characterization of two novel tissue-specific splice variants","volume":"18","author":"Chen","year":"2004","journal-title":"Mol. Endocrinol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"26959","DOI":"10.1074\/jbc.272.43.26959","article-title":"Dimerization of the delta opioid receptor: Implication for a role in receptor internalization","volume":"272","author":"Cvejic","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"38636","DOI":"10.1074\/jbc.M406276200","article-title":"The role of subtype-specific ligand binding and the C-tail domain in dimer formation of human somatostatin receptors","volume":"279","author":"Grant","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"6639","DOI":"10.1523\/JNEUROSCI.4364-14.2015","article-title":"Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine","volume":"35","author":"Navarro","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.bbr.2011.02.044","article-title":"Hcrtr1 and 2 signalling differentially regulates depression-like behaviors","volume":"222","author":"Scott","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S0006-3223(02)01740-7","article-title":"Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects","volume":"54","author":"Salomon","year":"2003","journal-title":"Biol. Psychiatry"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1038\/npp.2012.70","article-title":"Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression","volume":"37","author":"Nollet","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Rogala, B., Li, Y., Li, S., Chen, X., and Kirouac, G.J. (2012). Effects of a post-shock injection of the kappa opioid receptor antagonist norbinaltorphimine (norBNI) on fear and anxiety in rats. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049669"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.pharmthera.2009.05.006","article-title":"30 years of dynorphins\u2014new insights on their functions in neuropsychiatric diseases","volume":"123","author":"Schwarzer","year":"2009","journal-title":"Pharmacol. Ther."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/j.cellsig.2015.03.026","article-title":"The orexin 1 receptor modulates kappa opioid receptor function via a JNK-dependent mechanism","volume":"27","author":"Robinson","year":"2015","journal-title":"Cell. Signal."},{"key":"ref_102","first-page":"1346","article-title":"Projection-target-defined effects of orexin and dynorphin on VTA dopamine neurons","volume":"18","author":"Baimel","year":"2017","journal-title":"Cell Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00213-010-1806-y","article-title":"Kinase cascades and ligand-directed signalling at the kappa opioid receptor","volume":"210","author":"Bruchas","year":"2010","journal-title":"Psychopharmacology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.neuroscience.2012.05.033","article-title":"The social defeat animal model of depression shows diminished levels of orexin in mesocortical regions of the dopamine system, and of dynorphin and orexin in the hypothalamus","volume":"218","author":"Nocjar","year":"2012","journal-title":"Neuroscience"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/sj.bjp.0706757","article-title":"Mu opioid and CB1 cannabinoid receptor interactions: Reciprocal inhibition of receptor signalling and neuritogenesis","volume":"148","author":"Rios","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1038\/sj.npp.1301375","article-title":"Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids","volume":"32","author":"Carriba","year":"2007","journal-title":"Neuropsychopharmacology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1038\/emboj.2011.139","article-title":"AT1R-CB1R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II","volume":"30","author":"Rozenfeld","year":"2011","journal-title":"EMBO J."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1152\/physrev.00019.2008","article-title":"Endocannabinoid-mediated control of synaptic transmission","volume":"89","author":"Kano","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"38812","DOI":"10.1074\/jbc.M602494200","article-title":"Orexin-1 receptor-cannabinoid CB1 receptor heterodimerization results in both ligand-dependent and -independent coordinated alterations of receptor localization and function","volume":"281","author":"Ellis","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"7048","DOI":"10.1021\/jm1006676","article-title":"Synthesis and biological evaluation of bivalent ligands for the cannabinoid 1 receptor","volume":"53","author":"Zhang","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5505","DOI":"10.1021\/jm4005219","article-title":"Bivalent ligands that target mu opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance","volume":"56","author":"Akgun","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.brainres.2014.11.002","article-title":"Changes and overlapping distribution in the expression of CB1\/OX1-GPCRs in rat hippocampus by kainic acid-induced status epilepticus","volume":"1597","author":"Zhu","year":"2015","journal-title":"Brain Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1097\/WNR.0b013e3283413231","article-title":"Acetaminophen inhibits status epilepticus in cultured hippocampal neurons","volume":"22","author":"Deshpande","year":"2011","journal-title":"Neuroreport"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"R103","DOI":"10.1186\/cc13883","article-title":"Is pentobarbital safe and efficacious in the treatment of super-refractory status epilepticus: A cohort study","volume":"18","author":"Pugin","year":"2014","journal-title":"Crit. Care"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"413","DOI":"10.31887\/DCNS.2007.9.4\/nkogan","article-title":"Cannabinoids in health and disease","volume":"9","author":"Kogan","year":"2007","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0168-0102(01)00241-3","article-title":"Endogenous cannabinoid as a retrograde messenger from depolarized postsynaptic neurons to presynaptic terminals","volume":"40","author":"Maejima","year":"2001","journal-title":"Neurosci. Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2976","DOI":"10.1523\/JNEUROSCI.4465-07.2008","article-title":"Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus","volume":"28","author":"Ludanyi","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.brainres.2009.01.036","article-title":"Temporal characterization of changes in hippocampal cannabinoid CB1 receptor expression following pilocarpine-induced status epilepticus","volume":"1262","author":"Falenski","year":"2009","journal-title":"Brain Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.eplepsyres.2011.10.020","article-title":"Changes in the cannabinoid (CB1) receptor expression level and G-protein activation in kainic acid induced seizures","volume":"99","author":"Bojnik","year":"2012","journal-title":"Epilepsy Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1111\/j.1460-9568.2004.03285.x","article-title":"Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity","volume":"19","author":"Khaspekov","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"E2229","DOI":"10.1073\/pnas.1219485110","article-title":"Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons","volume":"110","author":"Cristino","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_122","first-page":"74","article-title":"Orexinergic system and pathophysiology of epilepsy","volume":"188","author":"Doreulee","year":"2010","journal-title":"Georgian Med. News"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/10\/4\/79\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:46:44Z","timestamp":1760208404000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/10\/4\/79"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,8]]},"references-count":122,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["ph10040079"],"URL":"https:\/\/doi.org\/10.3390\/ph10040079","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,8]]}}}