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Pharmaceuticals 2017, 10(4), 79; doi:10.3390/ph10040079

Orexin Receptor Multimerization versus Functional Interactions: Neuropharmacological Implications for Opioid and Cannabinoid Signalling and Pharmacogenetics

1
Department of Pediatrics, University of California, San Diego 92093, CA, USA
2
Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa 920-8620, Japan
3
Department of Neuroscience, University of Turin, Torino 10124, Italy
4
Department of Biochemistry, School of Medicine, Saint George’s University, Saint George’s 11739, Grenada
5
Biochemistry and Cell Biology, Department of Veterinary Biosciences, University of Helsinki, Helsinki 11739, Finland
6
Department of Physiology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki 00100, Finland
*
Author to whom correspondence should be addressed.
Received: 28 August 2017 / Revised: 29 September 2017 / Accepted: 29 September 2017 / Published: 8 October 2017
(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications)
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Abstract

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. View Full-Text
Keywords: orexin/hypocretin; OX1 orexin receptor; OX2 orexin receptor; homo-dimerization; hetero-dimerization; opioid receptor; CB1 cannabinoid receptor; status epilepticus; feeding behavior; sleep disorder orexin/hypocretin; OX1 orexin receptor; OX2 orexin receptor; homo-dimerization; hetero-dimerization; opioid receptor; CB1 cannabinoid receptor; status epilepticus; feeding behavior; sleep disorder
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Thompson, M.D.; Sakurai, T.; Rainero, I.; Maj, M.C.; Kukkonen, J.P. Orexin Receptor Multimerization versus Functional Interactions: Neuropharmacological Implications for Opioid and Cannabinoid Signalling and Pharmacogenetics. Pharmaceuticals 2017, 10, 79.

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