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Pharmaceuticals (Basel). 2017 Oct 8;10(4). pii: E79. doi: 10.3390/ph10040079.

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

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Department of Pediatrics, University of California, San Diego 92093, CA, USA.
Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa 920-8620, Japan.
Department of Neuroscience, University of Turin, Torino 10124, Italy.
Department of Biochemistry, School of Medicine, Saint George's University, Saint George's 11739, Grenada.
Biochemistry and Cell Biology, Department of Veterinary Biosciences, University of Helsinki, Helsinki 11739, Finland.
Department of Physiology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki 00100, Finland.


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 interactions and/or heterodimerization between wild-type and variant orexin receptors and opioid and cannabinoid receptors is discussed in the context of its relevance to depression and epilepsy.


CB1 cannabinoid receptor; OX1 orexin receptor; OX2 orexin receptor; feeding behavior; hetero-dimerization; homo-dimerization; opioid receptor; orexin/hypocretin; sleep disorder; status epilepticus

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