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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.

Author information

1
Department of Pediatrics, University of California, San Diego 92093, CA, USA. mithompson@ucsd.edu.
2
Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa 920-8620, Japan. tsakurai@med.kanazawa-u.ac.jp.
3
Department of Neuroscience, University of Turin, Torino 10124, Italy. innocenzo.rainero@unito.it.
4
Department of Biochemistry, School of Medicine, Saint George's University, Saint George's 11739, Grenada. mary.c.maj@gmail.com.
5
Biochemistry and Cell Biology, Department of Veterinary Biosciences, University of Helsinki, Helsinki 11739, Finland. jyrki.kukkonen@helsinki.fi.
6
Department of Physiology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki 00100, Finland. jyrki.kukkonen@helsinki.fi.

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 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.

KEYWORDS:

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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