The orexins or hypocretins, are neuropeptides synthesized in the lateral hypothalamic area (LHA). Two orexin peptides [orexin-A (OX-A) and orexin-B (OX-B)] are produced from one gene transcript. These neurons project widely to numerous brain regions including the cortex, thalamus, hypothalamus, brainstem, and spinal cord. This diffuse projection pattern suggests that the orexin system regulates multiple complex physiological functions. Indeed, involvement in feeding behavior, autonomic modulation, and both neuroendocrine and sleep regulation have been hypothesized as roles of the orexin system.
Two orexin receptors, orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R), have been identified. These receptors display different affinities for the two orexin peptides. Specifically, OX2R binds OX-A and OX-B with the similar affinities, whereas OX1R is 30-100 times more responsive to OX-A than OX-B. Thus, OX1R is considered to be a selective receptor for OX-A and OX2R is considered to be a nonselective receptor for both OX-A and OX-B peptides.
Initial studies investigating the physiological role of the orexins focused mainly on feeding behavior. This was due in large part to the fact that the LHA is a brain region known to contribute to feeding regulation as it produces several other neuropeptides with effects on food intake. Immunohistochemical analyses of orexinergic projections, as well as initial descriptions of orexin receptor mRNA suggested orexin signaling in areas involved in appetite, satiety, and energy balance. Furthermore, intracerebroventricular injection of orexin peptide increased food consumption and fasting caused upregulation of preproorexin mRNA in the hypothalamus of rats.However, neuroanatomical and genetic data have also implicated the orexin system in the modulation of sleep/wake states. Specifically, orexinergic neurons densely innervate brain areas thought to be involved in sleep regulation. These areas include the noradrenergic cells of the locus coeruleus, serotonergic cells of the dorsal raphe nucleus, cholinergic cells of the basal forebrain and pedunculopontine nucleus, and histaminergic cells of the tuberomammillary nucleus. Moreover, targeted deletion of the orexin gene in mice results in a narcolepsy-like phenotype consisting of cataplexy and dysregulation of REM sleep. Similarly, spontaneous mutations in the OX2R gene cause a narcolepsy phenotype in dogs. Finally, narcoleptic humans have been reported to have no detectable orexin in cerebrospinal fluid. Thus,it is now established that central orexin systems are critical regulators of sleep/wake states. However, the sites in the central nervous system involved in mediating these diverse effects and the differential contributions of the OX1R and OX2R receptors to this regulation are not fully understood.
The overall regional distribution of orexin receptor mRNAs in the rat brain has been described previously. A recent paper has provided additional detail for forebrain structures. However, a systematic analysis of the nuclear and subnuclear patterns of expression across the entire rat brain has not appeared. Additionally, immunocytochemical studies cited above that demonstrated widespread projections of orexinergic neurons have not been reconciled with the orexin receptor localization patterns. We therefore undertook a systematic examination of the rat brain, from the anterior olfactory nucleus to the caudal medulla, to assess the distribution of OX1R and OX2R receptor mRNA. We used two distinct probes for each receptor subtype and in situ hybridization histochemistry to compare the differential expression of each receptor.
Marcus, J. N. (2005). Orexin receptors and the central autonomic system.
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