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Figure 1. Schematic representation of central and peripheral outputs and inputs of orexin neurons.Orexin neurons originating in the lateral hypothalamic (LH) area (black spots), are found projecting (orange arrows) throughout the entire central nervous system (CNS). Orexin neurons regulate sleep/wakefulness and the maintenance of arousal by sending excitatory projections to the LDT and PPT nuclei (harboring cholinergic neurons that produce neurotransmitter Ach), the LC (harboring noradrenergic neurons that produce neurotransmitter NA), the DR nuclei (harboring serotonergic neurons that produce neurotransmitter 5-HT), the VTA (harboring dopaminergic neurons that produce neurotransmitter DA), the TMN (harboring histaminergic neurons that produce neurotransmitter HA), and the LH itself (containing the orexin neurons). Orexin neurons also receive inhibiting projections from the ventrolateral preoptic nucleus (VLPO) containing GABAergic and galaninergic neurons [20, 47-49]. The brain region involved in food reward behavior and energy homeostasis is mainly located in the LH, other regions such as the VTA, NAc, and SN coordinately reinforce the rewarding actions. The regions partly overlapped with those involved in addiction and reward seeking behavior. For instance, the neurons in LH act as an input to VTA and NAc for stimuli associated reward seeking. Orexin neurons receive inhibited input (blue lines) by serotonergic neurons and noradrenergic neurons in the brain stem. These neurons project inhibitors such as 5-HT (from the DR) [50-52], GABA (from the VLPO) [47]. The CNS orexin system may affect the peripheral orexin system indirectly and more research is needed to establish the convincing link between the two systems. The peripheral orexin system is found in the adipose tissue, gastrointestinal tract (jejunum), adrenal glands (mainly the cortex), gonad (testes, ovaries), and pancreas [2, 38, 40-42]. Projection of orexins from the LH to the VTA increases the excitation of medullary sympathetic premotor neurons controlling BAT sympathetic outflow and BAT thermogenesis. This affects the long-term regulation of adiposity [53-54]. Orexin increases motility of submucosal plexus through exciting the secretomotor neurons that are located within the gastrointestinal tract. This exitation helps sensing and regulating machinery of the gut involved in energy metabolism [42, 55]. Orexins, mainly OxA, acutely activates adrenal cortex to increase production of corticosterone through the hypothalamic-pituitary-adrenal (HPA) axis [56-57]. Orexins stimulate gonadotropin-releasing hormone (GnRH) release from the hypothalamus, and affects the plasma estrogens (testosterone) levels through the hypothalamic-pituitary-ovarian (testicular) axis or by directly acting on ovary (testis) [58-59]. Orexin neurons also play a critical role in stimulating the sympathetic outflow to the pancreas and may under some circumstances helping increase blood glucose, which in turn provides negative feedback inhibition to orexin neurons [60].Abbreviations: Ach, acetylcholine; HA, histamine; DA, dopamine; NA, noradrenaline; 5-HT, 5-hydroxytryptamine, also known as serotonin; GABA, gamma-aminobutyric acid; DR, dorsal raphe nucleus; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; TMN, tuberomammillary nucleus; VTA, ventral tegmental area; VLPO, ventrolateral preoptic nucleus; SN, substantia nigra.

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Figure 2. Typical orexin sigalling. The binding of OxA (blue) and OxB (purple) with Ox1R (blue) and OX2R (purple) activates Gq/PLC/PKC/ERK, Gs/AC/cAMP/PKA/ERK (and/or CREB, p38 MAPK) and Gi cascades. The OX2R signalling through the Gq/PLC/PKC pathway seems stronger than that of the OX1R. The binding also triggers a PKC-mediated influx of calcium across the plasma membrane via L-type calcium channels. Intracellular calcium stores are released by a PLC mediated pathway. The elevated level of calcium produces sustained excitation of the neurons [65-69].

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Figure 3. OX1R signalling in apoptosis induction. (A) Prior to binding of orexins and the OX1R, the receptor is in its resting state. (B) Orexin binding activates OX1R and subsequently promotes the dissociation of Gq protein into Gαq-GTP monomer and βγ dimer. The traditional pathway of Gαq induced PLC activation (resulting in elevation of intracellular Ca^2 +) is not involved in OX1R-mediated apoptosis. (C) Released βγ subunit stimulates the Src-tyrosine kinase. This leads to phosphorylation of the ITIM and ITSM in OX1R. (D) The phosphotyrosine phosphatase SHP-2 (SH2 domain-containing phosphotyrosine phosphatase-2) is then recruited and activated by OX1R. Activated SHP-2 leads to subsequent cytochrome c-mediated mitochondrial apoptosis [167].

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Table 1. Selectivity OXR antagonists appear in this review.

K_i: determined in radioligand binding.IC₅₀ (nM): determined from cell-based Ca^2 + mobilization assay.K_b: determined by antagonism of orexin activation of either cellular Ca^2 + mobilization or IP3 signalling cellular assay.

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