## 2 Orexins
### Orexin Receptor  
Two orexin receptors highly conserved across species are described: orexin 1 and orexin 2. Rat and human orexin 1 and 2 receptors show, respectively, 94% and 95% homology. Orexin B shows a higher affinity for orexin receptor 2 than for orexin receptor 1, whereas orexin A shows equal affinity for both receptors [30] (Table 1). Both orexin receptors are G protein-coupled receptors (Table 1): orexin 1 receptor is abundant in the spinal cord, laterodorsal tegmentum, locus coeruleus, dorsal raphe, hypothalamus (ventromedial region), paraventricular thalamic nucleus, hippocampus (CA2 region) and prefrontal cortex, whereas the orexin 2 receptor is prominent in the neocortex, central amygdala, hippocampus (CA3 region), septum, thalamus, and hypothalamus (dorsomedial region) [29]. The orexin receptor can form homodimers, heterodimers or oligomers and it was reported that orexin A increased the dimerization/oligomerization, whereas antagonists decreased both processes [31] (Table 1). For example, orexin 1 and corticotropin-releasing factor receptor dimerization and orexin 1 receptor and kappa opioid receptor heteromerization were reported [31]. In general, the distribution of orexin receptors and fibers containing the peptide was similar, and it is known that the distribution of the orexin receptors was similar to that observed for the melanin-concentrating hormone receptor [29; 32] (Table 1). Orexinergic terminals show two bouton types: large (ovoid, diameter: >1.4 \(\upmu\)m) or small (spherical, <1.4 \(\upmu\)m) [15]. It is known that animals without the orexin 2 receptor had slow essations of movements (sleep attacks), whereas those lacking the orexin 1 receptor showed disrupted sleep but fewer signs of sleep attacks [47]. In the medulla oblongata, it was reported that chronic aldosterone exposure and salt intake did not change the expression of both orexin 1 and 2 receptors; however, in the hypothalamus, the expression of the latter receptor was increased [48]. It is also known that orexin 1 and 2 receptors are involved in the control of body weight and energy metabolism [14]. During the estrus cycle, it was reported that the expression of orexin receptors was increased exclusively during proestrus and that the administration of orexin receptor antagonists blocked ovulation as well as the effects mediated by the follicle-stimulating and luteinizing hormones [49]. The administration of orexin 1 receptor antagonists inhibited behavioral satiety and hyperphagia mediated by orexin B [33], and the inhibition of the orexin A signaling decreased overfeeding from a high fat diet under the condition of satiation. This means that orexin A regulates unconditioned reward-based high fat feeding, and that the peptide is involved in the modulation of cognitive-emotional mechanisms [34] (Table 1). Recently, a subtype-selective orexin 1 receptor antagonist was developed, showing the potential of structure-based drug designs to obtain new selective ligands for the orexin receptors [50] and it was reported that the neural depolarization mediated by orexin A depended on non-selective cation channels [51]. It was demonstrated that an enhanced orexin 2 receptor signaling improved leptin sensitivity and prevented diet-induced obesity [35] (Table 1). It is known that dynein light chain Tctex-type 1 and beta-arrestin are coupled to the C-terminus of the orexin receptor and it seems that the extracellular portion of the receptor contributes to the binding of the peptide [31; 52; 53; 54]. The signaling pathways activated by the orexinergic system remains obscure, although it is known that proteins Go, Gs and Gi are activated and that an increase in the level of Ca\({}^{2+}\) occurs [36] (Table 1). Orexin 1 receptor activates adenylyl cyclase via a high potency phospholipase C/protein kinase C coupling and a low potency Gs coupling [38] (Table 1). In fact, the response of orexin was blocked when inhibitors of phospholipase C or protein kinase C were used [55].