## 5 Relationships between Orexins and Other Substances
### Opioids  
In obesity, opioids and orexin A located in the basomedial amygdala are involved in feeding behavior and in the control of gastric distension neuronal excitability [114]. In a diet-induced obesity rat model, the expressions of both \(\upmu\)-opioid receptors and orexin A were increased in the basomedial amygdala [114] (Table 5). In the same experimental model, the administration of orexin A in the latter region augmented both the firing of basomedial amygdala gastric distension neurons and food consumption [114] (Table 5).  
Figure 3: Interactions of orexin with other substances. Green arrows represent activation and red arrows represent inhibition. Blue arrows mean related actions: glucose activates the secretion of orexin by neurons of the lateral hypothalamus, and this activation leads to an increase in glutamate in dopaminergic neurons of the ventral tegmental area. Abbreviations: AgRP—agoutilated protein; Arc—arcuate hypothalamic nucleus; DA—dopamine; Dyn-A—dynorphin-A; GABA—gamma-aminobutyric acid; Glut—glutamate; LH—lateral hypothalamus; NPY—neuropeptide Y; NT—neurotensin; POMC—pro-opiomelanocortin; VTA—ventral tegmental area.  
Thus, these effects could be inhibited with orexin 1 receptor antagonists (e.g., SB-334,867) and could also be somewhat attenuated by the co-administration of naloxone [114].  
It is known that dynorphin and orexin peptides are co-released; in the ventral tegmental area, dynorphin inhibits the reward behavior promoted by orexins; and in the paraventricular hypothalamic nucleus, dynorphin, but not orexin, increases hedonic intake [115] (Table 5). It is also known that obesity modifies the expression of both dynorphin and orexin receptors [115] (Table 5). The administration of DYN-A\({}_{1-13}\) into the paraventricular hypothalamic nucleus increases hedonic intake as well as the injection of orexin A into the ventral tegmental area [115] (Table 5). In the paraventricular hypothalamic nucleus, orexin A blunted the increase (hedonic intake) mediated by DYN-A\({}_{1-13}\); when an opioid receptor antagonist was administered in the same nucleus; a decrease in hedonic intake was observed but the administration of orexin A did not increase the hedonic intake. This means that in the paraventricular hypothalamic nucleus, the action mediated by orexin A is not regulated by opioids and that both peptides control the hedonic intake in an opposing manner (Table 5). It was reported that the administration of a non-opioid peptide (dynorphin A\({}_{2-17}\)) in the paraventricular hypothalamic nucleus augmented the short-term food intake and energy expenditure [116]. The DYN-A\({}_{1-13}\) opioid peptide increased palatable food intake, whereas orexin-A and DYN-A\({}_{2-17}\) decreased this intake [116]. Moreover, orexin A increased chow intake [116]. The findings suggest that orexin, opioid and non-opioid peptides play different roles in food intake/choice when non-palatable and palatable food possibilities are available (Table 5). Finally, it was reported that orexin A, via the orexin 1 receptor, blocked satiety-inducing pro-opiomelanocortin neurons [117, 118] (Table 5).