Specifically, orexin (OX) A and OXB are peptides with neuronal cell bodies primarily localized in the LH (Fig. 1). However, orexin containing INK 128 mouse neurons have been shown to project to the cortex, thalamus, hypothalamus, brainstem (including the locus coeruleus and the raphe nucleus), as well to the gastrointestinal tract.46 Orexin acts on 2 G-protein coupled receptors, OXR1 and OXR2, which have been shown to contribute to the regulation of food intake as well as arousal and pain.47-49 In animal studies, centrally administered orexin increases food intake and has also been shown to reverse the cholecystokinin-induced

loss of appetite. In addition in VAT orexin has been shown to decrease the expression of hormone-sensitive lipase, which suggests that orexin might also modulate adipose tissue metabolism by inhibiting lipolysis.49 In addition to their role in feeding, the orexins

also participate in inflammatory processes. Several animal studies have demonstrated anti-nociceptive properties of the orexins. In mouse and rat models of nociception and hyperalgesia, intravenous OXA has been shown to be analgesic with an efficacy similar to that of morphine in both the hotplate test and carrageenan-induced thermal hyperalgesia tests.48 Similarly, intrathecally administered OXA in rats has been shown to inhibit heat-evoked hyperalgesia as well as to reduce mechanical allodynia.50 Finally, OXA has also been shown to inhibit Bortezomib neurogenic vasodilation as well as TNC neuronal nociceptive responses to electrical stimulation of the dura mater in rats.51,52 However, the orexins may also have a pro-nociceptive role. The orexins have been shown to excite the histaminergic neurons in the tuberomammillary nucleus (which terminates in the dorsal raphe nucleus and periaqueductal grey region), which can attenuate the antinociceptive effects of OXA. Specifically OXA activates histamine receptors, H1 and H2; and intra-cerebro-ventricular (ICV) injections of a histamine

receptor antagonist along with OXA in mice has shown greater antinociceptive PI-1840 effects than ICV OXA alone.47 Furthermore, OXA levels have been shown to be elevated in the cerebrospinal fluid of chronic daily headache sufferers.53 This would suggest that the orexin receptor antagonists, such as ACT-078573 or SB649868, which have been reported to be under development by Actelion and GSK for sleep disorders, could also have a role in migraine therapy.54,55 Thus, although the full role of the orexins and their receptors in migraine is still being determined, the current data suggest that the OXA can modulate neurogenic vasodilation, TNC activation, and pain. In addition, the existing data linking OXA and migraine further support the importance of the regulation of the hypothalamus, in not just feeding, but also pain. Further research evaluating orexin levels during or between migraine attacks is warranted. Adipocytokines.