Orexin 1 Receptor Activation Attenuates Neurogenic Dural Vasodilation in an Animal Model of Trigeminovascular

The pathophysiology underlying the pulsating quality of the pain of a migraine attack is not fully understood, although trigeminal vascular afferents containing the sensory neuropep-tide calcitonin gene-related peptide (CGRP) must have a role. Antimigraine drugs, such as triptans, serotonin 5-hydro-xytryptamine1B/1D receptor agonists, reproducibly block neuro-genic vasodilation associated with CGRP release. We exam-ined the effects of the hypothalamic neuropeptides orexin A and orexin B on neurogenic dural vasodilation, dissecting out the receptor pharmacology with the novel orexin 1 (OX1) recep-tor antagonist N-(2-methyl-6-benzoxazolyl)-N-1,5-naphthyri-din-4-yl urea (SB-334867). Electrical stimulation of dural affer-ents (50–300 A) resulted in reproducible dural vasodilation of 136 9%. Orexin A 30 g kg1, but not 3 and 10 g kg1, inhibited the dilation brought about by electrical stimulation over 60 min and maximally after 15 min by 60 % (t7 7.138; P 0.001; n 8). This response was reversed by pretreatment wit