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

Abstract

The pathophysiology underlying the pulsating quality of the pain of a migraine attack is not fully understood, although trigeminal vascular afferents containing the sensory neuropeptide calcitonin gene-related peptide (CGRP) must have a role. Antimigraine drugs, such as triptans, serotonin 5-hydroxytryptamine_1B/1D receptor agonists, reproducibly block neurogenic vasodilation associated with CGRP release. We examined 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) receptor antagonist N-(2-methyl-6-benzoxazolyl)-N″-1,5-naphthyridin-4-yl urea (SB-334867). Electrical stimulation of dural afferents (50–300 μA) resulted in reproducible dural vasodilation of 136 ± 9%. Orexin A 30 μg kg^–1, but not 3 and 10 μg kg^–1, 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 with the OX₁ receptor antagonist SB-334867. Addition of CGRP_8-37 at the point of maximal effect of orexin A produced a further significant decrease in neurogenic dural vasodilation compared with orexin A only. CGRP administration (1 μg kg^–1) produced a reproducible dural blood vessel dilation of 145 ± 7% that was not inhibited by intravenous administration of orexin A (30 μg kg^–1). Orexin B had no significant effect even at the highest dose. The current study demonstrates that orexin A is able to inhibit neurogenic dural vasodilation via activation of the OX₁ receptor, resulting in inhibition of prejunctional release of CGRP from trigeminal neurons.