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-hydroxytryptamine1B/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 CGRP8-37 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.
Footnotes
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The work was supported by the Wellcome Trust.
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doi:10.1124/jpet.105.090951.
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ABBREVIATIONS: CGRP, calcitonin gene-related peptide; OX1, orexin 1; SB-334867, N-(2-methyl-6-benzoxazolyl)-N″-1,5-naphthyridin-4-yl urea; TNC, trigeminal nucleus caudalis.
- Received June 14, 2005.
- Accepted September 8, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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