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Received for publication June 15, 2005.
Revised September 8, 2005.
Accepted for publication September 8, 2005.
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. Anti-migraine drugs such as triptans, serotonin 5-HT1B/1D receptor agonists, reproducibly block neurogenic vasodilation associated with CGRP release. We examined their effects of the hypothalamic neuropeptides orexin A and B on neurogenic dural vasodilation, dissecting out the receptor pharmacology with the novel orexin 1 (OX1) receptor antagonist SB-334867. Electrical stimulation of dural afferents (50-300 µA) resulted in reproducible dural vasodilation of 136 ± 9 %. Orexin A 30 µgkg-1, but not 3 and 10 µgkg-1, inhibited the dilation brought about by electrical stimulation over 60 minutes and maximally after 15 minutes by 60% (t7 = 7.138, n = 8, P < 0.001). This response was reversed by pre-treatment 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 when compared to orexin A only. CGRP administration (1 µgkg-1) produced a reproducible dural blood vessel dilation of 145 ± 7% that was not inhibited by intravenous administration of orexin A (30 µgkg-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 pre-junctional release of CGRP from trigeminal neurons.
Key words:
calcitonin gene-related peptide, migraine, orexin, pain, trigeminal, trigeminovasculat
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