Orexin 1 receptor activation attenuates neurogenic dural vasodilation in an animal model of trigeminovascular nociception.
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 microA) resulted in reproducible dural vasodilation of 136 +/- 9%. Orexin A 30 microg kg(-1), but not 3 and 10 microg 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 microg kg(-1)) produced a reproducible dural blood vessel dilation of 145 +/- 7% that was not inhibited by intravenous administration of orexin A (30 microg 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.
Holland
P R
PR
Headache Group, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Akerman
S
S
Goadsby
P J
PJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004388:Dura Mater / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D004558:Electric Stimulation; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D018715:Microscopy, Video; D008881:Migraine Disorders / Q000517:prevention & control; D023421:Models, Animal; D009479:Neuropeptides / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D000068797:Orexins; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014276:Trigeminal Nerve / Q000187:drug effects* / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects*
D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D000068797:Orexins