RT Journal Article
SR Electronic
T1 Orexin 1 Receptor Activation Attenuates Neurogenic Dural Vasodilation in an Animal Model of Trigeminovascular Nociception
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1380
OP 1385
DO 10.1124/jpet.105.090951
VO 315
IS 3
A1 P. R. Holland
A1 S. Akerman
A1 P. J. Goadsby
YR 2005
UL http://jpet.aspetjournals.org/content/315/3/1380.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics