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

J Pharmacol Exp Ther. 2005 Dec;315(3):1380-5. doi: 10.1124/jpet.105.090951. Epub 2005 Sep 13.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Dura Mater / blood supply
  • Dura Mater / drug effects*
  • Dura Mater / physiology
  • Electric Stimulation
  • Intracellular Signaling Peptides and Proteins / pharmacology*
  • Male
  • Meningeal Arteries / drug effects
  • Meningeal Arteries / innervation
  • Meningeal Arteries / physiology
  • Microscopy, Video
  • Migraine Disorders / prevention & control
  • Models, Animal
  • Neuropeptides / pharmacology*
  • Neurotransmitter Agents / pharmacology
  • Orexins
  • Pain Measurement
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Trigeminal Nerve / drug effects*
  • Trigeminal Nerve / physiology*
  • Vasodilation / drug effects*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Neurotransmitter Agents
  • Orexins