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

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 (OX 1 ) receptor antagonist N-(2-methyl-6-benzoxazolyl)-NЉ-1,5-naphthyridin-4-yl urea (SB-334867). Electrical stimulation of dural afferents (50 -300 A) resulted in reproducible dural vasodilation of 136 Ϯ 9%. Orexin A 30 g kg Ϫ1 , but not 3 and 10 g kg Ϫ1 ,inhibited the dilation brought about by electrical stimulation over 60 min and maximally after 15 min by 60% (t 7 ϭ 7.138; P Ͻ 0.001; n ϭ 8). This response was reversed by pretreatment with the OX 1 receptor antagonist SB-334867. Addition of CGRP 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 g kg Ϫ1 ) produced a reproducible dural blood vessel dilation of 145 Ϯ 7% that was not inhibited by intravenous administration of orexin A (30 g kg Ϫ1 ). 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 OX 1 receptor, resulting in inhibition of prejunctional release of CGRP from trigeminal neurons.

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

“…On the other hand, OX-B facilitates these same responses suggesting an involvement of OX 2 as well (Bartsch et al, 2004;Holland et al, 2005Holland et al, , 2006. In a rat model of dural vasodilation thought to be representative of migraine pathophysiology, intravenous administration of OX-A but not OX-B resulted in the inhibition of vasodilation, and pretreatment with SB-334867 blocked this effect (Holland et al, 2005). Increased levels of OX-A have been reported in the CSF of chronic migraine sufferers, although the significance of this finding is currently unknown (Sarchielli et al, 2008).…”

“…OX-A inhibits spontaneous and stimulus-evoked responses in trigeminal nucleus caudalis neurons; an-412 tagonist treatment suggests the effect might be mediated via OX 1 receptors. On the other hand, OX-B facilitates these same responses suggesting an involvement of OX 2 as well (Bartsch et al, 2004;Holland et al, 2005Holland et al, , 2006. In a rat model of dural vasodilation thought to be representative of migraine pathophysiology, intravenous administration of OX-A but not OX-B resulted in the inhibition of vasodilation, and pretreatment with SB-334867 blocked this effect (Holland et al, 2005).…”

Cluster headache, hypothalamus, and orexin

“…However, in an animal model of trigeminovascular nociception, systemically administered orexin-A signifi cantly inhibits nociceptive responses of TNC neurons to electrical stimulation of the dura mater surrounding the middle meningeal artery [13••]. The orexinergic trigeminal modulatory effect is further evidenced via the orexin-A inhibition of neurogenic dural vasodilation [12]. Activation of trigeminovascular afferents as described results in activation of hypothalamic neurons [24], a subpopulation of which has been shown to be orexin-synthesizing neurons in the lateral and posterior hypothalamic nuclei [42].…”

Obesity and Chronic Daily Headache

“…In an animal model, orexin A, but not orexin B, was able to inhibit neurogenic dural vasodilatation, resulting in inhibition of prejunctional release of CGRP from trigeminal neurons. The response was reversed by pretreatment with antagonists [68].…”