Intravital Microscope Studies on the Effects of Neurokinin Agonists and Calcitonin Gene-Related Peptide on Dural Vessel Diameter in the Anaesthetized Rat

Williamson, Dominic J.; Hargreaves, RJ; Hill, Ray; Shepheard, Sara L.

doi:10.1046/j.1468-2982.1997.1704518.x

Cited by 163 publications

(177 citation statements)

References 21 publications

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“…CGRP receptors have been functionally located on intracranial arterial blood vessels, where they induce vasodilatation and increases in intracranial blood flow Brian et al, 1996;Williamson et al, 1997). CGRP receptors may also be located on primary afferents, because they have been demonstrated in cultured dorsal root ganglion cells using nanogoldlinked CGRP (Segond et al, 2002).…”

Section: Cgrp Receptor Location and Possible Sites Of Actionmentioning

confidence: 99%

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

Fischer¹,

Koulchitsky²,

Meßlinger³

2005

J. Neurosci.

124

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Calcitonin gene-related peptide (CGRP) has been suggested to play a major role in the pathogenesis of migraines and other primary headaches. CGRP may be involved in the control of neuronal activity in the spinal trigeminal nucleus (STN), which integrates nociceptive afferent inputs from trigeminal tissues, including intracranial afferents. The activity of STN neurons is thought to reflect the activity of central trigeminal nociceptive pathways causing facial pain and headaches in humans.In a rat model of meningeal nociception, single neuronal activity in the STN was recorded. All units had receptive fields located in the exposed parietal dura mater. Heat and cold stimuli were repetitively applied to the dura in a fixed pattern of ramps and steps. The nonpeptide CGRP receptor antagonist BIBN4096BS was topically applied onto the exposed dura or infused intravenously. BIBN4096BS (300 g/kg, i.v.) reduced spontaneous activity by ϳ30%, the additional dose of 900 g/kg intravenously by ϳ50% of the initial activity, whereas saline had no effect. The activity evoked by heat ramps was also reduced after BIBN4096BS (900 g/kg, i.v.) by ϳ50%. Topical administration of BIBN4096BS (1 mM) did not significantly change the spontaneous neuronal activity within 15 min.We conclude that the endogenous release of CGRP significantly contributes to the maintenance of spontaneous activity in STN neurons. Blockade of CGRP receptors, possibly at central and peripheral sites, may therefore be an effective way to decrease nociceptive transmission. This may offer a new therapeutic strategy for the treatment of facial pain and primary headaches.

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Section: Cgrp Receptor Location and Possible Sites Of Actionmentioning

confidence: 99%

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

Fischer¹,

Koulchitsky²,

Meßlinger³

2005

J. Neurosci.

124

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“…, and this has been shown previously to produce a maximal dilation (Williamson et al, 1997a). In those preparations where capsaicin was used to dilate the dural blood vessels, capsaicin was given as an intravenous bolus up to 7 g kg Ϫ1 , until a maximal dilation was observed (Akerman et al, 2003b).…”

mentioning

confidence: 92%

“…Neurogenic dural vasodilation identifies potential migraine targets such as sumatriptan (Williamson et al, 1997b) and opioid agonists (Williamson et al, 2001). CGRP injections trigger both migraine (Lassen et al, 2002) and dural vessel dilation (Williamson et al, 1997a) and CGRP antagonists have acute antimigraine properties (Olesen et al, 2003). NO is another known trigger of migraine (Dalsgaard-Nielsen, 1955;Thomsen et al, 1994) and dural vessel dilation (Akerman et al, 2002c).…”

mentioning

confidence: 99%

Anandamide Is Able to Inhibit Trigeminal Neurons Using an in Vivo Model of Trigeminovascular-Mediated Nociception

Akerman

Kaube²,

Goadsby³

2004

J Pharmacol Exp Ther

128

107

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Arachidonylethanolamide (anandamide, AEA) is believed to be the endogenous ligand of the cannabinoid CB 1 and CB 2 receptors. CB 1 receptors have been found localized on fibers in the spinal trigeminal tract and spinal trigeminal nucleus caudalis. Known behavioral effects of anandamide are antinociception, catalepsy, hypothermia, and depression of motor activity, similar to ⌬ 9 -tetrahydocannanbinol, the psychoactive constituent of cannabis. It may be a possible therapeutic target for migraine. In this study, we looked at the possible role of the CB 1 receptor in the trigeminovascular system, using intravital microscopy to study the effects of anandamide against various vasodilator agents. Anandamide was able to inhibit dural blood vessel dilation brought about by electrical stimulation by 50%, calcitonin gene-related peptide (CGRP) by 30%, capsaicin by 45%, and nitric oxide by 40%. CGRP 8 -37 was also able to attenuate nitric oxide (NO)-induced dilation by 50%. The anandamide inhibition was reversed by the CB 1 receptor antagonist AM251. Anandamide also reduced the blood pressure changes caused by CGRP injection, this effect was not reversed by AM251. It would seem that anandamide acts both presynaptically, to prevent CGRP release from trigeminal sensory fibers, and postsynaptically to inhibit the CGRP-induced NO release in the smooth muscle of dural arteries. CB 1 receptors seem to be involved in the NO/CGRP relationship that exists in causing headache and dural blood vessel dilation. It also seems that some of the blood pressure changes caused by anandamide are mediated by a noncannabinoid receptor, as AM251 was unable to reverse these effects. It can be suggested that anandamide is tonically released to play some form of modulatory role in the trigeminovascular system.

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“…Williamson et al (1997a) demonstrated that electrical stimulation of dura mater causes CGRP release from the prejunctional nerve fibers innervating the dural blood vessels, resulting in reproducible vasodilation. Blocking this vasodilation has proved to be an effective indicator of acute antimigraine efficacy, with many compounds, including the triptans (Williamson et al, 1997b,c) and CGRP antagonists (Williamson et al, 1997a), able to inhibit the vasodilation as well as provide effective antimigraine therapy Olesen et al, 2004).…”

mentioning

confidence: 99%

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

Holland¹,

Akerman²,

Goadsby³

2005

J Pharmacol Exp Ther

120

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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.

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Intravital Microscope Studies on the Effects of Neurokinin Agonists and Calcitonin Gene-Related Peptide on Dural Vessel Diameter in the Anaesthetized Rat

Cited by 163 publications

References 21 publications

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

Anandamide Is Able to Inhibit Trigeminal Neurons Using an in Vivo Model of Trigeminovascular-Mediated Nociception

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

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