Research reportThe role of histamine in dural vessel dilation☆
Introduction
Migraine is a common [25] and disabling condition [26] whose pathogenesis is not completely understood [14]. The cranial blood vessels and their trigeminal innervation appear to play a role in the throbbing quality of migraine pain [43]. Human studies suggest that histamine may trigger migraine via a nitrergic mechanism [29], so that an understanding of the pharmacology of this interaction especially in terms of the cranial vessels may be useful in developing migraine treatments.
Histamine has been shown to induce headache and migraine in control subjects and migraine patients [20], [24]. Headache occurs during histamine infusion, and is followed post infusion by a delayed headache that often fulfils the International Headache Society criteria for migraine [16]. Nitric oxide (NO), when given from a suitable donor, such as nitroglycerin in an intravenous infusion, in control subjects or migraine patients, again induces an immediate headache and frequently a delayed migraine response [18], [28]. It is believed that the histamine-induced headache is actually caused by histamine activating NO synthase via H1-receptors [20], [29], which is thought to catalyse the formation of NO in the endothelium [19]. The H1-receptor antagonist mepyramine, when given as a pretreatment before a histamine infusion prevents or reduces the severity of the immediate headache [24]. It also reduces the likelihood of a delayed headache response, with, in particular, no clear migraine being triggered.
The nociceptive innervation of the cranial vessels arises from the trigeminal nerve from cells in the trigeminal ganglion [10]. The trigeminal sensory fibres contain the potent vasodilator peptides calcitonin gene-related peptide (CGRP) and substance P [39]. CGRP and substance P both cause dilation of dural vessels when given intravenously in the rat [40], while trigeminal ganglion stimulation causes CGRP and substance P release in human and cat [13]. In the model of electrical stimulation of the closed cranial window neurogenic vasodilation of dural vessels, such as the middle meningeal artery, can be monitored continuously [40]. This dilation is mediated by CGRP release from the trigeminal sensory fibres [40]. Clinically effective anti-migraine agents, such as the triptans-5-HT1B/1D receptor agonists [11], block the meningeal dilation in the rat caused by cranial window and trigeminal ganglion stimulation [41]. This action of triptans is believed to be via direct constriction of the cranial blood vessels, and inhibition of the release of vasodilatory peptides from trigeminal sensory nerve fibres innervating these blood vessels [12].
The purpose of this study was, first, to examine the effects of histamine on dural vessel diameter and then the effects of histamine after pre-treatment with antagonists at the various histamine receptors, using the intravital microscopy technique to measure meningeal vessel diameter continuously and in vivo. Secondly, we looked at the effect of histamine receptor antagonists on neurogenic dural vasodilation to see if there is a component of their action related to trigeminal sensory neurones innervating intracranial vessels. Finally, it is has been shown that the headache caused by histamine is actually due to the action of endogenous NO in the periphery [20], [29], so additionally we looked at the response of histamine infusion after pretreatment with an NO synthase inhibitor.
Section snippets
Surgical preparation
Male Sprague–Dawley rats (300–400 g) were anaesthetised throughout the experiments with sodium pentobarbitone (60 mg/kg i.p. and then 18 mg/kg per hour i.v. infusion). The left femoral artery and vein were cannulated for blood pressure recording and intravenous infusion of anaesthetic, respectively. Temperature was maintained at 37 °C throughout using a homeothermic blanket system. The rats were placed in a stereotaxic frame, the skull exposed and the right parietal bone thinned by drilling with
Effects of histamine and electrical stimulation on dural vessel diameter
Histamine produced an increase in vessel diameter of 103.5±6% (n=40 separate infusions in 31 animals, using infusions that had not been preceded by any treatment). The dilation was time-linked to the infusion (15 min) and reproducible in the same animal (Fig. 1). The dilation was accompanied by a decrease (29.5±2%) in arterial blood pressure that returned to normal post infusion. In the control studies (n=4 animals) with histamine the mean dilations were 87.9±16%, 79.1±5% and 87.6±18%,
Discussion
In this study we used intravital microscopy to measure histamine-induced changes in meningeal vessel diameter. When histamine was injected via the carotid artery it produced increases in vessel diameter that could be switched on and off by continuing or ceasing the histamine infusion, was readily reproducible and mediated by H1- and H2-receptors. The data are consistent with a mechanism of action that has a very short half-life, and is therefore a useful tool in an experimental setting. The
Acknowledgements
The authors would like to thank the Pharmacology Group at Merck for their assistance during the experiments, and in particular Drs R Hill and R. Hargreaves for facilitating these studies. The work has been supported by the Wellcome Trust. P.J.G. is a Wellcome Senior Research Fellow.
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