Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin gene‐related peptide

Abstract

Japan1 The dura mater encephali of the rat was exposed and the blood flow around branches of the medial meningeal artery was monitored with a laser Doppler flowmeter. Changes in the meningeal blood flow (MBF) following electrical stimulation of the dura mater at a parasagittal site were registered. The effects of human calcitonin gene-related peptide (h-aCGRP) and the CGRP antagonist (h-aCGRP8-37) on the MBF were tested. 2 Electrical stimulation with rectangular pulses of 0.5 ms, 10-20 V, 5-10 Hz and a duration of 30 s caused an increase of the MBF in 14 out of 16 rats tested. The increases were dependent on stimulus strength and frequency. 3 The increase in MBF was inhibited in a dose-dependent manner by topical application of 0.1 ml of h-mCGRP837 at concentrations of 10-7-10-'M. The highest dose abolished the increase in MBF. 4 Topical administration of 0.1 ml of h-aCGRP at a concentration of 10-4 M increased the basal MBF by 15% on average. 5 It is suggested that the increase in MBF following electrical stimulation of the dura mater is mediated by the release of CGRP. The contribution of the dural afferent and sympathetic and parasympathetic efferent nerve fibres to this response are discussed.

Nitric Oxide Releases Calcitonin-Gene-Related Peptide from Rat Dura mater Encephali Promoting Increases in Meningeal Blood Flow

“…Solutions of the CGRP receptor antagonist CGRP 8–37 have been shown to inhibit electrically evoked increases in meningeal blood flow dose-dependently when applied to the dura mater during stimulation [35]. In these experiments, CGRP 8–37 at 10 –5 M suppressed the evoked increases in flow nearly totally for 30 min but rapid recovery was seen when the CGRP 8–37 solution was removed from the dura.…”

“…The increases in flow caused by this combination were not significantly higher than the flow increases caused by NONOate alone. In a previous study [35], CGRP at a concentration of 10 –4 M locally applied onto the exposed rat dura mater increased the blood flow by a similar value, namely 15%, on average. Therefore it seems that a small concentration of NO is necessary to facilitate the release and vasodilatory action of CGRP.…”

“…Since it was known from earlier studies that the electrically evoked increases in blood flow depend on the release and the vasodilatory action of CGRP [35], we suggested that NO might interact with the CGRP release from dural afferents or with the vasorelaxant effect of CGRP. In a previous paper, Wei et al [36]have found that the vasodilatory effect of the NO donors nitroglycerin and nitroprusside on cerebral arterioles of the cat was reduced after chronic trigeminal denervation (trigeminal ganglionectomy) and after application of the CGRP receptor antagonist CGRP 8–37 .…”

Neuropeptide Effects in the Trigeminal System: Pathophysiology and Clinical Relevance in Migraine

“…Interestingly, inhibition was observed when CGRP inhibitors were applied topically or administered systemically. 22,23 These striking actions of the inhibitors raise questions about the localization of the CGRP receptors.…”

“…20 CGRP-dependent vasodilatory effects in the rodent dura can be observed through a cranial window by video microscopy 21 or by using blood flow as a readout via laser Doppler flow recordings. 22 For example, administrations of the CGRP receptor antagonists CGRP or olcegepant (BIBN4096BS, Boehringer Ingelheim) were able to inhibit increases in meningeal blood flow induced by periodic electrical stimulation of the dura in rats. Interestingly, inhibition was observed when CGRP inhibitors were applied topically or administered systemically.…”