Neurogenically Mediated Plasma Extravasation in Dura Mater: Effect of Ergot Alkaloids: A Possible Mechanism of Action in Vascular Headache

Abstract

C-fiber-dependent neurogenic plasma extravasation developed in the dura mater but not the brain after electric stimulation of the rat trigeminal ganglion or after chemical stimulation of perivascular axons with intravenous capsaicin, a drug that depolarizes sensory nerve fibers. C-fiber-independent extravasation also developed in this tissue after intravenous injections of substance P or neurokinin A (two constituents of unmyelinated C fibers) and after serotonin, bradykinin, or allergic challenge in presensitized animals. Intravenous dihydroergotamine or ergotamine tartrate, in doses similar to those used to treat migraine and cluster headache, prevented the stimulation-induced leakage of plasma proteins within the dura mater. Not unexpectedly, the acute administration of methysergide, a drug effective in the prophylactic treatment of headache, was inactive in this acute model. Neither acute nor chronic administration of propranolol affected stimulation-induced leakage of plasma protein. These results demonstrate that neurogenic inflammation develops within the dura mater in the rat and that ergot alkaloids prevent the process by a C-fiber-dependent mechanism.

Expression of metabotropic glutamate receptors in rat meningeal and brain microvasculature and choroid plexus

“…Specifically, substance P receptor was expressed in both endothelial cells and pericytes within the microvasculature. Substance P has been shown to enhance permeability in dural vessels (Markowitz et al, 1988) and produce vasodilation of cerebral parenchymal vessels (Kobari et al, 1996). Therefore, like the substance P neuropeptide, glutamate may have potent effects on regulation of microvascular tone in conditions of migraine, as well as in inflammation, wound healing (Brain, 1997), and cerebral ischemia (Stumm et al, 2001).…”

Lack of effect of the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine on arteriovenous anastomotic shunting in the dura mater of the pig

“…These effects include plasma protein extravasation and oedema caused by the release of vasoactive peptides (e.g. substance P, calcitonin gene-related peptide, neurokinin A) from trigeminal afferents (Markowitz et al, 1988;Buzzi & Moskowitz, 1990). An involvement of the trigeminal system, whether confined to the dura mater or not, is probably reflected by the increased level of calcitonin gene-related peptide in the jugular venous blood, which can be observed during a migraine attack and which can equally be normalized by sumatriptan (Goadsby et al, 1990;Goadsby & Edvinsson, 1991).…”

“…Interestingly, arteriovenous anastomoses have been anatomically located in the human dura mater, which is endowed with rich vascularization (Rowbotham & Little, 1965;Kerber & Newton, 1973). The dura mater is currently held as a possible origin of the migraine pain, involving vasodilatation and extravasation of plasma protein, induced by peptide release from the peripheral endings of the trigeminal nerve (Markowitz et al, 1988;Goadsby et al, 1990). Such vascular changes in the dura mater, when experimentally induced in rats and guinea-pigs, can be inhibited by the same antimigraine drugs (Markowitz et al, 1988;Buzzi & Moskowitz, 1990).…”

“…The dura mater is currently held as a possible origin of the migraine pain, involving vasodilatation and extravasation of plasma protein, induced by peptide release from the peripheral endings of the trigeminal nerve (Markowitz et al, 1988;Goadsby et al, 1990). Such vascular changes in the dura mater, when experimentally induced in rats and guinea-pigs, can be inhibited by the same antimigraine drugs (Markowitz et al, 1988;Buzzi & Moskowitz, 1990). The mechanism involved in this inhibition of protein extravasation has not yet been fully elucidated; both a presynaptic inhibition of neuropeptide release (Buzzi et al, 1991) and cranial vasoconstriction (Humphrey et al, 1990;Saxena & Den Boer, 1991) remain as possibilities.…”

Role of 5‐HT1‐like receptors in the reduction of porcine cranial arteriovenous anastomotic shunting by sumatriptan

“…Furthermore, it is possible that the reduction in plasma extravasation by these drugs is secondary to the constriction of the leaking vessels within the carotid vascular bed. The lack of inhibition of neurogenic and capsaicin-induced plasma extravasation by angiotensin II and phenylephrine (see Markowitz et al, 1988;Saito et al, 1988;Buzzi & Moskowitz, 1990) does not necessarily signify independence from the vasoconstrictor effect of the antimigraine drugs, since these results were not backed up by simultaneous measurement of dural (or carotid) blood flow or even arterial blood pressure.…”