Capsaicin-sensitive neurogenic sensory vasodilatation in the dura mater of the rat

The neurogenic sensory vascular responses of the dura mater encephali are considered to contribute significantly to the mechanisms of meningeal nociception and headache. Although the fundamental role of capsaicin-sensitive afferent nerves in the development of the neurogenic inflammatory responses of a variety of tissues is well established, their participation in meningeal vascular reactions is unclear. In the present study, the effects of the topical application of capsaicin on the dural blood flow and on the morphology of the dural nerve fibres were examined in control and capsaicin-pretreated rats by means of laser Doppler flowmetry and electron microscopy, respectively. In the control rats, the dural application of capsaicin at concentrations of 50 and 100 nM induced significant increases in blood flow in the branches of the medial meningeal artery. This capsaicin-induced vasodilatation was abolished by capsazepine, a transient receptor potential vanilloid 1 (TRPV1) receptor antagonist, and by hCGRP(8-37), a calcitonin gene-related peptide (CGRP) receptor antagonist. Administration of capsaicin at higher concentrations (1 and 10 muM) resulted in marked, dose-dependent decreases in dural blood flow. The capsaicin-induced vasodilatation was abolished, whereas vasoconstriction was augmented, by systemic pretreatment of the animals with capsaicin. Electron microscopy revealed degenerating unmyelinated axons in the dura mater after an acute exposure to capsaicin (10,m), providing support for the existence and possible functional role of capsaicin-sensitive dural afferent nerves. The results indicate that capsaicin-induced vasodilatation in the rat dura mater is mediated by the release of CGRP from the sensory nerves, whereas the vasoconstrictor response may be attributed to a direct action of capsaicin on the vascular smooth muscle. The present study demonstrates for the first time that capsaicin-sensitive nociceptive afferent nerves contribute significantly to the dural vasodilatory responses and suggests an important role in meningeal nociception.