This review focuses on the critical pathophysiological significance of capsaicin-sensitive trigeminal primary afferent neurons in the mechanisms of neurovascular responses in animal models of cranial pain and their possible relevance for primary headaches. In the rat dura mater, neurogenic sensory vasodilator responses elicited by activation of the transient receptor potential vanilloid type 1 (TRPV1) receptor are mediated by the release of calcitonin gene-related peptide (CGRP) from sensory nerves, which suggests that similar mechanisms may operate in man during migraine attacks, when an increased concentration of CGRP is measured in the jugular venous blood. Capsaicin-sensitive trigeminal afferent nerves also contribute to the vasodilatory responses induced by the activation of protease-activated receptor 2 (PAR-2), which involves the release of CGRP from capsaicin-sensitive afferent nerves. Importantly, the activation of PAR-2 has been shown to sensitize the TRPV1 receptor. Demonstration of the colocalization of PAR-2 and TRPV1 receptors in the meningeal axons lends further support to this mechanism. Neurogenic vasodilatory responses mediated by capsaicinsensitive afferent nerves may serve a protective function via the elimination of inflammatory mediators from the tissue, a mechanism which may play a role in the resolution of headaches. Pathological conditions such as diabetes mellitus may compromise this protective mechanism through decreases in the expression of TRPV1 and the release of CGRP. These observations indicate an important role of capsaicin-sensitive meningeal afferent nerves in the pathophysiology of headaches and suggest that pharmacological manipulation of the TRPV1 receptor may offer a promising approach to the management of headaches.
Keywords: Calcitonin gene-related peptide, capsaicin, headache, meningeal blood flow, nociception, transient receptor potential vanilloid type 1 receptor, Capsaicin sensitive, Meningal vasodilation, extravasation, Trigeminal ganglia
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