Interaction of Calcitonin Gene-Related Peptide, Nitric Oxide and Histamine Release in Neurogenic Blood Flow and Afferent Activation in The Rat Cranial Dura Mater

Abstract

Calcitonin gene-related peptide (CGRP), nitric oxide (NO) and histamine are implicated in primary headaches but their role in vascular and nociceptive events in the dura mater is not well described. In an in vitro preparation of the hemisected rat skull, CGRP and histamine release from the cranial dura was measured using enzyme-linked immunoassays. While the NO donator NONOate (10-4 M) was without effect, CGRP (10-5 M) induced considerable histamine release from the rat cranial dura, which was blocked by the CGRP receptor antagonist CGRP8-37 (10-5 M). Conversely, histamine (10-4 M) did not stimulate CGRP release. In vitro recordings from single rat meningeal afferents showed that only one of 12 mechanically identified units but several mechanically insensitive units responded to histamine (up to 10-5 M). Increases in meningeal blood flow after histamine application (10-4 M) to the rat cranial dura remained unchanged during CGRP receptor blockade with CGRP8-37, inhibition of NO synthesis with L-NAME (20 mg/kg i.v.) and H3 receptor blockade with thioperamide (10-4 M). We conclude that histamine produces direct vasodilatation and activates a subset of largely non-mechanically sensitive, non-CGRP containing afferents in the rat meninges. Histamine is released from meningeal mast cells which are stimulated by CGRP. Similar mechanisms may be involved in the pathogenesis of headaches.