TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation.

The TRPA1 receptor is a member of the transient receptor potential (TRP) family of ion channels expressed in nociceptive neurons. TRPA1 receptors are targeted by pungent compounds from mustard and garlic and environmental irritants such as formaldehyde and acrolein. Ingestion or inhalation of these chemical agents causes irritation and burning in the nasal and oral mucosa and respiratory lining. Headaches have been widely reported to be induced by inhalation of environmental irritants, but it is unclear how these agents produce headache. Stimulation of trigeminal neurons releases CGRP and substance P and induces neurogenic inflammation associated with the pain of migraine. Here we test the hypothesis that activation of TRPA1 receptors is the mechanistic link between environmental irritants and peptide-mediated neurogenic inflammation. Known TRPA1 agonists and environmental irritants stimulate CGRP release from dissociated rat trigeminal ganglia neurons and this release is blocked by a selective TRPA1 antagonist, HC-030031. Further, TRPA1 agonists and environmental irritants increase meningeal blood flow following intranasal administration. Prior dural application of the CGRP antagonist, CGRP(8-37), or intranasal or dural administration of HC-030031, blocks the increases in blood flow elicited by environmental irritants. Together these results demonstrate that TRPA1 receptor activation by environmental irritants stimulates CGRP release and increases cerebral blood flow. We suggest that these events contribute to headache associated with environmental irritants.

The role of histamine in dural vessel dilation.

The pain of migraine is often throbbing suggesting an important role for the cranial blood vessels and their innervation by the trigeminal nerve. It is proposed that clinically effective anti-migraine compounds, such as 5-HT(1B/1D) agonists, have actions that include inhibiting calcitonin gene-related peptide (CGRP) release from trigeminal nerves. Human studies suggest that histamine can induce migraine possibly by activating nitric oxide (NO) synthase to promote endogenous NO production. The present studies investigated the effect of histamine and its antagonists on the cranial blood vessels using intravital microscopy to assess directly the diameter of dural arteries in sodium pentobarbitone anaesthetised rats. Electrical stimulation of a closed cranial window produces, by local depolarisation of nerves, dural vessel dilation that is monitored continuously on-line using video-microscopy and a video dimension analyser. Histamine infusion caused immediate and reproducible dilation of meningeal blood vessels (103.5+/-6%; n=40) that could be blocked by H(1)- (mepyramine) and H(2) (famotidine)-receptor antagonists (P<0.05), as well as a nitric oxide synthase inhibitor (N(G)-nitro-L-arginine methylester; P<0.05). Neurogenic dural vasodilation was not inhibited by H(2)-receptor antagonists, but was significantly inhibited by a H(1)-receptor antagonist at the high dose of 10 mg/kg. The present studies demonstrate that histamine is likely to activate NO synthase to promote NO production. There is also evidence that H(1)-receptors may be present on trigeminal neurones as the H(1)-receptor antagonist inhibited neurogenic vasodilation, albeit at a large dose.

Properties of feline thalamic neurons activated by stimulation of the middle meningeal artery and sagittal sinus.

Previous studies have identified a population of neurons in the cat trigeminal brainstem complex that respond to stimulation of the middle meningeal artery (MMA) and/or superior sagittal sinus (SS). In the present study, neuronal responses to stimulation of the MMA and SS were sought in the thalamus of the cat. Sixty-one neurons excited by electrical stimulation of the MMA and/or SS were located in the ventroposteromedial (VPM) nucleus, and surrounding regions in lateral thalamus. Of these 61 neurons, 23% were excited only by MMA stimulation, 39% only by SS stimulation and 38% by both MMA and SS stimulation. The latencies to activation from MMA and/or SS stimulation suggest the involvement of small, myelinated primary afferent fibers. Most neurons (48/61) responded to electrical stimulation of the MMA or SS with a burst of 2-5 spikes. Mechanical stimulation of the MMA and SS was also an effective stimulus and in some cases evoked a burst response. Of the neurons tested for the existence of orofacial inputs, all were found to have an excitatory receptive field (RF) on the face and usually (22/26 neurons) involved the ophthalmic distribution. Twelve of these neurons were excited by a tap stimulus applied to the face, 6 by pinching (nociceptive specific), 6 by low-threshold mechanical stimuli (LTM), one by both pinch and low-threshold stimuli and one by mechanical stimulation of the cornea. The firing properties, RF and modalities of these thalamic neurons suggest that they may play a role in the appreciation of pain of cerebrovascular origin.