title: TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation.
abstract: 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.
authors.affiliation: The Department of Biochemistry and Molecular Biology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA The Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Phillip Edward
authors.initials: PE
authors.lastname: Kunkler
authors.forename: Carrie Jo
authors.initials: CJ
authors.lastname: Ballard
authors.forename: Gerry Stephen
authors.initials: GS
authors.lastname: Oxford
authors.forename: Joyce Harts
authors.initials: JH
authors.lastname: Hurley
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000171:Acrolein / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D017487:Ankyrins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000494:pharmacology*; D005737:Garlic / Q000737:chemistry; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008576:Meningeal Arteries / Q000187:drug effects* / Q000502:physiology; D009149:Mustard Plant; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010938:Plant Oils / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D018689:Sensory System Agents / Q000494:pharmacology; D013373:Substance P / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D012668:Trigeminal Ganglion / Q000166:cytology; D014664:Vasodilation / Q000187:drug effects
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D017487:Ankyrins; D015220:Calcium Channels; D010446:Peptide Fragments; D010938:Plant Oils; D011687:Purines; D018689:Sensory System Agents; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; C058636:calcitonin gene-related peptide (8-37); D005557:Formaldehyde; D013373:Substance P; D000171:Acrolein; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin; C027793:mustard oil