title: Endovanilloids are potential activators of the trigeminovascular nocisensor complex.
abstract: BACKGROUND
  In the dura mater encephali a significant population of trigeminal afferents coexpress the nociceptive ion channel transient receptor potential vanilloid type 1 (TRPV1) receptor and calcitonin gene-related peptide (CGRP). Release of CGRP serves the central transmission of sensory information, initiates local tissue reactions and may also sensitize the nociceptive pathway. To reveal the possible activation of meningeal TRPV1 receptors by endogenously synthetized agonists, the effects of arachidonylethanolamide (anandamide) and N-arachidonoyl-dopamine (NADA) were studied on dural vascular reactions and meningeal CGRP release.
  
  
  METHODS
  Changes in meningeal blood flow were measured with laser Doppler flowmetry in a rat open cranial window preparation following local dural applications of anandamide and NADA. The release of CGRP evoked by endovanilloids was measured with ELISA in an in vitro dura mater preparation.
  
  
  RESULTS
  Topical application of NADA induced a significant dose-dependent increase in meningeal blood flow that was markedly inhibited by pretreatments with the TRPV1 antagonist capsazepine, the CGRP antagonist CGRP8-37, or by prior systemic capsaicin desensitization. Administration of anandamide resulted in minor increases in meningeal blood flow that was turned into vasoconstriction at the higher concentration. In the in vitro dura mater preparation NADA evoked a significant increase in CGRP release. Cannabinoid CB1 receptors of CGRP releasing nerve fibers seem to counteract the TRPV1 agonistic effect of anandamide in a dose-dependent fashion, a result which is confirmed by the facilitating effect of CB1 receptor inhibition on CGRP release and its reversing effect on the blood flow.
  
  
  CONCLUSIONS
  The present findings demonstrate that endovanilloids are potential activators of meningeal TRPV1 receptors and, consequently the trigeminovascular nocisensor complex that may play a significant role in the pathophysiology of headaches. The results also suggest that prejunctional CB1 receptors may modulate meningeal vascular responses.
authors.affiliation: Department of Physiology, University of Szeged, Dóm tér 10, H-6720, Szeged, Hungary. dux.maria@med.u-szeged.hu.
authors.forename: Mária
authors.initials: M
authors.lastname: Dux
authors.affiliation: Department of Physiology, University of Szeged, Dóm tér 10, H-6720, Szeged, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Deák
authors.affiliation: Department of Physiology, University of Szeged, Dóm tér 10, H-6720, Szeged, Hungary.
authors.forename: Noémi
authors.initials: N
authors.lastname: Tassi
authors.affiliation: Department of Physiology, University of Szeged, Dóm tér 10, H-6720, Szeged, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Sántha
authors.affiliation: Department of Physiology, University of Szeged, Dóm tér 10, H-6720, Szeged, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Jancsó
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004388:Dura Mater / Q000098:blood supply / Q000187:drug effects; D063388:Endocannabinoids / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D017078:Laser-Doppler Flowmetry; D009619:Nociceptors / Q000187:drug effects*; D010446:Peptide Fragments / Q000378:metabolism*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D050916:TRPV Cation Channels / Q000187:drug effects*; D014276:Trigeminal Nerve / Q000187:drug effects*
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D010446:Peptide Fragments; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D018015:Receptors, Calcitonin Gene-Related Peptide; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C474941:arachidonyl dopamine; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin; C078814:anandamide; D004298:Dopamine
keywords: Dura mater encephali; Endovanilloid; Headache; Meningeal blood flow; Transient receptor potential vanilloid 1; Trigeminovascular nocisensor complex