title: Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat.
abstract: Nitroglycerin (glycerol trinitrate, GTN) induces headache in migraineurs, an effect that has been used both diagnostically and in the study of the pathophysiology of this neurovascular pain syndrome. An important feature of this headache is a delay from the administration of GTN to headache onset that, because of GTN's very rapid metabolism, cannot be due to its pharmacokinetic profile. It has recently been suggested that activation of perivascular mast cells, which has been implicated in the pathophysiology of migraine, may contribute to this delay. We reported that hyperalgesia induced by intradermal GTN has a delay to onset of ∼ 30 min in male and ∼ 45 min in female rats. This hyperalgesia was greater in females, was prevented by pretreatment with the anti-migraine drug, sumatriptan, as well as by chronic pretreatment with the mast cell degranulator, compound 48/80. The acute administration of GTN and compound 48/80 both induced hyperalgesia that was prevented by pretreatment with octoxynol-9, which attenuates endothelial function, suggesting that GTN and mast cell-mediated hyperalgesia are endothelial cell-dependent. Furthermore, A-317491, a P2X3 antagonist, which inhibits endothelial cell-dependent hyperalgesia, also prevents GTN and mast cell-mediated hyperalgesia. We conclude that delayed-onset mechanical hyperalgesia induced by GTN is mediated by activation of mast cells, which in turn release mediators that stimulate endothelial cells to release ATP, to act on P2X3, a ligand-gated ion channel, in perivascular nociceptors. A role of the mast and endothelial cell in GTN-induced hyperalgesia suggests potential novel risk factors and targets for the treatment of migraine.
authors.affiliation: Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143-0440, United States.
authors.forename: L F
authors.initials: LF
authors.lastname: Ferrari
authors.affiliation: Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Department of Dental Science and Medicine, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143-0440, United States. Electronic address: Jon.Levine@ucsf.edu.
authors.forename: J D
authors.initials: JD
authors.lastname: Levine
authors.affiliation: Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Department of Preventative & Restorative, University of California at San Francisco, San Francisco, CA 94143-0440, United States; Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143-0440, United States.
authors.forename: P G
authors.initials: PG
authors.lastname: Green
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D005996:Nitroglycerin / Q000633:toxicity*; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D017830:Octoxynol / Q000494:pharmacology / Q000633:toxicity; D017288:Pain Threshold / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D018170:Sumatriptan / Q000494:pharmacology; D013501:Surface-Active Agents / Q000633:toxicity; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000633:toxicity*; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
chemical_list: C470346:A-317491; D010636:Phenols; D011083:Polycyclic Compounds; D058920:Purinergic P2X Receptor Antagonists; D013501:Surface-Active Agents; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D003189:p-Methoxy-N-methylphenethylamine; D018170:Sumatriptan; D017830:Octoxynol; D005996:Nitroglycerin
keywords: P2X3; endothelium; mast cells; migraine; nitroglycerin; vascular pain