title: Neurogenic dural protein extravasation induced by meta-chlorophenylpiperazine (mCPP) involves nitric oxide and 5-HT2B receptor activation.
abstract: The compound m-chlorophenylpiperazine (mCPP), which is known to trigger migraine-like head pain in some subjects, was evaluated for its ability to induce dural plasma protein extravasation (PPE) in guinea pigs. Intravenous mCPP dose-dependently increased PPE. This effect was inhibited by non-selective 5-HT2 receptor antagonists (methysergide, LY53857, LY215840), by a peripherally restricted 5-HT2 receptor antagonist (xylamidine) and by a 5-HT2B selective receptor antagonist (LY202146). These data suggests that peripheral 5-HT2B receptors mediate mCPP-induced PPE. The nitric oxide synthase inhibitor L-NAME and 5-HT1 agonist sumatriptan also blocked mCPP-induced PPE, suggesting a role for nitric oxide (NO) and the trigeminal system, respectively. NO release has been linked to activation of the 5-HT2B receptor on the vascular endothelium. However, LY202146 did not block PPE induced by electrical stimulation of the trigeminal ganglion. These data are consistent with activation of peripheral 5-HT2B receptors initiating PPE and the theory that selective 5-HT2B antagonists might be effective prophylactic therapies for migraine.
authors.affiliation: Neuroscience Research and Discovery Chemistry Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA. JOHNSON_KIRK_W@Lilly.Com
authors.forename: K W
authors.initials: KW
authors.lastname: Johnson
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: D K
authors.initials: DK
authors.lastname: Dieckman
authors.forename: D B
authors.initials: DB
authors.lastname: Wainscott
authors.forename: V L
authors.initials: VL
authors.lastname: Lucaites
authors.forename: J E
authors.initials: JE
authors.lastname: Audia
authors.forename: W M
authors.initials: WM
authors.lastname: Owton
authors.forename: L A
authors.initials: LA
authors.lastname: Phebus
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004388:Dura Mater / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004558:Electric Stimulation; D006168:Guinea Pigs; D007275:Injections, Intravenous; D008297:Male; D008881:Migraine Disorders / Q000139:chemically induced / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage*; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin / Q000378:metabolism*; D012016:Reference Values
chemical_list: D001798:Blood Proteins; D010879:Piperazines; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D009569:Nitric Oxide; C015068:1-(3-chlorophenyl)piperazine