Neurogenic dural protein extravasation induced by meta-chlorophenylpiperazine (mCPP) involves nitric oxide and 5-HT2B receptor activation.
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.
Johnson
K W
KW
Neuroscience Research and Discovery Chemistry Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA. JOHNSON_KIRK_W@Lilly.Com
Nelson
D L
DL
Dieckman
D K
DK
Wainscott
D B
DB
Lucaites
V L
VL
Audia
J E
JE
Owton
W M
WM
Phebus
L A
LA
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
D001798:Blood Proteins; D010879:Piperazines; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D009569:Nitric Oxide; C015068:1-(3-chlorophenyl)piperazine