Possible antimigraine mechanisms of action of the 5HT1F receptor agonist LY334370.
This study investigated whether the selective 5HT1F receptor agonist LY334370 has other possible antimigraine mechanisms in addition to the proposed inhibition of dural plasma extravasation. LY334370 (up to 10(-5) M) had no vasoconstrictor effects on human cerebral arteries in vitro. It had no effect (up to 10 mg kg-1, i.v.) on neurogenic vasodilation of dural blood vessels produced by electrical stimulation of the dura mater in anesthetized rats. Nor had it any effect (at 3 mg kg-1, i.v.) on the hyperalgesia produced by injection of carrageenan into the paw of conscious rats or on nociceptive reflex responses in the spinalized, decerebrate rabbit (up to 3 mg kg-1, i.v.), indicating that it has no general analgesic properties. However, it significantly inhibited activation of second-order neurons in the trigeminal nucleus caudalis produced by electrical stimulation of the dura mater in anesthetised rats at 3 mg kg-1, i.v. These results provide evidence to suggest that LY334370 has a central mechanism of action in blocking the transmission of nociceptive impulses within the trigeminal nucleus caudalis and that this may represent a mechanism through which it has its antimigraine effect.
Shepheard
S
S
Department of Pharmacology, Merck, Sharp and Dohme Neuroscience Research Laboratories, Harlow, Essex, UK. sara_shepheard@merck.com
Edvinsson
L
L
Cumberbatch
M
M
Williamson
D
D
Mason
G
G
Webb
J
J
Boyce
S
S
Hill
R
R
Hargreaves
R
R
D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002536:Cerebral Arteries / Q000187:drug effects; D003655:Decerebrate State / Q000503:physiopathology; D004558:Electric Stimulation; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018170:Sumatriptan / Q000494:pharmacology; D014276:Trigeminal Nerve / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D000096642:Receptor, Serotonin, 5-HT1F
D001549:Benzamides; D007211:Indoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D018170:Sumatriptan; D014662:Vasoconstrictor Agents; D000096642:Receptor, Serotonin, 5-HT1F; C108218:4-fluoro-N-(3-(1-methyl-4-piperidinyl)-1H-indol-5-yl)benzamide