title: Possible antimigraine mechanisms of action of the 5HT1F receptor agonist LY334370.
abstract: 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.
authors.affiliation: Department of Pharmacology, Merck, Sharp and Dohme Neuroscience Research Laboratories, Harlow, Essex, UK. sara_shepheard@merck.com
authors.forename: S
authors.initials: S
authors.lastname: Shepheard
authors.forename: L
authors.initials: L
authors.lastname: Edvinsson
authors.forename: M
authors.initials: M
authors.lastname: Cumberbatch
authors.forename: D
authors.initials: D
authors.lastname: Williamson
authors.forename: G
authors.initials: G
authors.lastname: Mason
authors.forename: J
authors.initials: J
authors.lastname: Webb
authors.forename: S
authors.initials: S
authors.lastname: Boyce
authors.forename: R
authors.initials: R
authors.lastname: Hill
authors.forename: R
authors.initials: R
authors.lastname: Hargreaves
mesh_terms: 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
chemical_list: 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