Characterization of the prostanoid receptor types involved in mediating calcitonin gene-related peptide release from cultured rat trigeminal neurones.
1. Prostaglandins and the vasodilator neuropeptide, calcitonin-gene related peptide (CGRP), have both been implicated in the pathogenesis of migraine headache. We have used primary cultures of adult rat trigeminal neurones to examine the effects of prostanoids on CGRP release in vitro. 2. CGRP release was stimulated by prostaglandin E2 (PGE2) and the IP receptor agonist, carbaprostacyclin (cPGI2). These responses were extracellular calcium-dependent, and the PGE2-induced CGRP release was unaltered by inhibition of nitric oxide synthase (NOS), ATP receptor blockade, or the addition of adenosine deaminase. 3. Increases in CGRP levels were also observed in response to prostaglandin D2 (PGD2), and the EP2 receptor selective agonist, butaprost. No increases in CGRP release were observed in response to prostaglandin F2alpha (PGF2alpha) or the TP receptor selective agonist, U46619, or the EP3 receptor selective agonist, GR63799X. 4. The selective DP receptor antagonist, BWA868C, antagonized the PGD2-, but not PGE2- or cPGI2-induced release. Furthermore, the EP1 selective antagonist, ZM325802, failed to antagonize the PGE2-induced CGRP release from these cells. 5. These data indicate that activation of DP, EP and IP receptors can each cause CGRP release from trigeminal neurones, and suggest that the predominant EP receptor subtype involved may be the EP2 receptor. Together with evidence that the cyclo-oxygenase inhibitor, aspirin, particularly when administered intravenously is effective in treating acute migraine, these findings further suggest a role for prostaglandins in migraine pathophysiology.
Jenkins
D W
DW
Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Cambridge, CB2 1QJ. dwj94941@gsk.com
Feniuk
W
W
Humphrey
P P
PP
D000243:Adenosine Deaminase / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D015237:Dinoprost / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D014276:Trigeminal Nerve / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D011459:Prostaglandins E, Synthetic; C491909:Ptgir protein, rat; D018015:Receptors, Calcitonin Gene-Related Peptide; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; C067522:GR 63799X; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D015237:Dinoprost; D019001:Nitric Oxide Synthase; D000243:Adenosine Deaminase; D015740:Calcitonin Gene-Related Peptide; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester