Prostaglandin E2 sensitizes primary sensory neurons to histamine.
1. Histamine is able to elicit a dose-dependent rise in intracellular Ca2+ in a proportion of rat dorsal root ganglion (DRG) neurons. Pre-treatment with prostaglandin (PGE2) prior to a histamine challenge increases the proportion of neurons responding to low concentrations of histamine (10-100 microM). 2. The dose-response curve for histamine is shifted to the left by approximately two orders of magnitude following 45 s pre-treatment with 1 microM PGE2. 3. The phospholipase C (PLC) inhibitor 1-[6-[[17-beta-3-methoxyestra-1,3,5(10)-trien-17-yl-]amino]hexyl]-1H-pyrrole-2,5-dione (U73122) completely blocked the response to histamine (100 microM) in non-sensitized cells but, after PGE2 pre-treatment, this inhibitor reduced the proportion of cells responding to histamine by approximately a half. Removal of extracellular Ca2+ blocked the response in the remaining cells so that, in this subgroup of histamine sensitive neurons, the PGE2 sensitization is the result of activation of a Ca influx pathway. 4. The sensitization is dependent on an increase in cAMP as it is mimicked by pre-treatment with 8-bromo cyclic AMP (8-Br-cAMP) and by forskolin stimulation of adenylyl cyclase activity. It is inhibited by THFA (tetrahydrofuryl adenine) an inhibitor of adenylyl cyclase. The sensitization is also blocked by pre-treatment with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), an inhibitor of protein kinase A. We conclude that the PGE2 sensitization of DRG neurons to histamine is dependent on activation of the cAMP-protein kinase A cascade.
Nicolson
T A
TA
Department of Physiology, University College London, Gower Street, London WC1E 6BT, UK.
Foster
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AF
Bevan
S
S
Richards
C D
CD
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005727:Ganglia, Spinal / Q000166:cytology; D006632:Histamine / Q000494:pharmacology*; D017442:Histamine Agonists / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008954:Models, Biological; D009475:Neurons, Afferent / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
D017442:Histamine Agonists; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D005576:Colforsin; D006632:Histamine; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D015232:Dinoprostone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium