Prostaglandin E2 sensitizes primary sensory neurons to histamine

1. Histamine is able to elicit a dose-dependent rise in intracellular Ca(2+) in a proportion of rat dorsal root ganglion (DRG) neurons. Pre-treatment with prostaglandin (PGE(2)) prior to a histamine challenge increases the proportion of neurons responding to low concentrations of histamine (10-100 mu M). 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 mu M PGE(2). 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-di- one (U73122) completely blocked the response to histamine (100 mu M) in non-sensitized cells but, after PGE(2) pre-treatment, this inhibitor reduced the proportion of cells responding to histamine by approximately a half. Removal of extracellular Ca(2+) blocked the response in the remaining cells so that, in this subgroup of histamine sensitive neurons, the PGE(2) 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-isoquinoline-sulfonamide (H89), an inhibitor of protein kinase A. We conclude that the PGE(2) sensitization of DRG neurons to histamine is dependent on activation of the cAMP-protein kinase A cascade. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.