Lack of interaction between prostaglandin E2 receptor subtypes in regulating adenylyl cyclase activity in cultured rat dorsal root ganglion cells

The hyperalgesic response to prostaglandin E-2 (PGE(2),) is thought to be mediated by activation of the cAMP/protein kinase A pathway in primary sensory neurones. The aim of this study was to investigate the relative contribution of different PGE, (EP) receptor subtypes to the overall activity of adenylyl cyclase in adult rat isolated dorsal root ganglion (DRG) cells, in vitro. PGE(2) and the prostanoid EP4 receptor agonist ONO-AE1-329 increased [H-3]cAMP production with EC50 values of 500 nM and 70nM, respectively, and showed similar efficacies. No combination of prostanoid EP1, EP2, EP3 or EP4 receptor selective agonists produced synergistic increases in [H-3]cAMP. The prostacyclin mimetic cicaprost increased [H-3]cAMP production with an EC(5)0 value of 42nM and produced a significantly greater maximal response compared with PGE(2). No evidence for prostanoid EP3 receptor-dependent inhibition of adenylyl cyclase activity could be obtained to account for the relatively weak effect of PGE, compared with prostacyclin receptor agonists. Interestingly, sulprostone (prostanoid EP3/EP1, receptor agonist) caused a Rho-kinase-dependent retraction of neurites, suggesting an alternative role for prostanoid EP3 receptors in DRG cells. In conclusion, PGE(2) mediated increases in adenylyl cyclase activity in primary sensory neurones is likely to be mediated by activation of prostanoid EP4 receptors, and is not under inhibitory control by prostanoid EP3 receptors. (c) 2006 Elsevier B.V. All rights reserved.