Characterization of prostanoid receptor-evoked responses in rat sensory neurones

1 Prostanoid receptor-mediated sensitization, or excitation, of sensory nerve fibres contributes to the generation of hyperalgesia. To characterize the prostanoid receptors present on sensory neurones, biochemical assays were performed on primary cultures of adult rat dorsal root ganglia (DRG) and the F-11 (embryonic rat DRG x neuroblastoma hybrid) cell line. 2 In DRG cultures, the IP receptor agonists, cicaprost and carbaprostacyclin (cPGI(2)) stimulated cyclic AMP accumulation. Prostaglandin E-2 (PGE(2)) also increased cyclic AMP levels, but to a lesser extent, while carbocyclic thromboxane A(2) (cTxA(2)), PGD(2) and PGF(2 alpha) had negligible effects. The rank order of agonist potency was cicaprost > PGE(2) = BMY45778 = cPGI(2) = PGI(2). In the F-11 cells, the rank order of agonist potency for the stimulation of cyclic AMP accumulation was: cicaprost > iloprost = cPGI(2) = PGI(2) = BMY45778 > PGE(2) = cTXA(2). In DRG cultures, cicaprost induced significantly more accumulation of inositol phosphates than PGE(2). 3 To examine the effects of prostanoids on C-fibre activity, extracellular recordings of d.c. potentials from the rat isolated vagus nerve were made with the 'grease-gap' technique. PGI(2) (0.1 nM-10 mu M) produced the largest depolarizations of the nerve. The rank order of agonist potency was: PGI(2) = cPGI(2) = PGE(1) > cTXA(2) > PGE(2) = PGD(2) = TXB2 > PGF(2 alpha). 4 Prior depolarization of nerves with either forskolin (10 mu M) or phorbol dibutyrate (1 mu M) alone significantly reduced the response to PGI(2) (10 mu M), while simultaneous application of both forskolin and phorbol dibutyrate attenuated PGI(2) responses almost completely. 5 Putative EP1 and/or TP receptor-selective antagonists had no effect on the responses to PGI(2), cPGI(2) or PGE(2) in the three preparations studied. 6 Collectively, these data are consistent with a positive coupling of IP receptors to both adenylyl cyclase and phospholipase C in sensory neurones. These findings suggest that IP receptors play a major role in the sensitization of rat sensory neurones.