Effects of prostaglandin D 2 on tetrodotoxin-resistant Na + currents in DRG neurons of adult rat

Abstract

Tetrodotoxin-resistant (TTX-R) Na + channels play a key role in the generation of action potentials in nociceptive dorsal root ganglion (DRG) neurons and are an important target for the proinflammatory mediator prostaglandin E 2, which augments these currents. Prostaglandin D 2 (PGD 2) is released in the tissue together with prostaglandin E 2, and it was reported to be antiinflammatory, but its effect on primary afferent neurons is unclear. In the present study we localised G s-protein-coupled DP1 and G i-protein-coupled DP2 receptors in DRG neurons, and we assessed the effect of PGD 2 on TTX-R Na + currents in patch-clamp recordings from small- to medium-sized cultured DRG neurons from adult rats. DP1 and DP2 receptor-like immunoreactivity was localised in the vast majority of DRG neurons. In all neurons, PGD 2 shifted conductance to more hyperpolarised potentials, depending on an action at Na v1.9 channels. In about one third of the neurons, PGD 2 additionally influenced Na v1.8 channels by facilitating conductance and by increasing maximal current amplitudes. Selective DP1 receptor activation increased the amplitude of TTX-R Na + currents of most neurons, but this effect was counteracted by DP2 receptor activation, which by itself had no effect. In the current-clamp mode, PGD 2 lowered the threshold for elicitation of an action potential and increased the number of action potentials per stimulus, an effect mainly depending on DP1 receptor activation. Thus, the net effect of PGD 2 on DRG neurons is pronociceptive, although the magnitude of the TTX-R Na + currents depends on the balance of DP1 and DP2 receptor activation. Prostaglandin D 2 regulates conductance and current amplitudes of tetrodotoxin-resistant sodium channels on dorsal root ganglion neurons by a balanced action at DP1 and DP2 receptor subtypes.