Progesterone Rapidly Attenuates ATP-Evoked Transient Currents in Cultured Rat Dorsal Root Ganglion Neurons

Abstract

Background: Progesterone has been shown to play a role in pain perception. However, the effects of progesterone on P2X3 receptors, the nociception-related receptors in primary sensory neurons, remain unclear. Methods: We investigated the effects of progesterone on P2X3-receptor-mediated responses of rat dorsal root ganglion neurons by using whole-cell patch clamp techniques. Results: Progesterone (10 pmol/l to 1 µmol/l) inhibited ATP (100 µmol/l)-induced transient currents and the transient component of biphasic currents in a dose-dependent manner, but had no effect on the sustained currents. The effect of progesterone could be blocked by its receptor inhibitor, RU38486. Actidione, an inhibitor of protein synthesis, did not change the rapid effect. Investigations of the signaling pathways of progesterone showed that a nonselective antagonist of protein kinase, H-9, totally blocked the depressive effect of progesterone on ATP currents in a dose-dependent manner. Blocking protein kinase A with H-89 or KT5720 also affected progesterone-induced depression. The protein kinase A activator, forskolin, mimicked the effect of progesterone on ATP currents. Conclusion: These results suggest that progesterone may modulate pain signal transmission on dorsal root ganglia via regulating P2X3 receptor function. The cAMP-PKA signaling pathway is involved in the downregulating effect of progesterone on P2X3 receptors.

Ectopic uterine tissue as a chronic pain generator

“…While the study of the mechanisms of the antinociceptive effect of progesterone on this model is beyond of the scope of this paper, one could speculate about the involvement of genomic and non-genomic effects. Among the non-genomic mechanisms, it is interesting to note that progesterone directly inhibits ATP-evoked P2X3 receptor-dependent inward currents (Fan et al, 2011), which are well-established players in muscle pain (Shinoda et al, 2008; Dessem et al, 2010). Long-lasting effects of progesterone may be related to additional genomic mechanisms, such as those involved in progesterone-induced inhibition of cytokine-mediated inflammation (Davies et al, 2004), which are known to contribute to endometriosis pain (Giudice, 2010; Umezawa et al, 2008; McKinnon et al, 2012).…”

Suppression of P2X3 receptor‐mediated currents by the activation of α2A‐adrenergic receptors in rat dorsal root ganglion neurons

“…Ma group reported that 17β‐estradiol and progesterone rapidly attenuate ATP currents in DRG neurons via a cAMP‐PKA signaling pathway. 38 , 39 On contrary, PGE2 enhances P2X3 receptor‐mediated currents in DRG neurons via its EP3 receptor and a cAMP/PKA‐dependent signaling pathway. 40 It has been also reported that PKC and PKA potentiate α,β‐meATP‐induced currents in rat DRG neurons in a synergistic manner.…”

“…Previous studies have showed that P2X3 receptor‐mediated ATP currents are regulated by intracellular cAMP/PKA signaling. Ma group reported that 17β‐estradiol and progesterone rapidly attenuate ATP currents in DRG neurons via a cAMP‐PKA signaling pathway 38,39 . On contrary, PGE2 enhances P2X3 receptor‐mediated currents in DRG neurons via its EP3 receptor and a cAMP/PKA‐dependent signaling pathway 40 .…”