Estrogen modulation of peripheral pain signal transduction: involvement of P2X3 receptors

Abstract

There is evidence that gonadal hormones may affect the perception of painful stimulation, although the underlying mechanisms remain unclear. This investigation was undertaken to determine whether the adenosine 5′-triphosphate (ATP) receptor subunit, P2X 3 , is involved in the modulatory action of estrogen in peripheral pain signal transduction in dorsal root ganglion (DRG). The mechanical pain behavior test, real-time quantitative reverse transcription-polymerase chain reaction analysis, and Western blot methods were used to determine the mean relative concentrations and functions of P2X 3 receptors in DRG in sham, ovariectomized (OVX), and estradiol replacement (OVX+E 2 ) female rats and in sham and orchiectomized male rats. The mechanical hyperalgesia appeared after ovariectomy, which was subsequently reversed after estradiol replacement, whereas it was not observed after orchiectomy in male rats. Plantar injection of 2′(3′)-O-(2,4,6-trinitrophenyl) ATP (TNP-ATP), a P2X 3 and P2X 2/3 receptor antagonist, resulted in an increase of the pain threshold force in OVX rats while had no effect on sham rats. Furthermore, A-317491, a selective P2X 3 /P2X 2/3 receptor antagonist, significantly reversed the hyperalgesia of OVX rats. Injection of ATP into the plantars also caused a significant increase of the paw withdrawal duration in OVX rats compared with that seen in the sham group, which became substantially attenuated by TNP-ATP. P2X 3 receptors expressed in DRG were significantly increased in both mRNA and protein levels after ovariectomy and then reversed after estrogen replacement, while a similar increase was not observed after orchiectomy in male rats. Furthermore, P2X 3 mRNA was significantly decreased 24 h after the application of 17β-estradiol in a concentrationdependent manner in cultured DRG neurons. ICI 182,780, an estrogen receptor antagonist, blocked the reduction in the protein level. These results suggest that the female gonadal hormone, 17β-estradiol, might participate in the control of peripheral pain signal transduction by modulating P2X 3 receptor-mediated events in primary sensory neurons, probably through genomic mechanisms.

Inhibitory effect of estrogen receptor beta on P2X3 receptors during inflammation in rats

“…Our results show that the expression of P2X3R in neurons was significantly increased in CFA-treated rat [44] and in TNBS-induced colitis in rats [23,25], indicating a vital role of P2X3R in inflammatory reactions. It has been reported that estrogen replacement decreased P2X3 upregulation in DRG after ovariectomy [30]. In the present study, estrogen replacement significantly decreased peripheral pain sensitivity and P2X3R expression in DRG from CFA-treated OVX rats.…”

“…Our previous study has shown that both P2X3 expression and functions could be affected by estrogen [28][29][30][31], while the effect of ERβ activation on P2X3R in colitis is unknown. In the present study, injection of DPN (10 μg) for 4 days decreased P2X3R protein expression in colitis.…”

“…As previously reported [30], experimental colitis was induced by administration of an intrarectal enema (8 cm from the anus) of 30 % TNBS in ethanol at a dose of 40 mg/kg body weight. The enemas were given through a 6-Fr medical-grade polyurethane enteral feeding tube while the rats were under light ether anesthesia.…”

“…The intracolonic balloon was manually inflated using an air-filled syringe which allowed slow, continuous inflation. The visceromotor response was measured using 20, 40, 60, 80 mmHg CRD (four distensions at each pressure, 20 s each, 3 min interstimulus interval) [19,30]. The intracolonic and balloon pressures and the EMG trace were continuously recorded after instrument calibration.…”

Interaction of purinergic receptors with GPCRs, ion channels, tyrosine kinase and steroid hormone receptors orchestrates cell function

“…The use of the estrogen receptor antagonist, ICI 182,780, blocked the reduction in the receptor subunit protein level. Thus, 17β-estradiol participates in the control of peripheral pain signal transduction by modulating the expression of the P2X 3 subunit and, consequently, P2X 3 receptormediated events [114]. On the other hand, P2X 3 receptor mRNA was significantly decreased in DRG neurons of ovariectomized rats.…”