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 concentration-dependent 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.