Earlier studies on genetically modified mice indicated that
plasma membrane calcium ATPase 2 (PMCA2), a
calcium extrusion pump, plays a novel and sex-dependent role in mechanical
pain responses: female, but not male, PMCA2+/- mice manifest increased mechanical
pain compared to female PMCA2+/+ mice. The goal of the present studies was to determine the contribution of ovarian
steroids to the genotype- and sex-dependent manifestation of mechanical
pain in PMCA2+/+ versus PMCA2+/- mice.
Ovariectomy increased mechanical
pain sensitivity and 17β-estradiol (E2) replacement restored it to basal levels in PMCA2+/+ mice, but not in PMCA2+/- littermates. Intrathecal administration of an
estrogen receptor alpha (ERα) agonist induced ERα signaling in the dorsal horn (DH) of female PMCA2+/+ mice, but was ineffective in PMCA2+/- mice. In male PMCA2+/+ and PMCA2+/- mice, E2 treatment following
orchidectomy did not recapitulate the genotype-dependent differential
pain responses observed in females and the agonist did not elicit ERα signaling. These findings establish a novel, female-specific link between PMCA2, ERα and mechanical
pain. It is postulated that PMCA2 is essential for adequate ERα signaling in the female DH and that impaired ERα signaling in the female PMCA2+/- mice hinders the
analgesic effects of E2 leading to increased sensitivity to mechanical stimuli.