A link between plasma membrane calcium ATPase 2 (PMCA2), estrogen and estrogen receptor \u03b1 signaling in mechanical pain

Veronika Khariv,Yuan-Xiang Tao,Li Ni,Ayomi Ratnayake,Lun Li,Cigdem Acioglu,Stella Elkabes,Robert F Heary

doi:10.1038/s41598-018-35263-0

Veronika Khariv, Yuan-Xiang Tao + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-35263-0

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Abstract

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.

Highlights

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
To determine whether circulating ovarian hormones modulate mechanical pain in a genotype-dependent manner and to assess whether E2 reverses the possible effects of OVX, we performed the von Frey filament test on SHAM-operated and ovariectomized plasma membrane calcium ATPase 2 (PMCA2)+/+ and PMCA2+/− mice treated with vehicle or E2
In agreement with our earlier report showing increased mechanical sensitivity in the intact female PMCA2+/− compared to the intact PMCA2+/+ mice[4], SHAM-operated PMCA2+/− mice were more sensitive to a mechanical stimulus than SHAM-operated PMCA2+/+ mice (p = 0.0005)

Summary

Introduction

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. Only female, but not male, PMCA2+/− and PMCA2+/+ mice manifested the genotype-dependent differential mechanical pain sensitivity. 17β-estradiol binds to the estrogen receptors ERα, ERβ26–28, or the G protein-coupled estrogen receptor (GPER/ GPR30)[29,30] Both intracellular and membrane-bound ERα and ERβ receptors have been described. The current study investigated whether ovarian sex hormones, and in particular E2, assume a central role in the disparate mechanical pain responses displayed by female PMCA2+/− versus PMCA2+/+ mice. We assessed whether E2 treatment of gonadectomized male PMCA2+/+ and PMCA2+/− mice recapitulates the female pattern of genotype-dependent pain sensitivity

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