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

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 17?-estradiol (E2) replacement restored it to basal levels in PMCA2^+/+ mice, but not in PMCA2^+/- littermates. Intrathecal administration of an estrogen receptor alpha (ER?) agonist induced ER? 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 ER? signaling. These findings establish a novel, female-specific link between PMCA2, ER? and mechanical pain. It is postulated that PMCA2 is essential for adequate ER? signaling in the female DH and that impaired ER? signaling in the female PMCA2^+/- mice hinders the analgesic effects of E2 leading to increased sensitivity to mechanical stimuli.

SUBMITTER: Khariv V

PROVIDER: S-EPMC6250714 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Khariv Veronika V Acioglu Cigdem C Ni Li L Ratnayake Ayomi A Li Lun L Tao Yuan-Xiang YX Heary Robert F RF Elkabes Stella S

Scientific reports 20181122 1

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+/+ v ...[more]

PMID: 30467368

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Project description:BACKGROUND:Neuropathic pain is often observed in individuals with multiple sclerosis (MS) and spinal cord injury (SCI) and is not adequately alleviated by current pharmacotherapies. A better understanding of underlying mechanisms could facilitate the discovery of novel targets for therapeutic interventions. We previously reported that decreased plasma membrane calcium ATPase 2 (PMCA2) expression in the dorsal horn (DH) of healthy PMCA2+/- mice is paralleled by increased sensitivity to evoked nociceptive pain. These studies suggested that PMCA2, a calcium extrusion pump expressed in spinal cord neurons, plays a role in pain mechanisms. However, the contribution of PMCA2 to neuropathic pain processing remains undefined. The present studies investigated the role of PMCA2 in neuropathic pain processing in the DH of wild-type mice affected by experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and following SCI. METHODS:EAE was induced in female and male C57Bl/6N mice via inoculation with myelin oligodendrocyte glycoprotein fragment 35-55 (MOG35-55) emulsified in Complete Freund's Adjuvant (CFA). CFA-inoculated mice were used as controls. A severe SC contusion injury was induced at thoracic (T8) level in female C57Bl/6N mice. Pain was evaluated by the Hargreaves and von Frey filament tests. PMCA2 levels in the lumbar DH were analyzed by Western blotting. The effectors that decrease PMCA2 expression were identified in SC neuronal cultures. RESULTS:Increased pain in EAE and SCI was paralleled by a significant decrease in PMCA2 levels in the DH. In contrast, PMCA2 levels remained unaltered in the DH of mice with EAE that manifested motor deficits but not increased pain. Interleukin-1? (IL-1?), tumor necrosis factor ? (TNF?), and IL-6 expression were robustly increased in the DH of mice with EAE manifesting pain, whereas these cytokines showed a modest increase or no change in mice with EAE in the absence of pain. Only IL-1? decreased PMCA2 levels in pure SC neuronal cultures through direct actions. CONCLUSIONS:PMCA2 is a contributor to neuropathic pain mechanisms in the DH. A decrease in PMCA2 in DH neurons is paralleled by increased pain sensitivity, most likely through perturbations in calcium signaling. Interleukin-1? is one of the effectors that downregulates PMCA2 by acting directly on neurons.

Dataset Information

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

Publications

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

Similar Datasets

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