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"Sex- and modality-specific nociceptive processing in the spinal cord: role of Plasma Membrane Calcium ATPase 2 (PMCA2)"

by
Veronika Khariv
Cell Biology, Neuroscience and Physiology (CBNP)
M.Sc., 2012, University of Medicine and Dentistry of New Jersey, NJ
B.Sc., 2010, New Jersey Institute of Technology, NJ


Thesis Advisors: Stella Elkabes, Ph.D. & Robert F. Heary, M.D.
Department of Neurological Surgery

Friday, May 5, 2017
1:00 P.M., Cancer Center, G-1196


Abstract

Plasma membrane calcium ATPase 2 (PMCA2) is an ion pump that extrudes Ca2+ from excitable cells. In the central nervous system (CNS), it is found primarily in neurons and plays a critical role in the function and viability of several neuronal sub-populations. Although PMCA2 is expressed in CNS regions that mediate pain processing, including the dorsal horn (DH) of the spinal cord (SC), its potential contribution to pain remains undefined. The current investigations were undertaken to unravel the role of PMCA2 in pain and in mechanisms governing pain processing in the DH by utilizing wild type (PMCA2+/+) and heterozygous (PMCA2+/-) mice. As pain responsiveness can show sex-bias, both male and female mice were evaluated. The overall hypothesis was that PMCA2 plays a role in the modulation and processing of pain in a modality-dependent and sex-specific manner. Moreover, it was postulated that gonadal hormones influence the pain responses mediated by PMCA2.
Female PMCA2+/- mice were more sensitive to a mechanical stimulus as assessed by the von Frey filament test. In contrast, the female PMCA2+/- mice show reduced heat sensitivity in the hot plate paw withdrawal test and no differences in the Hargreaves’, tail immersion, and cold plate paw withdrawal tests. Importantly, the disparity in pain responses occurred only in females but not males. The female-specific pain responses were paralleled by female-specific alterations in the expression of neurotransmitter receptors and transporters implicated in DH pain processing.
The potential involvement of sex hormones in genotype- and sex-dependent pain responseiveness was investigated by gonadectomy and hormone treatment. These studies indicated that 1) ovarian hormones have opposing modulatory effects on mechanical pain responses in female PMCA2+/+ and PMCA2+/- mice, 2) depletion of circulating ovarian hormones abolishes genotype-specific differential mechanical pain sensitivity in the female PMCA2+/+ vs PMCA2+/- mice, 3) 17â-estradiol (E2) replacement restores pain sensitivity in PMCA2+/+ but not PMCA2+/- mice, 4) estrogen receptor alpha (ERá) signaling is aberrant in female PMCA2+/- mice, 5) feminization of male PMCA2+/+ and PMCA2+/- mice by orchidectomy followed by E2 treatment does not recapitulate the female pattern of mechanical pain responses.
These findings, taken together, suggest a female-specific and modality-dependent role for PMCA2 in pain. The manifestation of differential mechanical pain sensitivity in female PMCA2+/+ versus PMCA2+/- mice is dependent on both PMCA2 expression levels and the presence female sex hormones. A potential link between ERá and PMCA2 warrants further investigations. These studies pave the way to future investigations on the role of PMCA2 in pathological and chronic pain utilizing animal models of injury and disease.


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