Mechanisms of G Protein-Coupled Estrogen Receptor-Mediated Spinal Nociception

Publication: Research - peer-reviewJournal article – Annual report year: 2012

  • Author: Deliu, Elena

    Department of Pharmacology, Temple University School of Medicine, United States

  • Author: Brailoiu, G. Cristina

    Department of Pharmacology, Temple University School of Medicine, United States

  • Author: Arterburn, Jeffrey B.

    Department of Chemistry and Biochemistry, New Mexico State University, United States

  • Author: Oprea, Tudor I.

    Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark

  • Author: Benamar, Khalid

    Center for Substance Abuse Research, Temple University School of Medicine, United States

  • Author: Dun, Nae J.

    Department of Pharmacology, Temple University School of Medicine, United States

  • Author: Brailoiu, Eugen

    Department of Pharmacology, Temple University School of Medicine, United States

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Human and animal studies suggest that estrogens are involved in the processing of nociceptive sensory information and analgesic responses in the central nervous system. Rapid pronociceptive estrogenic effects have been reported, some of which likely involve G protein-coupled estrogen receptor (GPER) activation. Membrane depolarization and increases in cytosolic calcium and reactive oxygen species (ROS) levels are markers of neuronal activation, underlying pain sensitization in the spinal cord. Using behavioral, electrophysiological, and fluorescent imaging studies, we evaluated GPER involvement in spinal nociceptive processing. Intrathecal challenging of mice with the GPER agonist G-1 results in pain-related behaviors. GPER antagonism with G15 reduces the G-1-induced response. Electrophysiological recordings from superficial dorsal horn neurons indicate neuronal membrane depolarization with G-1 application, which is G15 sensitive. In cultured spinal sensory neurons, G-1 increases intracellular calcium concentration and induces mitochondrial and cytosolic ROS accumulation. In the presence of G15, G-1 does not elicit the calcium and ROS responses, confirming specific GPER involvement in this process. Cytosolic calcium concentration elevates faster and with higher amplitude following G-1 intracellular microinjections compared to extracellular exposure, suggesting subcellular GPER functionality. Thus, GPER activation results in spinal nociception, and the downstream mechanisms involve cytosolic calcium increase, ROS accumulation, and neuronal membrane depolarization. PerspectiveOur results suggest that GPER modulates pain processing in spinal sensory neurons via cytosolic calcium increase and ROS accumulation. These findings extend the current knowledge on GPER involvement in physiology and disease, providing the first evidence of its pronociceptive effects at central levels and characterizing some of the underlying mechanisms.
Original languageEnglish
JournalJournal of Pain
Publication date2012
Volume13
Issue8
Pages742-754
ISSN1526-5900
DOIs
StatePublished
CitationsWeb of Science® Times Cited: 9

Keywords

  • GPR30, estrogen, pain, calcium, reactive oxygen species
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