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Opposing Roles of Estradiol and Testosterone on Stress-Induced Visceral Hypersensitivity in Rats

  • Yaping Ji
    Affiliations
    Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland

    University of Maryland Center to Advance Chronic Pain Research, Baltimore, Maryland
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  • Bo Hu
    Affiliations
    Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland

    Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Xi'an Jiaotong University College of Stomatology, Xi'an, Shaanxi, China
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  • Jiyun Li
    Affiliations
    Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland
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  • Richard J. Traub
    Correspondence
    Address reprint requests to Richard Traub, PhD, Department Neural and Pain Sciences, 650 W. Baltimore St., 8 south, Baltimore, MD 21201.
    Affiliations
    Department of Neural and Pain Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland

    University of Maryland Center to Advance Chronic Pain Research, Baltimore, Maryland
    Search for articles by this author
Published:February 26, 2018DOI:https://doi.org/10.1016/j.jpain.2018.02.007

      Highlights

      • Stress induced visceral hypersensitivity in male and female Sprague Dawley rats.
      • The hypersensitivity persisted several weeks in female rats; a few days in male rats.
      • Ovariectomy blocked and orchiectomy facilitated the hypersensitivity.
      • β-Estradiol 3-benzoate in male rats increased hypersensitivity; testosterone in female rats decreased it.
      • β-Estradiol 3-benzoate and testosterone altered glutamatergic receptor expression in the dorsal horn.

      Abstract

      Chronic stress produces maladaptive pain responses, manifested as alterations in pain processing and exacerbation of chronic pain conditions including irritable bowel syndrome. Female predominance, especially during reproductive years, strongly suggests a role of gonadal hormones. However, gonadal hormone modulation of stress-induced pain hypersensitivity is not well understood. In the present study, we tested the hypothesis that estradiol is pronociceptive and testosterone is antinociceptive in a model of stress-induced visceral hypersensitivity (SIVH) in rats by recording the visceromotor response to colorectal distention after a 3-day forced swim (FS) stress paradigm. FS induced visceral hypersensitivity that persisted at least 2 weeks in female, but only 2 days in male rats. Ovariectomy blocked and orchiectomy facilitated SIVH. Furthermore, estradiol injection in intact male rats increased SIVH and testosterone in intact female rats attenuated SIVH. Western blot analyses indicated estradiol increased excitatory glutamate ionotropic receptor NMDA type subunit 1 expression and decreased inhibitory metabotropic glutamate receptor 2 expression after FS in male thoracolumbar spinal cord. In addition, the presence of estradiol during stress increased spinal brain-derived neurotrophic factor (BDNF) expression independent of sex. In contrast, testosterone blocked the stress-induced increase in BDNF expression in female rats. These data suggest that estradiol facilitates and testosterone attenuates SIVH by modulating spinal excitatory and inhibitory glutamatergic receptor expression.

      Perspective

      SIVH is more robust in female rats. Estradiol facilitates whereas testosterone dampens the development of SIVH. This could partially explain the greater prevalence of certain chronic visceral pain conditions in women. An increase in spinal BDNF is concomitant with increased stress-induced pain. Pharmaceutical interventions targeting this molecule could provide promising alleviation of SIVH in women.

      Key words

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