Regulation of Expression of Hyperalgesic Priming by Estrogen Receptor α in the Rat

  • Luiz F. Ferrari
    Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
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  • Dionéia Araldi
    Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
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  • Jon D. Levine
    Address reprint requests to Jon D. Levine, MD, PhD, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0440.
    Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
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Published:January 09, 2017DOI:


      • Hyperalgesic priming is a sexually dimorphic model of transition to chronic pain.
      • Priming involves activation of an autocrine mechanism at the nociceptor membrane.
      • Adenosine, produced by this mechanism, triggers hyperalgesia in primed nociceptors.
      • In females, estrogen, via estrogen receptor α, regulates the autocrine mechanism.
      • Interaction estrogen receptor α/ecto-5'nucleotidase modulates adenosine synthesis.


      Hyperalgesic priming, a sexually dimorphic model of transition to chronic pain, is expressed as prolongation of prostaglandin E2-induced hyperalgesia by the activation of an additional pathway including an autocrine mechanism at the plasma membrane. The autocrine mechanism involves the transport of cyclic adenosine monophosphate (AMP) to the extracellular space, and its conversion to AMP and adenosine, by ecto-5′phosphodiesterase and ecto-5′nucleotidase, respectively. The end product, adenosine, activates A1 receptors, producing delayed onset prolongation of prostaglandin E2 hyperalgesia. We tested the hypothesis that the previously reported, estrogen-dependent, sexual dimorphism observed in the induction of priming is present in the mechanisms involved in its expression, as a regulatory effect on ecto-5′nucleotidase by estrogen receptor α (EsRα), in female rats. In the primed paw AMP hyperalgesia was dependent on conversion to adenosine, being prevented by ecto-5′nucleotidase inhibitor α,β-methyleneadenosine 5′-diphosphate sodium salt and A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. To investigate an interaction between EsRα and ecto-5′nucleotidase, we treated primed female rats with oligodeoxynucleotide antisense or mismatch against EsRα messenger RNA. Whereas in rats treated with antisense AMP-induced hyperalgesia was abolished, the A1 receptor agonist N6-cyclopentiladenosine still produced hyperalgesia. Thus, EsRα interacts with this autocrine pathway at the level of ecto-5′nucleotidase. These results demonstrate a sexually dimorphic mechanism for the expression of priming.


      This study presents evidence of an estrogen-dependent mechanism of expression of chronic pain in female rats, supporting the suggestion that differential targets must be considered when establishing protocols for the treatment of painful conditions in men and women.

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