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

Abstract

Hyperalgesic priming, a sexually dimorphic model of transition to chronic pain, is expressed as prolongation of prostaglandin E2 (PGE2)-induced hyperalgesia by the activation of an additional pathway including an autocrine mechanism at the plasma membrane. The autocrine mechanism involves the transport of cAMP 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 PGE2 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 alpha (EsRα), in female rats. In the primed paw AMP hyperalgesia was dependent on conversion to adenosine, being prevented by ecto-5′nucleotidase inhibitor AMPCP and A1 receptor antagonist DPCPX. To investigate an interaction between EsRα and ecto-5′nucleotidase, we treated primed female rats with ODN antisense or mismatch against EsRα mRNA. While in rats treated with antisense AMP-induced hyperalgesia was abolished, the A1 receptor agonist N6-cyclopentiladenosine (CPA) 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. Perspective This study presents evidence of an estrogen-dependent mechanism of expression of chronic pain in females, supporting the suggestion that differential targets must be considered when establishing protocols for the treatment of painful conditions in males and females.

Estrogen modulation of pain perception with a novel 17β-estradiol pretreatment regime in ovariectomized rats

“…ERα activation was concluded to be antinociceptive in the formalin model [35]; at the same time, it exaggerated visceral pain in several conditions [36]. Khomula et al proved that ERα agonist facilitates hyperalgesic priming though IP3 receptor by electrophysiological means [37], and ERα antisense attenuated AMP-induced hyperalgesia in primed female rats [38]. These studies collectively confirmed that ERα is involved in central pain pathways.…”

Age-Dependent Sexual Dimorphism in Susceptibility to Develop Chronic Pain in the Rat

“…While the mechanical hyperalgesia induced by injection of PGE 2 in a naïve control paw lasts ~2h, in the primed paw it is markedly prolonged, lasting more than 4h, due to protein kinase C epsilon (PKCε)-triggered changes in the nociceptor (Aley and Levine, 1999; Aley et al, 2000), which strongly and permanently affects the signaling pathways activated by pro-algesic stimulation (Parada et al, 2005; Khasar et al, 2008; Dina et al, 2009; Ferrari et al, 2013c; Ferrari and Levine, 2015). Hyperalgesic priming has been shown to be sexually dimorphic (Joseph et al, 2003; Ferrari et al, 2016; Ferrari et al, 2017; Khomula et al, 2017); in female rats, the PKCε-dependent induction of priming is negatively regulated by estrogen, such that gonad intact adult females cannot be primed by direct or receptor-mediated activation of PKCε. However, in gonadectomized females, activation of PKCε induces priming (Joseph et al, 2003).…”

“…In this study, we demonstrate that post-natal developmental stage influences the susceptibility of rats to develop priming in a sexually dimorphic manner. Also, since sex hormones vary in level during post-natal development (Weisz and Ward, 1980; Amateau et al, 2004; Balthazart and Ball, 2006; Cornil et al, 2006), and priming is sexually dimorphic and estrogen-dependent (Joseph et al, 2003; Ferrari et al, 2016; Ferrari et al, 2017; Khomula et al, 2017), we evaluated the role of estrogen in such age dependent differences in the induction of priming at young ages in males and females.…”

Unveil the pain of endometriosis: from the perspective of the nervous system

“…Oestrogen can not only prolong induced hyperalgesia by regulating the autocrine mechanism activation at the plasma membrane but it is also related to neurogenesis and neurodegeneration by affecting proliferation or differentiation in neural stem/ progenitor cells (Ref. 82). Researchers found in patients with endometriosis who received combined oral contraceptives that the amount of NGF and its receptors significantly decreased in the endometrium (Ref.…”