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. 2014 Dec;155(12):2680-2686.
doi: 10.1016/j.pain.2014.09.035. Epub 2014 Oct 2.

Role of nociceptor estrogen receptor GPR30 in a rat model of endometriosis pain

Pedro Alvarez  1 , Oliver Bogen, Jon D Levine
Affiliations

Role of nociceptor estrogen receptor GPR30 in a rat model of endometriosis pain

Pedro Alvarez et al. Pain. 2014 Dec.

Abstract

Endometriosis, the most common cause of chronic pelvic pain, is an estrogen-dependent disease in which classic estrogen receptors (ERα, ERβ) play an important role. Although recent evidence suggests that the novel G protein-coupled estrogen receptor (GPR30) also plays a key role in the progression of endometriosis, whether it is also involved in endometriosis pain is still unknown. Here we tested the hypothesis that GPR30 expressed by nociceptors contributes to endometriosis pain. Intramuscular injection of the GPR30 agonists raloxifene or 17β-estradiol produced a fast-onset, persistent, mechanical hyperalgesia at the site of the injection. Intrathecal antisense (AS) oligodeoxynucleotides (ODN), but not mismatch (MM) ODN, targeting mRNA for GPR30 markedly inhibited its protein expression in nociceptors and attenuated the mechanical hyperalgesia induced by local raloxifene or 17β-estradiol. Pretreatment with the GPR30 antagonist G-36 also inhibited the hyperalgesia induced by raloxifene or 17β-estradiol in naive control rats. Surgical implant of autologous uterine tissue onto the gastrocnemius muscle, which induces endometriosis-like lesions, produced local mechanical hyperalgesia. Intrathecal AS, but not MM, ODN targeting GPR30 mRNA reversibly inhibited the mechanical hyperalgesia at the site of endometriotic lesions. Finally, intralesional injection of the GPR30 antagonist G-36 also inhibited the mechanical hyperalgesia at the site of ectopic uterine tissue. We conclude that local GPR30 agonists produce persistent mechanical hyperalgesia in naive female rats, whereas local GPR30 antagonists inhibit mechanical hyperalgesia in a model of endometriosis pain. Thus, GPR30 expressed by nociceptors innervating ectopic uterine lesions might play a major role in endometriosis pain.

Keywords: 17β-Estradiol; Ectopic endometrium; Mechanical hyperalgesia; Raloxifene.

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Conflict of interest statement

Conflicts of interest statement

The authors have no conflict of interest with respect to this manuscript.

Figures

Figure 1
Figure 1. Intramuscular 17β-estradiol and raloxifene produce primary mechanical hyperalgesia by action at GPR30
Intramuscular injection of 17β-estradiol (A) or raloxifene (B) produces a dose-dependent mechanical hyperalgesia in intact female rats (n = 6 rats/group). Pre-treatment with the selective GPR30 antagonist G36, but not its vehicle (Veh), inhibits the hyperalgesia produced by both, 17β-estradiol (n = 6) (C) and raloxifene (n = 8) (D). ***P < 0.001.
Figure 2
Figure 2. Effects of the intrathecal administration of antisense (AS) oligodeoxynucleotides (ODN) directed against GPR30 mRNA
(A) Western blot analysis of DRG extracts from rats submitted to intrathecal (i.t.) AS, but not mismatch (MM), ODN treatment (80 µg daily for 3 consecutive days) produced a marked a decrease in the GPR30 immunoreactivity (P = 0.0065, unpaired Student's t-test, n = 6 rats/group). Protein kinase C epsilon (PKCΕ) was used as housekeeping protein in this analysis. Using the same protocol, rats injected i.t. with AS (open bars) compared to the effect of MM (solid bars), directed against GPR30 mRNA (Post ODN) did not affect baseline nociceptive threshold but markedly attenuated the local hyperalgesia produced by intramuscular (B) 17β-estradiol (n = 6 rats/group), or (C) raloxifene (n = 6 rats/group). ***P < 0.001.
Figure 3
Figure 3. Effects of interventions targeting GPR30 on mechanical hyperalgesia induced by ectopic uterine tissue, a model of endometriosis pain
(A) While both groups of rats exhibited similar nociceptive thresholds before (base) and two weeks after the induction of experimental endometriosis (EMS), i.t. treatment (80 µg daily for 3 consecutive days) with AS (open bars), but not MM (solid bars), directed against GPR30 mRNA reversibly attenuated the endometriosis associated hyperalgesia. (B) In the same model, a single intralesional injection of the selective antagonist for GPR30 antagonist G36, but not vehicle (Veh), produced a persistent increase in the nociceptive mechanical threshold. **P < 0.01; ***P < 0.001.
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