Estrogen receptors beta and alpha have specific pro- and anti-nociceptive actions.

It is strongly suggested that estrogen plays a key role in pain modulation. Estrogen's effects are mediated mainly by two receptors, ERα and ERβ. However, the specific role of these receptors is still not clear. In this study, the involvement of both receptors on nociceptive responses was measured in ERα and ERβ knockout (KO) C57BL/6j mice and their respective wild type (WT) littermate (male and female). It was also measured in four groups of ovariectomized mice injected for 7 days with either (1) vehicle, (2) 17β-estradiol, (3) ERα-selective agonist propylpyrazoletriol (PPT) or (4) ERβ-selective agonist diarylpropionitril (DPN). As previously described, ERβ KO females showed lower nociceptive responses compared to WT female mice during the interphase and early tonic phase 2 of the formalin test. The observed pronociceptive nature of ERβ was confirmed using ERβ-selective agonist DPN injections in ovariectomized mice. Moreover, we found that ERα KO male and female mice presented a small increase in nociceptive behaviors during phase 1 of the formalin test, suggesting an anti-nociceptive effect of ERα. These results were confirmed by the injection of ERα-selective agonist PPT in ovariectomized mice. Interestingly, both ER agonists reduced nociceptive responses during late phase 2, suggesting an anti-inflammatory action of estrogen. Results were supported by spinal c-Fos immunohistochemistry. In conclusion, both ERα and ERβ appear to be involved in pain transmission and modulation but may be acting at distinct levels of the pain pathways.