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

doi:10.1016/j.neuroscience.2011.02.057

Neuroscience

Volume 184, 16 June 2011, Pages 172-182

https://doi.org/10.1016/j.neuroscience.2011.02.057 Get rights and content

Abstract

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.

Highlights

▶Estrogen plays a key role in pain by the activity of two receptors. ▶The action of the receptors alpha and beta are opposite. ▶Alpha receptors are pro-nociceptive while beta receptors are anti-nociceptive. ▶These receptors specific effects may explain the discrepancies in the literature on estrogen and pain.

Section snippets

Animals

To better characterize the role of estrogen receptors, two models of C57BL/6j mice were used in this study: an ER agonist and an ER KO model (Table 1, Table 2). In every case, mice were housed in groups of same sex and same hormonal condition in an environmentally controlled facility (25 °C, 55% of relative humidity) with ad libitum access to food and water. The mice were acclimatized to manipulations and to the testing apparatus in order to reduce the stress induced by the environment (15 min

Results

In order to better characterize the involvement of both receptors in nociceptive responses, results are presented separately for ERβ and ERα.

Discussion

The aim of this study was to determine the specific implication of ERα and ERβ on pain transmission and pain inhibition mechanisms. The use of the formalin test allowed us to evaluate the involvement of each ER receptor on different excitatory and inhibitory mechanisms. The interphase of the formalin test, located between phase 1 and phase 2, has long been ignored. However, studies demonstrated the association of this phase with active pain inhibitory mechanisms (Henry et al., 1999, Gaumond et

Conclusion

In conclusion, this study shows the involvement of both ERα and ERβ in pain modulation. We suggest that these two receptors act on different targets, which produce distinct effects on nociceptive responses. Our study shows that ERα has hypoalgesic properties. Its action appears to be dominant during the first part of the formalin test, which is suggested to act mainly on pain transmission in the nociceptive afferent fibers. However, the action of ERα on the endogenous inhibitory system is still

Acknowledgments

S Marchand and J Carrier are supported members of the Centre de recherche clinique Étienne-Le Bel du Centre Hospitalier Universitaire de Sherbrooke. MA Coulombe is holder of a doctoral research award from the Canadian Institute of Health Research (CIHR). S Marchand and J Carrier hold grants from the CIHR. The CIHR had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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Pain Mechanisms and Sensory NeuroscienceResearch PaperEstrogen receptors beta and alpha have specific pro- and anti-nociceptive actions

Abstract

Highlights

Section snippets

Animals

Results

Discussion

Conclusion

Acknowledgments

Neuroscience

Eur J Pharmacol

Pain

Horm Behav

Pain

Brain Res

Neuroscience

Life Sci

Pain

Pain

Eur J Pain

Life Sci

Brain Res

Brain Res

Neuroscience

Pain

Pain

J Neurosci Methods

Pain

Trends Endocrinol Metab

Brain Res

Horm Behav

Front Neuroendocrinol

Pain

Eur J Pharmacol

Trends Endocrinol Metab

Neurosci Lett

J Pain

Pain

Trends Pharmacol Sci

Peptides

Brain Res Bull

J Pharmacol Methods

Brain Res Mol Brain Res

Brain Res Mol Brain Res

Pain

Regul Pept

Pain

Pain

Pain

Prog Brain Res

Neuroscience

Eur J Pain

Pain

Neuroscience

Pain Mechanisms and Sensory Neuroscience
Research Paper
Estrogen receptors beta and alpha have specific pro- and anti-nociceptive actions