Modulation of pain by estrogens

Here are 4 PubMed scientific studies exploring how estrogen affects all different aspects of pain: its sensation, its interaction with opioid receptors, and its memory. Estrogen is clearly important, but the interactions with pain sensation are very complex.

Just like with hormone replacement therapy, the effects of estrogen on pain probably differ a great deal between individuals.

Pronociceptive and Antinociceptive Effects of Estradiol through Endogenous Opioid Neurotransmission in Women – NCBI – May 2006

Prominent interindividual and sex-dependent differences have been described in responses to sustained pain and other stressful stimuli. Variations in μ-opioid receptor-mediated endogenous opioid neurotransmission may underlie some of these processes.  

We examined both baseline μ-opioid receptor levels and the activation of this neurotransmitter system during sustained pain using positron emission tomography in a sample of young healthy men and women.

Women were studied twice, during low and high estrogen states.

The high-estrogen state was associated with

  • regional increases in baseline μ-opioid receptor availability in vivo and
  • a greater activation of endogenous opioid neurotransmission during the pain stressor.

The latter did not differ from that obtained in males.

During the low estrogen condition, however,

  • significant reductions in endogenous opioid tone were observed at the level of thalamus, nucleus accumbens, and amygdala, which were
  • associated with hyperalgesic responses.

Estrogen-associated variations in the activity of μ-opioid neurotransmission correlated with individual ratings of the sensory and affective perceptions of the pain and the subsequent recall of that experience.

These data demonstrate a significant role of estrogen in modulating endogenous opioid neurotransmission and associated psychophysical responses to a pain stressor in humans.


we demonstrate that estradiol-induced modulation of endogenous opioid system function was associated with the recall accuracy of the pain experience (overstating and understating past pain) in both its sensory and affective qualities.

The reductions in endogenous opioid tone observed in the low-estradiol state would require that substantial tonic release of this neurotransmitter is present under nonpainful conditions

The data presented demonstrate a substantial influence of estradiol on a neurochemical system that regulates various aspects of pain and stress responses.

The psychophysical consequences of this bidirectional regulation included the capacity to both enhance and suppress the individual’s ratings of the pain and the recall accuracy of the sensory and affective qualities of the pain experienced.

The effects of estradiol took place in a series of interconnected brain nuclei known to be potently regulated by endogenous opioid peptides and μ-opioid receptors in animal models and in humans. These regions were a subset of those involved in the supraspinal regulation of pain.

Also novel to the present set of results, we demonstrate that larger magnitudes of μ-opioid system activation were associated with an underestimation of sensory and affective qualities of the experience of pain when rated 24 h after the challenge, and vice versa.

Substantial correlations with pain-affect ratings were observed in the amygdala, a brain region known to be involved in the processing and consolidation of memories for salient events (i.e., emotional memory) and sex differences in these processes.

Recent data has also shown that among the regions implicated in estradiol effects, nucleus accumbens endogenous opioid systems are also involved in placebo-induced endogenous opioid activation when there is expectation of analgesia.

In addition to stress modulation and stress-induced analgesia, dependent on the activation of endogenous opioid neurotransmission, μ-opioid receptors also mediate the effects of exogenous opiate medications used for the treatment of pain.

The enhanced pain perception mediated by the endogenous opioid system during low-estradiol states may represent a mechanism by which female gonadal steroids participate in the development of hyperalgesia and possibly the increased risk for the development of some idiopathic painful states observed in women.

The present study was specifically designed to isolate the effects of estradiol from those of progesterone, and therefore the low levels of progesterone present across conditions in this study do not permit any assessments as to the possible effects of this hormone in the sample studied.

In this regard, it has been suggested that progesterone may induce opposite effects to those of estradiol on both μ-opioid receptor binding and in the capacity to release endogenous opioids activating those receptors

The data presented demonstrate that a low-estradiol, low-progesterone condition is associated with a pain vulnerability state by a reduction in endogenous opioid system function, possibly through β-endorphin mediated mechanisms.

Modulation of pain by estrogens. [Pain. 2007] – PubMed – NCBI

It has become increasingly apparent that women suffer a disproportionate amount of pain during their lifetime compared to men.

Over the past 15 years, a growing number of studies have suggested a variety of causes for this sex difference, from cellular to psychosocial levels of analysis.

From a biological perspective, sexual differentiation of pain appears to occur similarly to sexual differentiation of other phenomena: it results in large part from organizational and activational effects of gonadal steroid hormones.

Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain.

Forging a more complete understanding of the myriad ways that estrogens can ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men.

Importance of sex to pain and its amelioration; relevance of spinal estrogens and its membrane receptors – free full-text article /PMC3778676/Oct 2012

This full-text article is more like a book and contains reams of information about the effects of estrogen on pain and the response to opioid medication.

Estrogens have a multitude of effects on opioid systems and are thought to play a key role in sexually dimorphic nociception and opioid antinociception.

Heretofore, classical genomic actions of estrogens are largely thought to be responsible for the effects of these steroids on nociception and opioid antinociception.

The recent discovery that estrogens can also activate estrogen receptors that are located in the plasma membrane, the effects of which are manifest in seconds to minutes instead of hours to days has revolutionized our thinking concerning the ways in which estrogens are likely to modulate pain responsiveness and the dynamic nature of that modulation.

This review summarizes parameters of opioid functionality and nociception that are subject to modulation by estrogens, underscoring the added dimensions of such modulation that accrues from rapid membrane estrogen receptor signaling. Implications of this mode of signaling regarding putative sources of estrogens and its degradation are also discussed.


This new-found complexity and sexual dimorphism thereof could provide solid ground for understanding the sex divide in the experience of pain and its treatment, the growing examples of which outpace our comprehension.

This newly appreciated complexity could also provide a starting point for interpreting the spectrum of contradictory findings that pervade the sex/pain literature.

The importance of estrogens in pain modulation can only be fully comprehended within the context of the male female dichotomy in nociception and opioid antinociception, a systematic investigation of which is mandated not only because of social considerations but also because of the translational opportunities is promises.

List of major points made in this article:

  • Rapid membrane estrogen receptor signaling influences pain regulation.
  • Membrane estrogen receptors modulate μ- and κ-opioid receptor heterodimerization.
  • Membrane estrogen receptors regulate pro- vs. anti-nociceptive functions of dynorphin
  • Spinal estrogen via its membrane receptor regulates dynorphin effects on nociception.
  • Membrane estrogen receptor activity influences sex difference in pain process.

Sex differences in opioid analgesia and addiction: interactions among opioid receptors and estrogen receptors [Mol Pain. 2013] – PubMed – NCBI

Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear.

Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids.

The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated.

We postulate that

  • the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators,
  • there are sex differences in reporting pain and seeking pain relief, and
  • health care providers make unwarranted psychogenic attributions regarding pain in female but not male.

Other thoughts?

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