Estrogen curbs fentanyl intake by suppressing brain’s reward response

A new study published in the journal Neuron provides evidence that biological sex differences in brain function and hormone levels may help explain why men are more likely than women to misuse opioids like fentanyl in response to chronic pain. In experiments with rats, male animals with inflammatory pain escalated their fentanyl use over time, while female rats kept their intake steady. This behavioral difference was tied to sex hormones and how they interact with brain regions that regulate reward.

The findings suggest that estrogen plays a protective role against opioid misuse in the context of chronic pain by reducing the brain’s response to the drug. Understanding how pain and hormones shape opioid use could lead to more targeted strategies for preventing addiction, particularly as fentanyl continues to drive overdose deaths in the United States.

Pain is one of the most common reasons people begin using opioids, and in many cases, it is the motivation for misuse. Yet the biological processes that connect chronic pain to increased opioid intake remain poorly understood. Complicating the issue is that women generally report more pain than men, while men are more likely to misuse opioids and die from overdoses.

Researchers at Washington University School of Medicine in St. Louis wanted to understand how chronic pain changes brain activity related to reward and whether these changes differ by sex. Their focus was on the dopamine system—specifically, neurons in the ventral tegmental area (VTA)—which plays a central role in the motivation to seek out rewarding experiences, including drug use. They also investigated the influence of estrogen, a key sex hormone, to see whether it helped explain the observed differences between males and females.

“Opioids are commonly prescribed to treat pain symptoms and while opioids are highly effective, they are also highly addictive,” explained study authors Jose Moron-Concepcion and Jessica Higginbotham, the Henry E. Mallinckrodt Professor of Anesthesiology and an instructor in the Department of Anesthesiology, respectively.

“The impact of pain on the propensity for opioid misuse and abuse has not been thoroughly examined, particularly with consideration of females. This is particularly concerning in the context of overdose deaths which have disproportionately impacted men for several decades. Amidst the current epidemic driven by synthetic opioids, like fentanyl, we wanted to see if pain alters how the brain’s reward system responds to fentanyl and if these responses emerge differently between sexes.”

“Our study exploited new wireless photometry technology that allowed us to record activity from specific subsets of neurons in real-time simultaneous to drug-taking, giving us a glimpse at what happens in the brain while drug use is occurring and how it changes over time.”

The research team used a rat model to simulate chronic pain and examine voluntary fentanyl self-administration. Both male and female rats were implanted with intravenous catheters that allowed them to self-administer fentanyl by pressing a lever. Chronic pain was induced by injecting an inflammatory agent into one of the hind paws. Control animals received saline injections.

Over several weeks, the rats participated in daily two-hour sessions where they could press a lever to receive fentanyl, accompanied by a light cue. Throughout the experiment, the researchers recorded real-time activity in dopamine neurons using wireless fiber photometry—a technique that uses genetically encoded fluorescent sensors to monitor neural activity as animals behave freely.

To examine the role of estrogen, the researchers also manipulated hormone levels. In some female rats, the ovaries were surgically removed to eliminate natural estrogen production. In others, the researchers administered estrogen directly, either systemically or into specific brain regions. Male rats were also treated with estrogen to assess how it affected their drug intake and brain activity.

The team used additional tools like chemogenetics—where neurons are made sensitive to specific drugs that can activate or inhibit them—to test whether changes in dopamine neuron activity caused differences in fentanyl intake. They also examined receptor signaling and used pharmacological agents to block specific estrogen receptors in the brain.

The main finding was a stark sex difference in how chronic pain altered fentanyl use. Male rats with chronic inflammatory pain gradually escalated their fentanyl intake over the course of three weeks. Female rats, by contrast, showed no such escalation, even though the level of pain was similar between the sexes.

This behavioral difference was linked to changes in the dopamine system. In male rats with chronic pain, dopamine neurons in the VTA became increasingly active in response to fentanyl over time. This activity was tightly linked to the amount of drug consumed. When the researchers silenced these neurons using chemogenetics, the escalation in drug use stopped. In contrast, stimulating these neurons in female rats was enough to make them take more fentanyl, suggesting this brain pathway plays a causal role in opioid use under pain conditions.

Importantly, estrogen seemed to suppress this dopamine activity. When male rats with chronic pain were given estrogen, they stopped escalating their fentanyl intake, and their dopamine responses dropped to levels similar to those of females. When the researchers blocked estrogen receptors in the VTA, this suppressive effect disappeared, indicating that estrogen works directly in this brain region to reduce reward-related signaling.

In female rats that had their ovaries removed, fentanyl use increased to levels comparable to those seen in pain-affected males. Estrogen treatment reduced this effect, but only in certain contexts. For example, estrogen had a suppressive effect in males with pain but a stimulatory effect in females without pain, suggesting that the hormone’s influence depends on both sex and the presence of chronic pain.

“One surprising thing from our results was that the suppressive effects of estrogen on dopamine neuron activity and fentanyl use were dependent on the presence of pain,” Moron-Concepcion and Higginbotham told PsyPost. “This suggests that pain may also disrupt the function of hormone systems within the brain, but it will be important for future studies to examine this interaction further.”

The researchers also found that the protective effect of estrogen was mediated specifically through estrogen receptor beta (ERβ) in the VTA. Blocking this receptor allowed dopamine neurons to become more responsive to fentanyl again, reinforcing the idea that ERβ signaling is key to this hormonal control.

“The main takeaway from this study is that pain can exacerbate fentanyl use by facilitating dopamine neuron activation during drug taking,” the researchers explained. “This activation is suppressed by higher concentrations of estradiol (estrogen) which inherently provides females with some level of protection from maladaptive opioid use under conditions of pain. Our work demonstrates that pain promotes opioid use by disrupting the function of reward processing centers in the brain rather than those responsible for nociception (pain-sensation); our evidence, for the first time, points to hormones as a critical regulator of these interactions.”

The study indicates that sex-specific mechanisms play a key role in opioid use under pain. But as with all research, there are limitations. First, while rat models are useful for understanding biological processes, they do not fully capture the complexity of human addiction. Factors such as social environment, psychological stress, and access to healthcare all influence real-world opioid misuse and may interact with biological vulnerabilities.

Second, the researchers focused mainly on estrogen, but other hormones—like progesterone and testosterone—likely also play roles. Future work will need to examine how the broader hormonal landscape shapes opioid-related behaviors.

“One caveat of these studies is that ovarian hormones are depleted via ovariectomy – meaning that, not just estrogen, but all sex hormones (e.g. testosterone, progesterone) are removed,” the researchers noted. “This allows us to isolate the putative contribution of estrogen but does not account for the potential influence of other hormones or how the balance/imbalance between these hormones regulates these effects.”

The authors suggest that understanding how hormones influence opioid reward could have implications for vulnerable populations, including menopausal women and adolescents. They also emphasize the importance of incorporating sex and hormone considerations into addiction research, particularly in light of the ongoing opioid epidemic.

“Our findings allude to the idea that high levels of estrogen relative to other hormones are important for suppressing opioid reward processing in pain,” Moron-Concepcion and Higginbotham explained. “Males and females have the same hormones (e.g., estrogen, progesterone, testosterone), but the balance between these hormones is distinct. Therefore, a major goal going forward will be to assess how these other potential hormonal regulators are involved in the relationship between pain and opioid reward.

“Along the same lines, existing evidence indicates that populations more vulnerable to opioid misuse are adolescents and women of menopausal age. Given that these represent critical times of change in hormone levels, it will be important to assess how age-related hormone surges and depletions play into this phenomenon.”

The study, “Estradiol protects against pain-facilitated fentanyl use via suppression of opioid-evoked dopamine activity in males,” was authored by Jessica A. Higginbotham, Julian G. Abt, Rachel H. Teich, Joanna J. Dearman, Tania Lintz, and Jose A. Morón.