Female sex hormone protects against opioid misuse, rat study finds

The opioid epidemic has claimed more than half a million lives in the U.S. since 1999, about three-quarters of them men, according to the National Institutes of Health. Although men’s disproportionate rates of opioid abuse and overdose deaths are well-documented, the reasons for this gender disparity are not well understood.

A new study in rats by researchers at Washington University School of Medicine in St. Louis suggests that one underlying cause may be biological. Male rats in chronic pain gave themselves increasing doses of an opioid – specifically, fentanyl – over time, while female rats with the same pain condition kept their intake at a constant level, similar to what is seen in people. The behavioral difference was driven by sex hormones, the researchers found: treating male rats with the hormone estrogen led to them maintain a steady level of fentanyl intake.

The findings, published March 10 in the journal Neuron, indicate that differences in how men and women use and misuse opioids may be driven by their hormones, and that a deeper understanding of how sex hormones interact with chronic pain could open up new approaches to addressing the opioid epidemic.

“These data suggest that men may be inherently predisposed to misuse opioids in the context of pain because of their balance of sex hormones,” said lead author Jessica Higginbotham, PhD, a postdoctoral researcher in the lab of Jose Moron-Concepcion, PhD, the Henry Elliot Mallinckrodt Professor of Anesthesiology at WashU Medicine and the paper’s senior author. “We focused on estrogen in this study, but I doubt the effect we saw is due to estrogen alone. It is more likely to be the balance of all the sex hormones in the body that influences risk. Men and women have the same sex hormones, just in different amounts, and our data suggest that females have a more protective balance than males. But if that balance changes, the risk of developing opioid use disorder could change, too.”

Pain’s influence on pleasure from opioids

Most people who misuse opioids take the drugs to relieve pain, but men are more likely to overdose on opioids than women are, even though they suffer less chronic pain, according to data from national surveys. Scientists hypothesize that something other than, or in addition to, chronic pain must be putting men at higher risk of developing problems managing their opioid use.

When a person – or a rat – takes an opioid such as fentanyl, it acts on the brain in two ways. The drug blocks the transmission of pain signals, relieving pain, and it triggers the release of dopamine from the reward center in the brain, creating a feeling of euphoria. Previous work by Moron-Concepcion and members of his laboratory had shown that pain itself affects dopamine levels in the brain, suggesting that opioids and pain may interact to influence dopamine levels.

To understand how pain influences opioid-seeking behavior in sex-specific ways, Higginbotham and Moron-Concepcion studied rats with chronic pain in their paws. They found no difference between males and females in terms of how much pain the animals experienced, as measured by how quickly they drew back their paws when touched. They also found no difference between the sexes in how much pain relief a dose of fentanyl provided, using the same measurement. And yet the males went back for more and more fentanyl over the course of the three-week study, while the females did not.

The researchers discovered an important difference between male and female rats in the amount of dopamine released after a dose of fentanyl. Females produced the same amount of dopamine from fentanyl over the course of the experiment, regardless of whether they were in pain or not. Males that were not in pain responded like females. In contrast, males in chronic pain generated a bigger and bigger dopamine response to fentanyl over time. In other words, pain made the feel-good part of opioids feel even better for males, but not for females.

“We had thought that maybe the males developed a tolerance to fentanyl and needed increasing amounts to relieve the pain, but that wasn’t it,” said Moron-Concepcion, also a professor of psychiatry and of neuroscience. “The males were taking more and more fentanyl to feel that ever-increasing high. In males, but not females, the pain condition itself affected the reward centers of the brain and drove them to take more drugs.”

Estrogen reduces fentanyl use

Further experiments revealed that sex hormones were responsible for the different dopamine responses in male and female rats.

Ovaries are the primary source of sex hormones in females, producing estrogen, progesterone and small amounts of testosterone. The researchers found that female rats whose ovaries had been removed responded to fentanyl like males did, with increasing amounts of dopamine released and an increase in opioid-seeking behavior. In contrast, males that were given estrogen had dopamine responses and opioid-seeking behavior similar to females.  The findings suggest that a drop in estrogen levels with menopause may help explain why older women have higher rates of opioid abuse compared to younger women, Higginbotham said.

“What we can do now is start thinking about how to find the right balance of hormones to prevent opioid use disorder in people with chronic pain,” Moron-Concepcion said. “We haven’t yet looked at the role of other sex hormones such as testosterone or progesterone. Is there a perfect combination of hormones that can reverse the effects of pain on opioid use? That’s something we’d like to find out.”