Women’s Health Research at Yale funds studies on pain relief, cannabis, and genetic origins of sex differences in disease

New, first-of-their-kind studies will explore such questions as: Can a novel target for the treatment of chronic pain lead to more effective relief for women?
A woman clutching her lower back.

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Women’s Health Research at Yale (WHRY) today announced funding for first-of-their-kind studies on pain relief, cannabis, and the genetic basis of sex differences across a broad range of ailments, including Alzheimer’s disease and heart disease.

We are changing science to improve lives by addressing what makes us unique as individuals,” said Dr. Carolyn M. Mazure, director of WHRY. “These studies represent our latest effort to confront an ever-more urgent need to study women and uncover the sex-and-gender differences we must understand to treat and prevent diseases and conditions that affect so many.”

The new studies will explore such questions as: Can a novel target for the treatment of chronic pain lead to more effective relief for women? Can a better understanding of sex-specific responses to the potential pain-relieving action of cannabis lead to more efficient and safe management of physical suffering for women? And: Can a big-data genetic analysis lead to a deeper understanding of sex differences in diseases and help design more effective, sex-specific treatment strategies?

As the opioid crisis continues to damage and destroy lives across this country, we must address the unique needs of women,” Mazure said, noting that prescription opioid overdose deaths for women are increasing at a much greater rate than for men. “By deploying the latest, powerful tools to examine huge databases of our shared genetic code, we are identifying practical solutions to a huge array of real-world problems.”

Pain relief

Chronic pain affects about 11% of the adult population in the United States. Seventy percent of chronic pain sufferers are women. The most common class of medications prescribed for treatment is opioids, which are addictive and can be deadly.

Over the last 20 years, more than 200,000 Americans have died from prescription opioid overdoses, according to the U.S. Centers for Disease Control and Prevention. A recent study published in the Journal of the American Medical Association estimated that if current trends continue, overdose deaths from prescription and illicit opioids in the country would amount to more than 700,000 people between 2016 and 2025.

Women are particularly vulnerable to this epidemic because women have a greater sensitivity to pain than men and are more likely than men to begin their misuse of opioids through medical treatment. Women are also more likely to be prescribed opioids with other medications that increase the likelihood of an overdose. Between 1999 and 2016, overdose deaths from opioid prescriptions increased by 583% for women — a rate 179% higher than for men.

Irina Esterlis, associate professor of psychiatry and director of the molecular imaging program for the VA National Center for PTSD, will address this problem by investigating a potential biological target for the development of non-addictive chronic pain treatments.

There is a molecule of the central nervous system known as glutamatergic receptor 5 (mGluR5). A large collection of previous laboratory research identifies these receptors as having a significant role in the experience of chronic pain. Working together, these protein structures on the surface of cells allow binding with molecules outside the cells active in brain functions, including the sensation of pain.

These prior studies have suggested that reducing MGluR5 activity can decrease the experience of pain without the addictive qualities of opiates.

With this year’s Wendy U. and Thomas C. Naratil Pioneer Award, Esterlis and her team will investigate for the first time in human subjects how mGluR5 activity differs in women and men with and without chronic pain. The researchers will use brain images created with positron emission tomography (PET) to see if women and men with chronic lower back pain have higher levels of MGluR5 and what differences might exist between the genders.

The researchers aim to produce preliminary data for a larger study that can test whether certain existing drugs can reduce mGluR5 levels and decrease pain for women.

It is critical that we develop effective, non-addictive treatments for chronic pain — particularly for women, who are more likely than men to suffer from this debilitating condition,” Esterlis said. “We first need to know more about the biological mechanisms behind chronic pain, which affects so many women in their daily lives.”

If successful, this work could provide a safe and effective treatment for chronic pain experienced by women, and also decrease misuse, dependence, and death associated with prescription opioids, Esterlis said.


It is now legal to use cannabis for medical purposes in 33 states, where more than two-thirds of the country’s population reside.

Despite limited rigorous research, patients now legally use cannabis to reduce the side effects of cancer treatments and the symptoms of diseases and conditions such as multiple sclerosis, epilepsy, post-traumatic stress disorder, AIDS, Parkinson’s disease, and glaucoma.

In addition, studies have shown a moderate ability for cannabis to relieve pain, offering a potential substitute for the addictive and potentially deadly risks of opioid medications. Despite limited data, many people use cannabis to treat their pain. And at least half of daily cannabis users meet the diagnostic criteria for cannabis use disorder, which means their use of the drug leads to difficulties with health or their ability to meet responsibilities.

Prescription cannabis
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As with opioids and other addictive substances, when women begin using cannabis, they progress more rapidly than men to problematic use. Women also show greater sensitivity than men to the “good feeling” effects of the drug and more severe symptoms of withdrawal when stopping use after developing a dependence.

While women who frequently smoke cannabis report less effective pain relief from cannabis than regular male smokers, until now no one has investigated the ability of cannabis to blunt pain in people who are not frequent users.

Ansel Hillmer, assistant professor of radiology and biomedical imaging and of psychiatry, will use PET imaging and pain threshold tests of female and male volunteers before and after smoking cannabis to determine if the drug offers pain relief for infrequent smokers and if there is any difference in therapeutic effectiveness between women and men.

Cannabis use to manage pain is rapidly expanding in the United States as a possible substitute for opioids,” Hillmer said. “But we need to know much more about how safe and effective this practice is, particularly for women, who are more susceptible to developing a cannabis use disorder.”

Hillmer works in a lab led by Kelly Cosgrove, associate professor of psychiatry, radiology and biomedical imaging, and neuroscience. He will work with Cosgrove to build on a 2016 WHRY-funded study in which the team collected PET imaging data showing a possible difference in how smoking cannabis affects the brains of women and men differently, allowing for better, more individualized treatments for addiction.

Genetic origins of sex differences in disease

Most human traits and diseases have sex or gender differences. These differences often have profound effects on women’s lives.

For example, women are more likely to suffer from chronic diseases and disability, to die following a heart attack, and to develop depression and anxiety, autoimmune diseases, and Alzheimer’s disease.

In addition to increased prevalence, other sex differences include age of onset, progression, and responses to treatment.

Many of these diseases involve a genetic component, passed down from one or both parents. Relatively new tools for identifying which genes are associated with particular diseases and conditions offer opportunities to improve prevention, diagnosis, prognosis, and treatment. Yet most genetic analyses assume a single genetic effect for both women and men or use a methodology not tailored to detect sex differences.

Hongyu Zhao, department chair and the Ira V. Hiscock Professor of Biostatistics, is developing new statistical methods to better analyze genome-wide association studies (GWAS), observational inquiries in which researchers examine the complete set of genes in a large group of individuals, searching for genetic variants related to particular traits, such as diseases.

DNA collage
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Zhao’s team has accumulated a growing body of evidence to suggest that diseases in women and men develop along different biological pathways, often triggered by different genes. In fact, a preliminary analysis of a large database of genetic and other health information from the United Kingdom suggests that current models might be less than ideal for predicting the high risk of women for developing several major diseases, notes the researcher.

In this new, WHRY-funded study, Zhao will examine genes associated with an array of diseases in search of sex differences and aspects of disease origin and development. Targeted diseases include Alzheimer’s disease, coronary artery disease, and autoimmune diseases. Ultimately, the team will develop sex-specific genetic risk models to predict diseases.

Through this study, we will gain a better understanding of the genetic basis for sex differences in a wide range of diseases, particularly Alzheimer’s disease, helping to better design treatment strategies for women,” Zhao said. “We will also be better able to identify women at high risk for disease, leading to more effective monitoring and prevention strategies.”

Since its inception, WHRY has awarded $5 million in annual seed grants that have gone on to generate more than $102 million in external funding.

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Rick Harrison: rick.harrison@yale.edu,