Can a novel target for the treatment of chronic pain lead to more effective relief for women?
Can we learn how the potential pain-relieving action of cannabis works differently in women?
Can we learn the genetic source of sex differences in diseases and help design more effective treatment strategies?
At WHRY, we are changing science to improve lives by addressing what makes us unique as individuals. These three new studies represent our latest effort to confront an urgent need to study women. And to uncover the sex-and-gender differences we must understand to treat and prevent diseases and conditions that affect so many.
The Wendy U. and Thomas C. Naratil Pioneer Award: Exploring Pain Relief for Women Without the Potential for Addiction
Chronic pain affects about 11 percent of the adult population in the United States. Among those with this problem, 70 percent 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. Experts predict more than 700,000 people will die from overdosing prescription and illicit opioids between 2016 and 2025.
Women are particularly at risk because women experience and report pain more than men. Women are more likely than men to begin their misuse of opioids through medical treatment. And women are 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 percent for women — a rate 179 percent higher than for men.
Irina Esterlis, Associate Professor of Psychiatry and Director of the Molecular Imaging Program for the VA National Center for PTSD, is addressing 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). It appears to have a significant role in the experience of chronic pain. 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.
Prior research suggests that reducing MGluR5 activity can reduce the experience of pain. And it can do so without the addictive qualities of opiates.
Esterlis and her team are investigating for the first time in human subjects how mGluR5 levels differ in women and men with and without chronic pain. The researchers are using brain images created with positron emission tomography (PET). They will 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. Then they 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," Esterlis said. "Particularly for women, who are more likely than men to suffer from this debilitating condition. 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. But it can also decrease misuse, dependence, and death associated with opioid prescription.
Investigating Sex Differences in the Capacity for Cannabis to Relieve Pain
It is now legal to use cannabis for medical purposes in 33 states, where more than 2/3 of the country’s population live.
Patients now legally use cannabis to reduce the side effects of cancer treatments. They also use cannabis to relieve the symptoms of several diseases and conditions. These include multiple sclerosis, epilepsy, post-traumatic stress disorder, AIDS, Parkinson’s disease, and glaucoma.
Studies have also shown some capacity for cannabis to relieve pain. This offers 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.
When women begin using cannabis, they progress more rapidly than men to problematic use. Women also show greater sensitivity than men to the euphoric, “good feeling” effects of the drug. And women show more severe symptoms of withdrawal when stopping use after developing a dependence.
Women who frequently smoke cannabis show less effective pain relief from cannabis than regular male smokers. But 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, is using PET imaging and pain threshold tests of female and male volunteers before and after smoking cannabis. His goal is to determine if the drug offers pain relief for infrequent smokers. And to see 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 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 on this new project to build on a 2016 WHRY-funded study. That study collected PET imaging data showing a possible difference in how smoking cannabis affects the brains of women and men differently. The results are leading the way toward better, more individualized treatments for addiction.
Uncovering Genetic Origins of Sex Differences in Disease
When studying the influence of sex and gender on health, researchers produce results that most often show differences. And these differences produce profound effects on the lives of women.
For example, women are more likely to suffer from chronic diseases and disability. Women are also more likely to die following a heart attack, develop depression and anxiety, develop autoimmune diseases, and develop Alzheimer’s disease.
Other sex differences in diseases and conditions include age of onset, progression, and responses to treatment.
Many of these diseases contain a genetic component, passed down from one or both parents. New tools help identify which genes link to particular diseases and conditions. This knowledge offers promising opportunities to improve prevention, diagnosis, prognosis, and treatment. And yet most genetic analyses assume a single genetic effect for both women and men or method not tailored to detect sex differences.
Hongyu Zhao, Department Chair and Ira V. Hiscock Professor of Biostatistics, is developing new statistical methods to better analyze genome-wide association studies (GWAS). These are 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.
Zhao’s team has built a growing body of evidence to suggest that diseases in women and men develop along different biological pathways. And these pathways are often triggered by different genes. In fact, research suggests that current models might be less-than ideal for predicting the high risk of women for developing several major diseases.
In this new, WHRY-funded study, Zhao is examining genes associated with an array of diseases. He is searching for 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," Zhao said. "Particularly Alzheimer’s disease, helping to better design treatment strategies for women. We will also be better able to identify women at high risk for disease. And this can lead to more effective monitoring and prevention strategies.”
Women's Health Research at Yale's Pilot Project Program
The Pilot Project Program is made possible by The Rice Family Foundation, The Werth Family Foundation, the Community Foundation for Greater New Haven, the Maximilian E. and Marion O. Hoffman Foundation, and the Seymour L. Lustman Memorial Fund.
The Wendy U. and Thomas C. Naratil Pioneer Award, supported by an endowment gift from a Yale College ’83 couple, expands the Pilot Project Program by funding investigations that are highly inventive or close to a major breakthrough in advancing women’s health.