FINAL REPORT: A Behavioral Model of Menstrual Migraine

Summary

In this project, we developed a behavioral model of migraine in rats and examined sex differences in migraine-like behaviors.  We based the behavioral assays on the diagnostic criteria for migraine established by the International Headache Society, allowing us to diagnose migraine in our rat model using the same criteria used in patients. Behavioral assays of activity allowed us to assess whether the rats reduced their activity during experimental migraine, and measurements of responses to touching their faces allowed us to assess facial allodynia (pain after light touch that normally isn’t painful) that is common during migraine. Additional behavioral measurements of preference for light or dark and tendency to avoid loud noise are being developed to assess photophobia and phonophobia.

We found that both male and female rats showed reduced activity and facial allodynia in our migraine model, but that the females showed behavioral changes after lower doses of the agent used to induce migraine than the males.

The second goal was to examine the biological basis for sex differences.  Here, we found that there are large sex differences in expression of genes that regulate pain, both before the rats have migraine and after repeated migraines, and that these differences are present in both the central and peripheral nervous system.

Hypothesis vs. Findings

The goal of the project was to develop a rodent behavioral model and to use that model to understand the biological basis for sex differences in migraine. That goal was met, with the exception that the photophobia and phonophobia tasks were not validated before the first study was complete. Those tasks are still under development.

Because we used a method to examine RNA, we were able to explore sex differences in several genes. We found that the sex differences were unexpectedly large. The main finding was that genes related to pain–those that make pain worse by increasing excitability of neurons that signal pain–were regulated at much higher rates in females than in males; some of them increased over 100 fold in the female rats with migraine and were not increased at all in males. We also found that the reverse is true; some genes are upregulated in males and not females.

These results suggest that the mechanism causing migraine pain may be sex dependent, and that optimal migraine treatments may be different for men and women.

Unanswered Questions

Unanswered questions include:

1. Are the genes that show sex differences regulated by hormones such as estrogen or testosterone?

2. Are treatments also sex specific, i.e. do male and female rats respond differently to current or newly emerging migraine treatments?

3. Do the genes that are increased in the migraine model in females have hormone response elements in their promoters?

4. Can we use this model to test new or alternative migraine treatments?

What this Research Means to You

Our research suggests that the mechanism causing migraine pain may be sex dependent, and that optimal migraine treatments may be different for men and women.

Learn More

Nancy Berman, PhD, received a 2008 research grant for her project A Behavioral Model of Menstrual Migraine, which studied how sex differences in rats affected migraine. Much to her surprise, it revealed unexpected results. Dr. Berman hadn’t anticipated finding that male rats produce an enzyme that converts testosterone into estrogen – an insight which she says could potentially lead to the development of gender-specific drugs for the treatment of migraine. She also found that ion channels involved in excitability are changed more in female rats with migraine.

Dr. Berman says that MRF’s grant allowed her to develop a better behavioral model of migraine in rats. She is grateful to MRF for funding her research because she now has preliminary data to present when applying for additional funding to continue her work studying migraine in women.

While Dr. Berman was always interested in problems involving the brain, it wasn’t until fairly recently in her 40 years of doing research that she became interested in migraine. As a teenager, she remembers seeing her psychiatrist father’s strict work schedule posted on the kitchen bulletin board and thinking that she would hate to have such inflexible working hours. Even though she decided psychiatry was not for her, Dr. Berman knew she wanted to learn more about the brain and help people with brain problems. Her interest in psychiatric illness prompted her to double major at Lawrence University in biology and psychology and to do her PhD work in Brain and Cognitive Sciences at MIT. But, her interest in migraine research was actually an accident.

Dr. Michael Welch transferred an NIH grant on cortical spreading depression and migraine to the University of Kansas Medical Center, and she took on the basic science side of that grant as a collaboration with him. From then on, she was “hooked.” She attended a few seminars about headaches, and soon realized there was a gap in knowledge about the topic, which she was eager to fill. Frustrated with the lack of research on migraine and women, she decided to focus her attention on menstrual migraine.

Being a researcher allows Dr. Berman to have the flexible work schedule she hoped for as a teenager, and gives her time to visit her son, two daughters and two grandchildren, travel with her husband, and sharpen her skills as a clog dancer, an Appalachian style tap dance she’s done for fun and exercise over the last 20 years.