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2013 MRF Research Grantee
FINAL REPORT: Studies of Gastroparesis in Monogenic Migraine Mouse Models
While headaches are typically the most frequent and disabling symptoms of migraine attacks, gastrointestinal symptoms, such as nausea, diarrhea, constipation, and abdominal pain, are also common. Delayed movement of food from the stomach into the intestines, a disorder called gastroparesis, is also a well-described feature of migraine attacks for some people. The likelihood that someone will develop migraine is believed to be strongly, but not exclusively, influenced by genetic factors. We sought to clarify if gastroparesis or other changes in intestinal movements (intestinal dysmotility) were caused by genetic mutations that also predispose people to migraine headaches.
We studied three different strains of mice, each engineered to carry a different single genetic mutation. These mutations had been previously discovered in human families to increase the risk of migraine, together with other identifiable traits, such as stroke (CADASIL migraine mice), one-sided paralysis (FHM1 migraine mice), and sleep-wake cycle abnormalities (CK1δ migraine mice). We tested these three migraine mouse strains to see whether they had gastroparesis or intestinal dysmotility compared to normal mice, and we found no differences, apart from modest, but significant, intestinal dysmotility in one strain (female FHM1 mice). We have studied sufficient CK1δ mice to determine that sex differences do not appear to be a determining factor in gastrointestinal motility in this strain, and we are continuing with experiments with male and female mice of the other strains to further assess this question.
We have subsequently begun to test these three strains of migraine mice to see whether nitroglycerine, a drug that can reliably provoke migraine in humans, has any pronounced effect on stomach or intestinal movements in these mice too. Our findings to date in tests of two of the three mouse strains (FHM1 and CADASIL mice) have also shown no significant gastroparesis or intestinal dysmotility.
Hypothesis vs. Findings
Our data do not generally support our original hypothesis that genetic mutations that can increase migraine susceptibility also are a major cause of gastrointestinal motility abnormalities.
Gastrointestinal traits associated with migraine remain incompletely understood. A number of possible explanations might account for our preliminary findings.
It is possible that the species differences between humans and mice are significant enough that mice with these human mutations are not close enough models of human migraine to help us understand migraine-related gastrointestinal traits. It is also possible that human genetic mutations actually do exist that predispose to both migraine headache and to gastroparesis, but that the CADASIL, FHM1, and CK1δ mutations we have studied do not. Furthermore, it is possible that specific aspects of our particular study design led us to miss detection of gastroparesis in these mice when it otherwise might have been found.
On the other hand, we may need to look in other directions to explain the strong link between migraine headaches and migraine-related gastrointestinal symptoms. For example, migraine-related gastroparesis might be due to environmental factors, rather than genetic factors. In this vein, one intriguing possibility is that the microbes that normally colonize the gastrointestinal tract of people with migraine also influence their susceptibility to migraine. Alternatively, dietary factors may play a role. Finally, genetic mechanisms are known to exist whereby human experiences can lead to persistent changes in the activity of specific genes (a process called epigenetics); these factors might also provide a clue.
What this Research Means to You
Our MRF/AMD funded research studies have provided valuable insights into which factors may and may not lead to gastrointestinal symptoms and traits in people with migraine.