June 18, 1999 Anybody who has ever battled through migraines knows just how agonizing they can be; however, nobody has ever figured out why the painful headaches persist as long as they do.
University of Iowa researchers Paul Durham, Ph.D., a postdoctoral fellow in physiology and biophysics, and Andrew Russo, Ph.D., an associate professor of physiology and biophysics, have identified a feedback loop mechanism that could at least partially explain the prolonged nature of migraines. The UI researchers discovered that inflammatory agents released during a migraine might lead certain neurons in the head to increase the secretion of neuropeptides known as calcitonin gene-related peptides (CGRP). The CGRP then stimulates the release of additional inflammatory agents. This feedback loop results in continued secretion of CGRP and persistent pain for the person suffering the migraine.
"We are very interested in understanding the steps involved in controlling how CGRP is made and released from neurons during inflammation," Durham said. "Results from our research will likely identify potential therapeutic targets for the development of anti-migraine drugs that are more selective and potent than those currently available."
The UI investigators made their discovery while studying the anti-migraine drug called sumatriptan. Sumatriptan is the most effective anti-migraine drug currently available, alleviating migraine pain in 50 to 75 percent of patients. Although clinicians know that it works, they had not understood how it worked. Durham and Russo wanted to answer the questions of why CGRP levels were elevated during migraines and then how sumatriptan worked its migraine-zapping magic. Once they identified the feedback loop, the UI researchers were able to show that sumatriptan blocks this loop.
"The long-term goal of this finding is to take some of this information to drug companies so they can identify ways to make sumatriptan more effective or to develop new drugs," Russo said.
What surprised Durham and Russo was how sumatriptan worked. Sumatriptan caused an unusually prolonged increase in the calcium levels of the affected neurons, known as trigeminal neurons. Usually, increases in calcium are associated with increased peptide secretion, not decreased secretion, which is the case with CGRP.
"We believe the calcium is like a light switch," Russo said. "If you just flick the calcium on high and then switch it off quickly, it causes increased secretion. But when it works like a dimmer switch set halfway, it inhibits secretion. It is a beautiful illustration of the complexity of our body's cells. The cells can take the exact same signal and, depending upon its amplitude and duration, get completely opposite results."
In the big picture, the UI findings are important because they provide biochemical evidence of the basis of migraines. Because sumatriptan blocks the CGRP release from neurons in complete absence of any vascular contribution, this indicates that the key regulators are the neurons.
Durham and Russo are now trying to identify the enzymes that stimulate the initial CGRP secretion.
"Although our study has yielded some very interesting results, it is important to realize that we are still a ways away from treatment," Russo said. "We need to continue to study the process to fully understand when, why and how it occurs."
The UI findings appear in a recent issue of the Journal of Neuroscience. The work was supported by grants from the National Institutes of Health and the American Heart Association.
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