- 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.
- Until now.
- 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
- 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,"
- 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
- 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.
- Note: This story has been adapted from
a news release issued by University Of Iowa for journalists and other
members of the public. If you wish to quote from any part of this story,
please credit University Of Iowa as the original source. You may also
wish to include the following link in any citation: <http://www.sciencedaily.com/releases/1999/06/990618063855.htmhttp://www.scien