CONTACT: JENNIFER CRONIN
2130 Medical Laboratories
Iowa City IA 52242
(319) 335-5661; fax (319) 335-9917
Release: June 16, 1999
UI researchers begin to unravel the underlying mechanism
IOWA CITY, Iowa -- 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 Health Care 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 stimulate 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 are 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.