Portland, Ore.-Scientists at Oregon Health Sciences University have discovered a brain signaling system that opposes the action of opioid drugs like morphine. Their findings appear in the October 3, 1996 issue of the journal Neuroscience. In their paper David Grandy, Ph.D., and his OHSU colleagues Jeffrey Mogil, Ph.D., Judith Grisel, Ph.D., and John Belknap, Ph.D., describe the action of a natural brain chemical called orphanin FQ, or simply OFQ, that opposes the effects of opioids. Their findings lay the foundation for the design of therapeutic drugs that could relieve the negative side effects of opioid pain killers.
Over the past 25 years, scientists have demonstrated that the body produces its
own opioids, which are collectively referred to as endorphins. Besides playing
a role in ameliorating pain, the endorphins also influence a variety of basic
behaviors including motivation and reward.
The powerful pain-relieving properties of morphine have been known and exploited
for centuries. To this day morphine is still the drug of choice for controlling
severe pain, as occurs in some cancer patients. Unfortunately, continued use of
opiates results in the development of toleranceOnly recently have scientists demonstrated that morphine and its close relative
heroin potently mimic the body's own endorphins by turning on a family of opiate
receptors. What has been difficult to explain is the cellular basis of opiate
tolerance and physical dependence.
"One hypothesis to explain the development of tolerance is that it is the body's
attempt to maintain homeostasis," says Grandy, a scientist working in OHSU's
Vollum Institute. "The body is always trying to maintain balance. If there is an
imbalance or overactivity in one part of the brain, a compensatory change
usually occurs to counterbalance it. Depending on the area of the brain
involved, if balance is not restored over time, mental illness may even result,"
says Grandy. "In the case of opiate abuse we do not speak of mental illness.
However, the changes that occur as a consequence of opiate addiction can have
equally devastating effects."
For many years scientists have been thinking that when the brain is chronically
exposed to opiates there must be changes at the cellular level that underlie
tolerance and dependence. The search for these cellular changes has focused
primarily on the opiate receptors themselves and the physiology of the neuron.
Few scientists expected that there might be another system involved. "When we
look at the genes for OFQ and its receptor and the genes encoding the opioid
peptides and their receptors, they appear to have evolved from common ancestral
genes. At this time it appears that the OFQ and opioid systems developed in
parallel as natural checks and balances.
"Our recent finding provides evidence that the OFQ system acts in the brain to
reverse the analgesic effects of opiates," says Grandy. "Therefore, therapeutic
drugs designed to block OFQ receptors may allow physicians to use less morphine
to relieve pain because the endogenous system opposing morphine's actions would
be blocked. We are hoping that an antagonist to the OFQ receptor will make
morphine more efficacious so patients could benefit from its pain relieving
effects without experiencing the unwanted side effects."
Their finding that the OFQ system can counteract the effects of narcotics, and
that the OFQ system is expressed in areas of the brain that are thought to be
involved in establishing dependence, raises several interesting possibilities.
For example, therapeutic agents acting at OFQ's receptor may offer relief from
heroin withdrawal. "Many people are looking for a less painful way to wean
heroin addicts from the narcotic," says Grandy. "Blocking the OFQ receptor may
decrease the irritability, anxiety and nausea characteristic of heroin
withdrawal." One hypothesis is that the more opiates a person takes, the more
OFQ may be produced. An increase in OFQ activity may help to explain the
tolerance that develops from heavy opiate use. Perhaps when the narcotic is
removed, too much OFQ may linger for awhile and cause some of the uncomfortable
symptoms of withdrawal.
This work was funded by the National Institute on Drug Abuse, a division of the
National Institutes of Health and the Markey Charitable Trust.