OHSU Scientists Discover Brain Signaling System That Modulates Sensitivity To Paing System

October 01, 1996

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 tolerance
Only 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.

Oregon Health & Science University

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