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National Institute on Drug Abuse -  NIDA NOTES
Research Findings
Volume 15, Number 3 (August, 2000)

Genetic Engineering Studies May Lead to Development Of More Effective Pain Relievers

By Steven Stocker, NIDA NOTES Contributing Writer

Morphine and related compounds, called opiates, are among the most effective pain-relieving medications currently available. If administered properly, they rarely produce addiction. However, patients who take these medications for more than several days develop a tolerance to them, meaning that they must take increasingly higher doses to achieve the same level of pain relief. Unfortunately, when patients take higher doses of opiates, they are more likely to experience side effects.

Differences in Degree

Although all opiates cause physiological tolerance with prolonged administration, the degree of tolerance produced can vary considerably from drug to drug, even under similar conditions. Researchers have noted many factors that may contribute to these differences in "tolerogenicity."

Dr. Mark von Zastrow and his colleagues at the University of California, San Francisco and Los Angeles campuses, have been exploring one of these factors-how various opiate drugs affect the regulation of opioid receptors, proteins on the surface of some nerve cells in the brain and spinal cord. Understanding how opiates differ in their effects on these receptors may help explain the biological underpinnings of opiate tolerance and may be useful in developing improved opiate analgesics, Dr. von Zastrow believes.

Morphine and many other opiates produce analgesia by activating a type of opioid receptor called the mu opioid receptor. When this receptor is activated, it may or may not undergo endocytosis-movement from the surface of the cell to the cell's interior. Research has demonstrated that some opiate drugs cause mu receptor endocytosis, while others do not. Dr. von Zastrow and his colleagues believe that differences in this process of endocytosis may be a determining factor in whether or not a drug will produce tolerance.

A Case of Biochemical Compensation

The researchers have examined the effects on the mu opioid receptor of morphine; DAMGO, a derivative of one of the body's native opioids; etorphine, an opiate used in veterinary medicine; and methadone, an opiate medication used to treat heroin addiction.

Their studies have found that when DAMGO, etorphine, and methadone activate opioid receptors, the receptors are rapidly internalized. Morphine, on the other hand, activates the receptors, but does so with no detectable endocytosis.

Understanding how opiates differ in their effects on these receptors may help explain the biological underpinnings of opiate tolerance and may be useful in developing improved opiate analgesics.

"Morphine may change the shape of the opioid receptor so that it is not internalized," Dr. von Zastrow says. Thus, he explains, the receptor continues to be exposed to activation by the morphine. "My colleagues and I believe that endocytosis of the opioid receptor is essential for normal homeostasis in the nervous system. We hypothesize that, as morphine continues to activate the immobilized receptor, biochemical events inside the cell compensate for this abnormally prolonged activation. In other words, by immobilizing the receptor and continuing to activate it, morphine forces a pathological change in the signaling circuitry that underlies drug tolerance and, perhaps, dependence."

"If this theory is correct, it means that scientists might be able to develop new opioid analgesics that would not produce tolerance," says Dr. Jonathan Pollock of NIDA's Division of Neuroscience and Behavioral Research. "These compounds would both activate the mu opioid receptor and allow its internalization."

To test their theory, Dr. von Zastrow and his colleagues are using genetic engineering techniques in a project to develop mice that, instead of mu opioid receptors, have a different type of opioid receptor that can internalize when morphine attaches to it. "If our theory of opioid tolerance is correct, morphine should produce less tolerance in the mice containing these genetically engineered receptors," he says.


Keith, D.E.; Murray, S.R.; Zaki, P.A.; Chu, P.C.; Lissin, D.V.; Kang, L.; Evans, C.J.; and von Zastrow, M. Morphine activates opioid receptors without causing their rapid internalization. Journal of Biological Chemistry 271(32): 19021-4, 1996. [Abstract and Full Text]

Whistler, J.L.; Chuang, H.; Chu, L.Y.; and von Zastrow, M. Functional dissociation of mu opioid receptor signaling and endocytosis: Implications for the biology of opiate tolerance and addiction. Neuron 23:737-746, 1999.

Whistler, J.L., and von Zastrow, M. Regulated internalization of opioid receptors: Implications for the biology of opiate tolerance. The Neuroscientist, in press.

NIDA NOTES - Volume 15, Number 3

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