International functional genomics study looks for genes that cause drug tolerance and dependence

December 19, 2002

Researchers at Doernbecher Children's Hospital are part of a new study they hope will identify genes that contribute to drug tolerance and dependence. For patients with chronic pain, this could put an end to high doses of various medications and the adverse side effects of tolerance. Instead, more effective versions of drugs, such as those that mimic morphine, may be developed that allow patients to take pain medications for longer periods of time without becoming physically dependent on them.

"In general life, tolerance and dependence are day-to-day issues, such as the use of alcohol or caffeine. What this grant will help us to understand is how we develop that tolerance so we can use the mechanisms to create better therapeutics and also to develop better preventive measures for dependence," said Srinivasa R. Nagalla, M.D., principal investigator for the OHSU component of this study and director of Doernbecher's Center for Biomarker Discovery.

The four-year, $1.4 million study is funded by the National Institute on Drug Abuse (NIDA). Doernbecher's team was chosen for its genomics and proteomics expertise, and will determine the gene expression of regular mice versus genetically altered mice who do not become tolerant of, or dependent, on pain medication. The Robert Wood Johnson Medical School at the University of Medicine & Dentistry of New Jersey (UMDNJ) and the University of Louis Pasteur (U. Louis Pasteur) of France are the two other participating sites that have developed these mice models. This unique collaboration across international lines will allow each institution to offer its expertise to the study.

Genomics uses DNA chips to determine which genes are turned on and turned off, or normal versus abnormal, to determine which genes are expressed in a particular disease or condition. Proteomics takes that a step further to analyze the characteristics and activity of the proteins that are produced from those genes.

Researchers at UMDNJ and U. Louis Pasteur have developed mice that have multiple mutations in genes that regulate their pain management systems so they do not respond to pain medications such as morphine. Researchers will compare the gene expression of these mice to regular mice that respond to pain medications, and, therefore, become tolerant and dependent on them. The next step will be to administer morphine to both groups of mice. This will show which genes in the mutant mouse are not affected by the drug, indicating which genes play a role in the body's ability to build tolerance or dependence, or both, on drugs like morphine.

"Morphine is nothing new and has been around for half a century because we still don't have any better drug than that to manage chronic pain," said Nagalla, assistant professor of pediatrics in the OHSU School of Medicine. "We need better drugs to manage pain without the adverse effects of tolerance, and we hope this study will help us do that."

For children born to drug-dependent mothers, the results of this study could mean an opportunity to prevent developmental issues as they grow. By determining how the drugs alter the baby's nervous system through gene expression analysis, researchers will be able to design therapies to reverse the drug's damaging effects on the baby.

This grant award to the Center for Biomarker Discovery, the genomics and proteomics research division of Doernbecher's pediatric research laboratories, extends the borders further into international science. The center is currently a recipient of two major national consortium awards in this new field, a $1.5 million grant given to 15 Biotechnology Centers by the National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK). Most recently, Doernbecher's research team and OHSU's Center for Research on Occupational and Environmental Toxicology (CROET) were selected together as one of five centers to participate in a $37 million National Institutes of Health Toxicogenomics Research Consortium.

Oregon Health & Science University

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