Study findings have implications for development of pain-relieving drugs

Morphine and other opioids are widely used to treat both acute and chronic pain - yet their benefits are often limited because some people experience side effects or do not respond to them efficiently.

Now, new research from the University of North Carolina at Chapel Hill's Center for Neurosensory Disorders, based within the School of Dentistry, has identified genetic variants that offer insight into individual responses to morphine. Researchers said long-term implications of the findings may include the development of drugs with greater pain-relieving effects and fewer side effects, as well as the development of genetic tests predicting individual responses to these medications.

Up to one-third of people treated with opioids develop substantial side effects, said Luda Diatchenko, M.D., Ph.D., an associate professor in the center and the study's co-senior author. In addition, there is more than a 10-fold difference in the responses - some patients show a very good response and others show a very poor response to the same amount.

The study, which appeared in the March 15, 2009, issue of the journal Human Molecular Genetics , identifies new variations in the gene that produces the OPRM1 receptor, the primary biological target for opioid analgesics such as morphine. The research also provides evidence that the receptor carries many more genetic variations than previously thought.

"Genetic variations in this receptor play a crucial role in individual responsiveness to these drugs, but we currently have very little understanding of its genetic structures and molecular and cellular mechanisms," Diatchenko said.

She added that collaboration with the National Institutes of Health's National Center for Biotechnology Information had provided crucial insights into these mechanisms. Bioinformatics is an emerging field combining information technology and biology.

"Bioinformatics has become one of the driving forces of modern biomedical science," said Svetlana Shabalina, Ph.D., a senior scientist at the National Center for Biotechnology Information and the other study co-senior author. "Bioinformatic tools are indispensable for the identification of underlying genetic causes in complex disorders. We expect many important discoveries in this field."

"The outcomes of these studies are very exciting and are likely to lead to new diagnostic tests that will permit clinicians to predict a patient's risk for inadequate or adverse responses to opioids," said William Maixner, D.D.S., Ph.D., co-author of the study, director of the Center for Neurosensory Disorders and professor of endodontics and pharmacology in the UNC schools of dentistry and medicine, respectively. "The outcomes may also enable the development of a new class of opioids that are safer and more effective than those currently available," he said.

The study was funded by grants from the National Institutes of Health.

Other study authors from the UNC School of Dentistry are Pavel Gris, Ph.D.; Josee Gauthier and Inna E. Tchivileva, M.D. Additional study authors are Dmitri V. Zaykin, Ph.D., and Kyoko Shibata, Ph.D., of the National Institute of Environmental Health Sciences; Aleksey Y. Ogurtsov, Ph.D., of the National Center for Biotechnology Information; Inna Belfer, M.D., Ph.D., of the National Institute of Dental and Craniofacial Research, the National Institute on Alcohol Abuse and Alcoholism and the University of Pittsburgh; Bikashkumar Mishra, M.D., and Carly Kiselycznyk, Ph.D. of the NIDCR and NIAAA; Margaret R. Wallace, Ph.D., of the University of Florida College of Medicine; Roland Staud, M.D., and Roger B. Fillingim, Ph.D., of the University of Florida College of Dentistry; Nikolay A. Spiridonov, Ph.D., of the U.S. Food and Drug Administration; Mitchell B. Max, M.D., Ph.D., of the NIDCR and University of Pittsburgh; and David Goldman, M.D., of the NIAAA.

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