Chronic Morphine Use Produces Visible Changes in Brain Cells

The National Institute on Drug Abuse (NIDA) today announced the results of a study that provides the first direct evidence that long-term, chronic opiate exposure is associated with structural changes in both the size and shape of specific neurons in the brain. In previous studies, scientists have shown that chronic exposure to opiates causes dramatic biochemical changes in brain cells, which could contribute to the intense craving for drugs during withdrawal states. Now, researchers at the Yale University School of Medicine in New Haven, Conn., report in the October 1, 1996, issue of the Proceedings of the National Academy of Sciences, that rats chronically exposed to morphine also experienced marked structural changes in the dopamine neurons in the brain's ventral tegmental area (VTA).

"This brain area is activated during the use or self-administration of virtually all drugs of abuse," said NIDA Director, Alan I. Leshner, Ph.D. "We now know that prolonged drug use produces both structural and functional changes in critical brain circuits. The next step is to determine exactly what those changes mean and how they might be addressed in the development of new medications for the treatment of the long-term consequences of opiate use."

Researchers implanted rats with pellets of morphine or placebo for 5 days to induce morphine tolerance and dependence. At the same time, some rats were administered naltrexone or BDNF, a brain-derived neurotrophic factor. Naltrexone has been shown to block the development of morphine tolerance and dependence, and BDNF has been shown to prevent many of the biochemical effects of morphine in the brain.

The research demonstrates that chronic morphine administration produces a dramatic decrease in the size of mesolimbic dopamine neurons originating in the VTA. This is accompanied by a change in the shape of the neurons as well as their processes. Importantly, while changes were observed in the one type of VTA neurons, dopamine neurons, no changes were observed in nondopaminergic neurons. And earlier studies have shown the importance of dopamine in the control and experience of drug use. Thus, the opioids are affecting exactly those brain cells involved in continuing drug use.

This study was directed by Dr. Eric J. Nestler, the Elizabeth Mears and House Jameson Professor of Psychiatry and Pharmacology at Yale. Dr. Nestler says that "While there was no evidence that chronic drug exposure killed the dopamine neurons, these findings clearly demonstrate the dramatic types of changes that drugs of abuse produce in selected brain regions that we believe underlie addiction. Given the prominence of these changes, it is no surprise that effective treatment of addictive disorders for most people would have to include treatments to undo or compensate for these biological changes."

This research was funded by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health. NIDA is the primary Federal agency for the conduct and support of research to increase knowledge and develop strategies to deal with the health problems and issues associated with drug abuse and addiction. The research was carried out in the Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center, which is a collaborative program of Yale University and the State of Connecticut Department of Mental Health and Addiction Services.

For additional information on this study and other NIDA research, contact the NIDA Press Office at (301) 443-6245. NIDA Media Advisories and other information are available on the NIDA Home Page at http://www.nida.nih.gov.