Change in brain cells linked to opiate addiction, narcolepsy

The image on the left shows hypocretin-producing cells in a typical brain, while the image on the right shows them in the brain of someone addicted to heroin.


Two discoveries — one in the brains of people with heroin addiction and the other in the brains of sleepy mice — shed light on chemical messengers in the brain that regulate sleep and addiction, UCLA researchers say.


In 2000, UCLA researchers discovered that human narcolepsy is caused by a loss of roughly 90 percent of the 80,000 brain cells containing hypocretin, also called orexin, a chemical messenger, or neurotransmitter, important in the regulation of sleep. Narcolepsy causes excessive sleepiness, sleep paralysis (a feeling of being conscious but unable to move), hallucinations and episodes of cataplexy, a partial or total loss of muscle control that is often triggered by a strong emotion such as laughter. Narcolepsy affects about one in 2,000 to 3,000 people but can go undiagnosed for years, according to the National Sleep Foundation. The sleep disorder usually has its onset in childhood or adolescence.


In a new study, these researchers discovered that people addicted to heroin have, on average, 54 percent more hypocretin-producing neurons than do people without addiction. They confirmed, in mice, that opiates caused this increase. The increase in hypocretin cells lasted for as long as four weeks after discontinuation of the morphine treatment, well after morphine had left the animals’ bodies.

The researchers hypothesized that morphine, the active ingredient in heroin, might restore the missing hypocretin-producing neurons in people with narcolepsy. To test this idea, researchers used mice that were made narcoleptic by the loss of hypocretin cells and gave them morphine. The researchers found that morphine increased the number of hypocretin-producing cells and the narcoleptic symptoms of the mice disappeared.


The continued production of hypocretin in mice, after discontinuing morphine treatment, suggests that humans may continue producing hypocretin after they have stopped using heroin. The researchers hypothesize that this hypocretin increase may be a factor in opiate craving.

In addition, raising the number of hypocretin cells to near normal levels could potentially reverse narcoleptic symptoms in humans. However, further work in mice is necessary before this can be recommended as a treatment for narcolepsy in people. Next, researchers would like to find out if reducing "excess" hypocretin cells — or blocking the action of the hypocretin peptide that they release — could make long-term withdrawal from opiates easier and prevent relapse.


The senior author is Jerome Siegel and the first author is Thomas Thannickal, both of the Semel Institute for Neuroscience and Human Behavior. Other authors are Joshi John, Ling Shan, Ming-Fung Wu, Lalini Ramanathan, Ronald McGregor and Keng-Tee Chew, all of the Semel Institute; Marcia Cornford, Harbor-UCLA Medical Center; Dick Swaab, Netherlands Institute for Neuroscience; Akihiro Yamanaka and Ayumu Inutsuka, Research Institute of Environmental Medicine, Nagoya University, Japan; Rolf Fronczek and Gert Jan Lammers, Leiden University Medical Centre, Netherlands; and Paul Worley, Johns Hopkins University School of Medicine.


The study appears in the June 27 issue of Science Translational Medicine.


This study was supported by grants from the National Institute on Drug Abuse and the Medical Research Service of the U.S. Department of Veterans Affairs.

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