Research ArticleAddiction

Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy

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Science Translational Medicine  27 Jun 2018:
Vol. 10, Issue 447, eaao4953
DOI: 10.1126/scitranslmed.aao4953

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Opiate addiction and narcolepsy: Opposite sides of the same coin?

The neurological mechanisms that maintain opiate addiction and prevent long-term withdrawal are not well understood. In a new study, Thannickal et al. found that human heroin addicts have, on average, 54% more hypocretin-producing neurons than do neurologically normal control individuals. They show that a similar increase in hypocretin-producing neurons could be induced in mice through long-term morphine administration. This long-lasting increase in hypocretin neurons may be responsible for maintaining addiction. Narcolepsy is caused by a loss of hypocretin-producing neurons. Morphine administration restored the population of hypocretin neurons in hypocretin cell–depleted mice back to normal numbers and decreased cataplexy in narcoleptic animals. Induction of specific long-term changes in neuropeptide production, outlasting the half-life of the administered drugs, may be useful in treating diseases characterized by loss of neurons producing these neuropeptides.

Abstract

The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.

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