Hypothalamic neurons that produce hypocretin neuropeptides (also known as orexins) are involved in pleasure-associated arousal and have thus been hypothesized to have a role in opioid addiction. In narcolepsy, a disorder characterized by chronic sleepiness and cataplexy (sudden-onset sleep), ~90% of hypocretin cells are selectively lost. By studying post-mortem human brains and mouse models, Thannickal et al. now identify a striking connection between narcolepsy, opioid addiction and hypocretin cells.
In a previous study of post-mortem human brain samples, the authors identified a ‘control’ brain that exhibited 50% more hypocretin-expressing cells than in other controls. The authors learned that this individual was formerly addicted to heroin. In the present study, the authors confirmed this upregulation of hypocretin neurons in the brains of five individuals who had been addicted to heroin.
The authors treated mice with morphine to test whether it would induce similar changes. Morphine treatment over 14 days induced a 38% increase in hypocretin cells that persisted for weeks after cessation of morphine treatment. Immunolabelling for markers of newborn neurons indicated that the increase in hypocretin cell number was not due to neurogenesis, suggesting that opiates may induce hypocretin production in existing neurons. In addition, morphine injected into freely moving, naive rats increased the activity of recorded hypocretin neurons, suggesting that opiates promote hypocretin release.
Morphine treatment over 14 days induced a 38% increase in hypocretin cells
Next, the authors used a mouse model of narcolepsy in which temporary withdrawal of doxycyline (DOX) causes a selective ablation of hypocretin cells. DOX withdrawal for 1.5 days led to a 30% loss of hypocretin neurons, but subsequent morphine treatment for 14 days restored the number of hypocretin cells to control levels. Withdrawal of DOX treatment for 18 days led to a loss of 95% of hypocretin cells and symptoms of narcolepsy, including cataplexy; long-term treatment of these mice with morphine reduced cataplexy.
Last, the authors studied the post-mortem brains of two individuals diagnosed with narcolepsy. One of these individuals had 3% of the number of hypocretin cells found in control brains. By contrast, the other individual, who had received long-term opiate treatment for pain, showed 16% of the control number of these cells, and indeed had been re-diagnosed with idiopathic hypersomnia without cataplexy.
Together, these results imply that long-term use of opiate drugs may increase the number of hypothalamic hypocretin cells and might ameliorate certain symptoms of narcolepsy, such as cataplexy. These findings may also explain previous reports that people with narcolepsy are resistant to drug addiction, and could have implications for treating narcolepsy and opiate addiction.
Thannickal, T. C. et al. Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy. Sci. Transl Med. 10, eaao4953 (2018)
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Bray, N. A narcotic–narcoleptic link. Nat Rev Neurosci 19, 518 (2018). https://doi.org/10.1038/s41583-018-0043-y