Removing brain cells associated with wakefulness and addiction can reduce symptoms of opioid withdrawal

UCLA RESEARCH ALERT – January 12, 2022


A study in mice led by UCLA researchers shows that removing chemical messengers in the brain that are involved in both wakefulness and addiction can facilitate withdrawal from opioids and prevent relapse.


In 2000, UCLA sleep researchers discovered that human narcolepsy – a condition that overwhelms people with daytime sleepiness and sudden fits of sleep – was caused by a loss of about 90% of the 80,000 brain cells that contain hypocretin (also called orexin) Chemical messenger important in regulating sleep and wakefulness. Typically, people with narcolepsy are treated with drugs that would be highly addicting for most people, but interestingly, these patients themselves show little sign of drug addiction or withdrawal.

The lack of hypocretin-producing neurons and addiction seen in narcolepsy took a different turn when researchers almost two decades later made the surprising discovery that the brains of people addicted to heroin (a commonly abused opioid) have, on average, 54% more hypocretin-producing neurons than people who do not have substance abuse disorder – and confirmed the same finding in mice. However, when they stopped the opioid treatment in the mice, they found that the rise in hypocretin continued and lasted for up to four weeks.

This finding suggested that persistently elevated levels of hypocretin may play a role in drug craving, and also sheds light on why narcoleptic patients with very few of these hypocretin-producing neurons show little, if any, signs of addiction.

Although human studies are needed to confirm these results, taken together they suggest that developing drugs that target the hypocretinic system may help treat addiction.


In this new study, UCLA researchers found that increasing the number of hypocretin-producing neurons in mice with opioids resulted in increases in hypocretin levels in the locus coeruleus (LC), an area of ​​the brain known to that it plays an important role in regulating opioid withdrawal symptoms.

In addition, they found that the increased levels of hypocretin present in the LC were directly involved in increasing the level of an enzyme called tyrosine hydroxylase (TH), which is used to make norepinephrine (NE), a naturally occurring neurochemical in the body Body who is responsible. Neurons in the LC produce NE and distribute it to other parts of the brain, where it stimulates functions such as arousal, alertness, attention, or a “fight or flight” stress response.

When opioids are stopped, the activity of the LC increases sharply, releasing more NE, which is widely believed to play a major role in opioid withdrawal symptoms. Therefore, the researchers hypothesized that removing hypocretin-producing neurons would reduce withdrawal symptoms in the mice. Their results confirmed this hypothesis and showed that the lack of hypocretin-producing neurons reduced both the physical and emotional symptoms of opioid withdrawal and stopped the rise in TH levels in the LC.


The reduction in withdrawal symptoms in mice lacking hypocretin-producing neurons suggests that drug therapies that regulate the production of hypocretin may be an effective treatment for opiate addiction and withdrawal.


The lead author is Jerome Siegel and the first author is Ronald McGregor, both of the Semel Institute for Neuroscience and Human Behavior and the Veterans Administration Greater Los Angeles Healthcare System. Other authors include Ming-Fung Wu of the Semel Institute and VA Greater Los Angeles; Brent Holmes of the Greater Los Angeles VA and the Department of Medicine at UCLA; Hoa Anh Lam from the Semel Institute and the Hatos Center for Neuropharmacology at UCLA; Nigel T. Maidment of the Semel Institute, UCLA’s Brain Research Institute, and the Hatos Center; Joseph Gera from VA Greater Los Angeles, Dept. of Medicine at UCLA, the Jonnson Comprehensive Cancer Center, and the Hatos Center; and Akihiro Yamanaka from the Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Japan.


The study appears in the January 12th issue of the Journal of Neuroscience.

Hypocretin / orexin interactions with norepinephrine contribute to opiate withdrawal syndrome in Ronald McGregor, Ming-Fung Wu, Brent Holmes, Hoa Anh Lam, Nigel T. Maidment, Joseph Gera, Akihiro Yamanaka and Jerome M. Siegel Journal of Neuroscience January 12, 2022 , 42 (2) 255-263; DOI:


This study was supported by the NIH / National Institute on Drug Abuse (DA-034748, DA-034748, AG-063090, UG3-TR-003148) and the Medical Research Service of the Department of Veterans Affairs (CA217820, I01BX002665).

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