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Immune receptors' primary purpose is to trigger the body's protective mechanisms into action to fight off disease. Now, an immune receptor in the brain has been found to stimulate the reward response to heroin and morphine that makes opioids addictive, researchers at the University of Colorado and University of Adelaide in Australia said. As a result, it may be possible to prevent dependence by blocking the immune receptor, while at the same time amplifying the medical benefits of such drugs for use as painkillers.
"It is fundamentally paradigm shifting," Linda Watkins, a professor in the University of Colorado's psychology and neuroscience department and study co-author, said in an email. "You can't find a way to solve the problem of addiction if you don't know there is a key missing player in all the models," she said.
The finding, published Wednesday in the Journal of Neuroscience, offers an alternative approach to tackling drug abuse, which the National Institute on Drug Abuse says costs $181 billion a year in the United States alone. Previous models of addiction were focused exclusively on the impulse-conducting neurons, overlooking the immune contribution, Watkins said.
Finding better approaches to treating and preventing addiction could curb a growing public health problem. There were 359,000 heroin-dependent people in the U.S. in 2010, 68 percent more than in 2002, according to a 2011 report by the Substance Abuse and Mental Health Services Administration.
Heroin, cocaine and other illicit drugs kill about 200,000 people globally each year, the United Nations Office on Drugs and Crime said in its 2012 World Drugs Report. An estimated 13 million to 21 million people use opiates, particularly heroin. Cocaine and opioid use may account for 0.7 percent of the global burden of disease, the World Health Organization estimated.
Studies by Watkins and colleagues in rats and mice identified a protein called toll-like receptor 4 (TLR4) as the key component of the immune signaling in drug reward. The researchers say they were able to block the receptor cells, which are found on glia, the brain's neuron-supporting white matter. The blocking agent is called plus-naloxone, a variant of Narcan, the Daiichi Sankyo Co. drug given to patients to counter opiate overdose.
"The most interesting thing about the study is the suggestion that the addition of plus-naloxone may increase the analgesic effect of the opioid while reducing its rewarding effects," said Wayne Hall, deputy director at the University of Queensland Centre for Clinical Research in Brisbane, Australia. Hall has studied addiction and treatment for about 20 years.
Patient studies combining plus-naloxone with drugs such as morphine to prevent opioid addiction may start in 18 months, said Mark Hutchinson, the first author of the paper and a researcher at the University of Adelaide in South Australia. Shutting down the immune pathway also has another beneficial effect: it improves the pain-relieving potential of opioids.
The researchers performed four experiments to test brain mechanisms and preference responses of rats and mice given various regimens of opioids, cocaine, and plus-naloxone as a TLR4 blocker. The authors found a heightened analgesic response from the painkillers remifentanil and oxycodone when it was given with plus-naloxone.
Heroin-dependent rats had their cravings suppressed when TLR4 was blocked, Watkins said, suggesting it could help prevent relapse to drug abuse. While the research, which was supported by the National Institutes of Health, focused on the potential to help injecting drug users and abusers of prescription painkillers, it may have broader application, Hutchinson said.
"If we try to give plus-naloxone to a mouse and try to get it drunk, it doesn't get drunk anymore," he said.
Drugs of abuse tap a reward system in the brain called dopamine. When they also bind with TLR4, they produce a cascade of inflammatory chemicals that amplify the dopamine response, Hutchinson said.
"It raises a lot of interesting questions about where plus-naloxone works and how it's doing that, because we really don't know that," said Mark Connor, professor of pharmacology at Macquarie University in Sydney, who wasn't involved in the research. It's possible plus-naloxone works elsewhere in the brain and changes preference behavior without necessarily blocking the addictive properties of opioids, he said.
'It's going to provoke a lot of debate in the opioid field," said Connor. "There are going to be people rushing to repeat these experiments.'"
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