- The body's endogenous opioid system has three classes of opioid receptors: mu, delta, and kappa.
- Previous research showed that mice lacking the mu opioid receptor do not drink alcohol.
- A new study shows that mice lacking the delta opioid receptor drink more alcohol.
- The delta opioid receptor may also play a mediating role between stress and alcohol consumption.
The body's endogenous opioid system has traditionally been linked with peptides such as enkephalins and endorphins, which influence the brain's reward pathway to act as the body's natural response to pain. A study in the September issue of Alcoholism: Clinical & Experimental Research has found that the endogenous opioid system may also be important for the reinforcing properties of alcohol. Researchers discovered that "knocking out" the delta opioid receptor led to an increased state of anxiety as well as an increase in drinking.
"There are three classes of opioid receptor currently recognized," said Amanda J. Roberts, assistant professor of neuropharmacology at The Scripps Research Institute and lead author of the study. "They are the mu, delta, and kappa receptors. We had previously shown that mice lacking the mu opioid receptor do not drink alcohol under several different experimental conditions." For the current study, Roberts and her colleagues used mice produced by co-author Brigitte L. Kieffer in France that had been genetically modified by having their delta receptor "knocked out."
"After becoming familiar with alcohol, mice lacking the delta receptor consumed more alcohol than their genetically intact counterparts (wild type mice) did," said Roberts, "suggesting that a decrease in delta receptor activity is associated with an increase in alcohol drinking behavior. This is a surprising finding as it suggests that, at least under certain conditions, the mu and delta receptors may act in an opposing manner to regulate alcohol consumption."
In addition to the endogenous opioid system's influence on the brain's reward pathway, it also plays an important role in the body's stress response. Alcohol researchers believe that stress and anxiety are important components of alcohol consumption. In fact, stress reduction is one of the most commonly reported psychosocial benefits of drinking alcohol. Another finding of Roberts' study supports a potential link among the endogenous opioid system, stress and alcohol consumption. The delta receptor knockout (KO) mice in this experiment exhibited increased anxiety prior to drinking and, in fact, seemed to use alcohol for its anxiolytic or calming effects.
"This suggests that the delta receptor," said Roberts, "while perhaps being important in directly modulating the activity of the brain's reward pathway, also may be a key player in mediating the link between stress and alcohol consumption."
According to Tamara Phillips, professor of behavioral neuroscience at Oregon Health & Science University and the Portland VA Medical Center, the study's findings also have ramifications for those alcoholism treatment strategies that utilize opiate antagonists. Opiates are drugs derived from opium - like heroin and morphine - that act like chemicals the brain produces naturally, called endogenous (from within) opioids, which stimulate pleasurable feelings and suppress pain. Medications known as opiate antagonists bind with the brain's receptors for endogenous opioids, thus blocking the desired effects of heroin and similar drugs while having no effect themselves. Although alcohol is not an opiate-like substance, opiate antagonists like naltrexone seem to block some of alcohol's rewarding effects.
"Drugs of abuse like alcohol," explained Phillips, "appear to activate some of the same brain neurochemical pathways as those activated by natural rewards such as food, water, sweets and sex. A key neurochemical is dopamine. Dopamine pathways play a well-documented role in alcohol reward and reinforcement. Opioids are known to moderate the activity of dopamine pathways, and it is possible that alcohol addiction is partly associated with alterations in opiate receptor-mediated processes. Animal and human studies documenting reductions in alcohol consumption by treatment with naltrexone, an opiate receptor antagonist drug, ultimately led to its clinical utilization for the treatment of alcoholism." Phillips added that although naltrexone is widely used in conjunction with clinical counseling, its success has been limited.
"Because this drug influences all three of the known opioid receptor subtypes, mu, delta and kappa," she said, "a worthwhile endeavor is to examine the specific roles that each of the opiate receptor subtypes might play in alcohol addiction. Naltrexone has a greater tendency to interact with mu than with delta and kappa opiate receptors. It is possible that its success in alcoholism treatment is associated with its relative affinities for these receptor subtypes, and that a better treatment agent could be developed. This study, for example, shows the importance of the delta receptor in influencing voluntary alcohol consumption."
Roberts and her colleagues plan to continue with their examination of the endogenous opioid system. They will more closely examine the brain regions and pathways responsible for the role of the mu and delta opioid receptors in alcohol's rewarding effects, as well as what role(s) the endogenous opioid system may play in addiction and relapse.
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Lisa H. Gold of Neurobiology, Pharmacia Corporation in Kalamazoo, MI; Ilham Polis, Jeffrey S. McDonald, and George F. Koob of the Department of Neuropharmacology at The Scripps Research Institute; and Dominique Filliol and Brigitte L. Kieffer of ESBS Université Louis Pasteur in Strasbourg, France. The study was funded by the National Institute on Alcohol Abuse and Alcoholism, and by the Mission Interministerielle de Lutte contre la Drogue at la Toxicomanie at the Centre National de la Recherche Scientifique in France.