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Published On May 27, 2015


The Cogs of Addiction

What role do brain mechanics play in opioid addiction?

Millions of patients are prescribed opioids for pain each year. Why can some of those people treat their pain safely and effectively for months, while others become addicted almost immediately?

After three decades of study, neuroscientists and genetic researchers have yet to find a definitive answer. “We have clues from genetic, epigenetic, behavioral and imaging studies, but still no conclusive answers,” says Christopher Evans, director of the Brain Research Institute at the University of California, Los Angeles.

The most promising leads come from genetic research. The American Society of Addiction Medicine estimates that genetic factors account for about half of the likelihood that someone will develop an addiction. Studies that look at patterns of substance use, abuse and dependence in pairs of human twins have provided some of the most compelling models of the interrelationship between genetic and environmental risks.

In such studies, researchers interview identical and fraternal twin pairs raised in common environments. If genes do play a role in drug abuse, researchers would expect to find that identical twins, who share the same genes, would exhibit more consistency in levels of abuse than would less genetically similar fraternal twins. And that is the case, to varying degrees. A Harvard study that looked at more than 3,000 twin pairs found a 54% likelihood that vulnerability for abusing opioids was due to genetic factors. Another study from the Medical College of Virginia, which included cocaine and other drugs as well as opiates, pegged that likelihood at 23%.

Researchers at the Stanford University School of Medicine also used twins to study how genetics might affect the particular way opioids affect a patient. Subjects were given alfentanil, an opioid commonly used in anesthesia. Genetic factors were found to account for more than 30% of the variability in common side effects that the sets of twins experienced, such as respiratory problems and nausea. Similar numbers experienced itchiness and mental impairment, though shared environmental, not just genetic, factors could also play a role in those side effects, researchers reported. “The study is a significant step in understanding individual variability in response to opioids,” says Martin Angst, a professor at the Stanford University Medical Center and one of the study’s principal investigators.

That could happen with the help of molecular genetics, which looks at how suspect genes operate in the body and might create specific biomarkers that a doctor could assess. Knowing a patient’s disposition toward painkillers might lead to better-informed decisions about opioid dosages and how many pills to prescribe.

But progress in identifying which genes are responsible for opioid addiction has been slow. At least several dozen may play a role—and not just in the brain’s or the nervous system’s immediate responses but also in other processes involved in both tolerance and withdrawal. “I’m very skeptical we’ll find one gene behind addiction, since addiction is a complex process that involves the psychological state of a person when they take the drug, their psychological and physiological responses to the drug and their responses once the drug has gone away,” says UCLA’s Evans.

But the genes that are implicated may eventually point toward the mu opioid receptor, a specific protein on nerve cells that is essential for the analgesic and rewarding effects of opiates. Evans and his colleagues have been working with mice bred not to have the gene for the mu opioid receptor. When given morphine, these mice don’t show pain-relieving effects and don’t exhibit the positive reward behaviors that would be expected to be elicited by the drug. This suggests, Evans says, that the mu opioid receptor mediates both the therapeutic as well as the addictive effects of opioid medications.

But the mu receptor is far from being a simple on/off switch, says Evans. “Mu opioid receptor activation modifies many circuits in the brain. These modifications can last milliseconds to months, perhaps even years,” he explains. Evans’ colleagues are currently inserting mu opioid receptors into specific brain cells and circuits in mice and testing what happens when morphine reaches those cells. “One goal is to identify new therapy targets, but we also want to better understand the whole process of what opioids do in what cell types and which circuits,” he adds.

The hardships of addiction lend such efforts a grim urgency. There are few complex brain diseases that carry such personal and social costs, disrupting lives and leading to self-abusive and even criminal behavior. Knowing the mechanics of addiction may go a long way in removing social stigma and opening the door to transformative therapies.