Oct. 28, 2004 SAN DIEGO — Smokers often say that lighting up a cigarette can calm their nerves, satisfy their craving and help them relax.
Now, a team of University of Michigan scientists is reporting new evidence of why that might be: Smoking produces major changes in the flow of “feel good” chemicals between brain cells, both temporarily and long-term. And those changes in flow match up with changes in how smokers say they feel before and after smoking.
It's the first time smoking has been shown to affect the human brain's natural system of chemicals called endogenous opioids, which are known to play a role in quelling painful sensations, heightening positive emotions, and creating a sense of reward. It's the same system that is stimulated by heroin and morphine.
The research team, from the U-M Medical School, will present the results Tuesday afternoon in a lecture at the annual meeting of the Society for Neuroscience.
The new results come from a pilot study involving a small group of young male pack-a-day smokers and non-smoking comparison subjects. Despite their study's small size, the researchers say the surprisingly large effect on opioid levels they found suggests a promising road for further discovery. That may lead to better understanding of why smoking affects people the way it does — including the mystery of why it's often so hard to quit, despite tobacco's many health dangers.
“It appears that smokers have an altered opioid flow all the time, when compared with non-smokers, and that smoking a cigarette further alters that flow by 20 to 30 percent in regions of the brain important to emotions and craving,” says David J. Scott, a graduate student in the U-M Neuroscience Program who will present the results. “This change in flow as seen on a brain scan correlated with changes in how the smokers themselves reported feeling before and after smoking.”
Scott and his colleagues made the findings using a type of brain scanning called positron emission tomography, or PET, imaging. This allowed them to literally see activity in the endogenous opioid system when the study participants first smoked a special cigarette with almost no nicotine, and then smoked a regular cigarette. Before, during and after the scans, the participants rated how relaxed, alert, sick and nervous they felt, and how much they were craving tobacco.
The new findings confirm previous animal studies, and add to scientists' previous understanding of how smoking affects the flow of another “feel good” chemical in the brain, called dopamine. Now, the team is studying the interaction of dopamine and opioids in the brains of smokers and non-smokers.
They also hope to look at underlying genetic differences that might explain variations between people in response to nicotine — and perhaps differences in how easily people become addicted to cigarettes or quit smoking.
“The interaction of tobacco, and especially nicotine, with brain chemistry is a fascinating area that we're just beginning to understand, especially when it comes to correlating neurochemistry with behavior,” says study leader Jon-Kar Zubieta, M.D., Ph.D., a U-M psychiatrist and neuroscientist. “Just as with the ‘hard' drugs of abuse, such as heroin and cocaine, the phenomena of pleasure, addiction, increased tolerance and craving from tobacco are firmly rooted in neurochemistry.”
Adds veteran tobacco researcher and U-M emeritus pharmacology professor Ed Domino, Ph.D., “Nicotine addiction is one of the most destructive forces in human health, and we must increase our comprehension of it in order to defeat it. This study represents a key step toward that goal.”
Zubieta's team has spent several years developing and testing a way of using PET imaging to study the endogenous opioid system, and specifically the chemicals called endorphins and enkephalins.
Those are the same chemicals involved in the “runner's high”, a pleasurable sensation brought on by strenuous exercise. But they're also important to blocking the flow of painful signals in the brain, and the U-M team has used the PET method to study how opioid levels change in response to pain, and how that response is affected by variations in hormone levels and genetic makeup.
The U-M team's PET scan method doesn't show the flow of opioids directly, but rather the status of tiny receptors on the surface of brain cells. These receptors, called mu-opioid receptors, act like locks that can only be opened when opioid molecules — either made by the brain or introduced from outside — bind to them. Morphine, heroin and some anesthetics produce their respective effects by binding to these receptors, and the drug-overdose treatment called Narcan blocks them.
The lower the level of natural opioids around, the more receptors there are available to other opioids — such as a special molecule developed by the U-M team. It's made of a short-lived radioactive carbon atom attached to a molecule of carfentanil, a morphine-like drug known to bind only to mu-opioid receptors. Using the PET scanner, the team can detect how much carfentanil is binding, and by extension how much natural opioid is flowing in that area.
In order to study the effect of nicotine on the opioid system, the team had to find a way to perform their study in the U-M PET scanner despite the strict no-smoking policy of the U-M's Hospitals and Health Centers. They also had to simulate every aspect of smoking except the nicotine, in order to control for all the other chemicals in tobacco smoke and sensory aspects of cigarette smoking.
So, they rigged up a system that allowed a person to smoke a cigarette while lying in the PET scanner having his or her brain scanned, and collected the smoke to vent it to the outdoors. They obtained special cigarettes from the Phillip Morris Research Center in Richmond, VA that had been treated to remove nearly all the nicotine. And they recruited six male smokers in their 20s who reported smoking more than 14 cigarettes each day.
They asked the participants to refrain from smoking for at least 12 hours before coming in for their scans, and tested their breath to make sure they hadn't cheated. The researchers injected the participants with the radioactive tracer form of carfentanil, and started the 90-minute PET scan. Then, they asked participants to rate their feelings on a sliding scale before lighting up a series of two de-nicotinized cigarettes, again between cigarettes, and again after two normal cigarettes.
At baseline, the smokers shower lower receptor levels before smoking. “This may suggest that continued exposure to nicotine had increased the neurotransmitter levels, that are being released under baseline conditions, for example after overnight abstinence from smoking,” says Scott. “We are specifically examining this possibility in ongoing studies.”
During the smoking of the de-nicotinized cigarettes, the smokers' brains started to show changes in opioid flow. But after they took a 20-minute break from smoking and then smoked regular cigarettes containing nicotine, the opioid levels changed dramatically.
In the area of the brain called the anterior cingulate, which is involved in emotion and emotion-memory integration, the activity of the opioid system increased by about 20 percent. This meant that far more endorphins and enkephalins were being released during smoking.
But the reverse was true in other key parts of the brain involved in memory, emotion and pleasure: the amygdala, the thalamus and the nucleus accumbens. In all three areas, the opioid system was 20 to 30 percent less active after the nicotine from the cigarettes was introduced.
This sharp drop in activity, most significantly in the amygdala and the thalamus, correlated with simultaneous reports from the smokers about how they were feeling after they smoked the normal cigarettes. As the opioid activity in their amygdala and thalamus decreased, they reported feeling more relaxed, less alert and nervous, and less craving than before.
Since smoking stimulates the release of dopamine in some of the same areas of the brain, Zubieta and his colleagues speculate that the connection between the opioid system and the dopamine system may be an important one to study.
As the research goes forward, the team will be analyzing brain scans, self-reported ratings and genetic samples from more smokers and non-smokers, to give them a better picture of the interaction between nicotine, the opioid system, behavior and inherited traits.
But for the moment, simply having shown that nicotine has an impact on the crucial “feel good” system is reward enough.
The research was funded by the National Institute on Drug Abuse, part of the National Institutes of Health. In addition to Scott, Zubieta and Domino, the research team included Lisong Ni, Ph.D., a research associate in Pharmacology, and Mary Heitzeg, Ph.D., a research fellow in the Department of Psychiatry and U-M Addiction Research Center. Zubieta is a member of the U-M Mental Health Research Institute, and a director of the U-M Depression Center.
U-M reseachers have also studied how the brain's opioid system responds to pain, and how differences in hormone levels and genes may help explain why some people can tolerate more pain than others. For more on this research, see press release Can't stand the pain? Your genes may be to blame or Pain and the brain.
For more information on how the U-M team developed and first tested their approach for making brain scan images that reveal the activity of the opioid system, see: http://www.med.umich.edu/opm/newspage/2001/brainpain.htm.
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