Category: Opium

The peak risk for misusing prescription pain relievers occurs in mid-adolescence, specifically about 16 years old and earlier than many experts thought, according to a new study by Michigan State University researchers.

The results, based on recent nationwide surveys of nearly 120,000 U.S. adolescents, suggest prevention programs may need to be introduced earlier, in childhood and early adolescence, said James C. Anthony of MSU's Department of Epidemiology and Biostatistics.

Recent trends show clinicians and public health professionals are prescribing more pain relievers, and research suggests an increased misuse of these drugs and increased rates of overdose deaths, said Anthony, who supervised the research of postdoctoral fellow Elizabeth Meier and graduate student Jonathan Troost.

"While much of the previous thinking was that misuse of these drugs emerged in the final year of high school and during the college-age years, we found that for adolescents the peak risk of starting to misuse these painkillers generally occurs earlier, not during the postsecondary school years," Anthony said. "We suspect many physicians, other prescribing clinicians and public health professionals, will share our surprise in this finding."

The study, supported by grants from the National Institute on Drug Abuse and MSU, was published in the Archives of Pediatrics & Adolescent Medicine, a network publication of the Journal of the American Medical Association.

The team of researchers analyzed data from the 2004 through 2008 National Surveys on Drug Use and Health to identify when young people are most likely to start using prescription pain relievers to get high or for other unapproved uses. The results show about 1 in 60 young people between 12 and 21 years old starts using prescription pain relievers each year, outside the boundaries of what a prescriber has intended.

Peak risk is concentrated at about 16 years, when roughly 1 in 30 to 40 youth start to use painkillers to get high, or for other reasons not intended by the prescriber.

"Getting a firm grasp of when the first onset occurs is very important when we try to take public health action to prevent first occurrence," Anthony said. "With the peak risk at age 16 years and a notable acceleration in risk between ages 13 and 14 years, any strict focus on college students or 12th graders might be an example of too little too late."

The results reveal a need to strengthen prescribing guidelines for clinicians and introduce early school-based prevention programs such as effective school-based alcohol and tobacco initiatives, he said.

Other types of prevention programs include peer-resistance programs such as the popular "Just Say No" campaigns. There also is an opportunity to work with pharmaceutical specialists who sometimes can reformulate these drugs so their effects are blunted when misused.

As for clinicians with a public health perspective, Anthony said that non-opioid pain relievers such as ibuprofen can be quite effective, and that when opioid pain killers are prescribed for adolescents or in reach of teens, the number of tablets can be limited or kept under lock and key.

"Patients in transient pain are often given a larger opioid prescription than is needed. It can end up stacked in the medicine cabinet, available to anyone in or visiting the household," he said.

— Scientists have for the first time determined the three-dimensional atomic structure of a human opioid receptor, a molecule on the surface of brain cells that binds to opioids and is centrally involved in pleasure, pain, addiction, depression, psychosis, and related conditions. Dozens of legal and illegal drugs, from heroin to hospital anesthetics, work by targeting these receptors. The detailed atomic structure information paves the way for the design of safer and more effective opioid drugs.

"This finding is going to have a major impact on understanding the fundamental principles of opioid receptor recognition and evolution," said Raymond Stevens, PhD, a professor at The Scripps Research Institute. Stevens is the senior author of the new study, which appears online in the journal Nature on March 21, 2012.

A Symphony of Activity

Opioid receptor subtypes in the human brain work together in a symphony of activity that is still not fully understood. The "mu" opioid receptors mediate feelings of pleasure and pain-relief; they are the prime targets of the body's own endorphin neurotransmitters as well as heroin, morphine, and most other opioid drugs. By contrast, "kappa" opioid receptors are bound by neurotransmitters known as dynorphins, and when activated can depress mood and produce dissociative, psychedelic experiences. The plant Salvia divinorum, which was originally cultivated by Mesoamerican societies for religious ceremonies and is now used widely as a recreational drug, has an active ingredient, Salvinorin A, that binds selectively and with high affinity to kappa opioid receptors.

"We don't know why kappa receptors evolved, but we know that they have been around for a long time in evolutionary terms; even frogs have them," said Bryan Roth, a professor of pharmacology and an opioid receptor expert at the University of North Carolina, whose group teamed with the Stevens lab for the new study.

If their psychedelic and mood-darkening effects could be avoided somehow, kappa opioid receptor activators, or "agonists," could be very useful medically. In animal studies, they act as mild and non-addicting pain-relievers, weaken the addictive effects of other drugs, and reduce irritable bowel signs. "Antagonist" compounds that block kappa opioid receptor activity also show promise as treatments for depression, anxiety, and other psychiatric conditions. Even the psychedelic effects associated with kappa receptor activation could be useful in providing insights into perception and consciousness. "This is a receptor that is important for how we see reality," said Roth.

In Pursuit of Missing Information

Not knowing the structural details of the kappa opioid receptor has made it hard for scientists to understand how the receptor works naturally and to design drugs that target it in the right ways. There are currently no FDA-approved drugs that bind selectively to kappa opioid receptors, either as agonists or antagonists.

To get these structural details, Scripps Research graduate student Huixian Wu, who was first author of the paper, first produced kappa opioid receptors in insect cells and used special techniques to keep the fragile receptor molecules stable in a single conformation. Working with Scripps Research Assistant Professor Vadim Cherezov, PhD, Wu was then able to crystallize and collect x-ray data that eventually led to the structure. An essential part of this stabilizing process involved the attachment of a suitable "ligand," a pharmacological molecule that binds the receptor tightly. "We tried a lot of different ligands, and Bryan suggested that we try JDTic, an experimental kappa opioid receptor antagonist," said Stevens. "It worked well in stabilizing the receptor, and once we discovered that, everything else quickly fell into place."

By X-raying such a crystallized protein complex from various angles, researchers can calculate a detailed three-dimensional model of its atomic structure. In this case, the X-ray data yielded a model with a resolution of about 2.9 angstroms, or 290 trillionths of a meter. The Stevens and Roth labs then designed and performed site-specific mutagenesis analyses in which they altered various residues of the receptor to better understand how its structure related to its function. Scripps Research Assistant Professor Seva Katrich, PhD, together with colleagues at Research Triangle Institute and Virginia Commonwealth University, then performed molecular modeling and docking analyses to further the understanding of the receptor-ligand interactions.

"This receptor's binding pocket is much bigger and deeper than any other we've studied; that may explain why so many different types of ligands bind to this receptor. A lot of work remains, though, in understanding opioid selectivity. As with the other receptor structures, this is just the beginning and we will see follow up studies take the understanding even further," said Stevens. He and his colleagues used their structural model to learn new details about the kappa receptor binding characteristics of Salvinorin A plus an array of experimental drugs.

With the publication of the receptor structure, scientists and drug companies also will be able to use the data to improve existing kappa-targeting compounds and design entirely new ones. "I can tell you, from e-mails and other conversations I've had recently, that people in the pharma industry are very eager to see this structural data," said Roth.

The Power of Collaboration

The kappa opioid receptor structure is the latest product of two interlinked, National Institutes of Health (NIH)-funded networks of laboratories, both based at Scripps Research.

The Joint Center for Innovative Membrane Protein Technologies, supported by the NIH Common Fund, develops improved techniques for the expression, purification, and structural characterization of membrane proteins and then disseminates those technologies rapidly to the broad scientific community. The GPCR Network, part of the Protein Structure Initiative (PSI:Biology) supported by the NIH's National Institute of General Medical Sciences (NIGMS), uses those techniques to determine the structures of human G-Protein Coupled Receptors (GPCRs) in close collaboration with the scientific community. GPCRS are the largest family of cell receptors and the one that includes opioid receptors. Of the nearly 800 human GPCRs for which scientists hope to develop atomic structural models, the kappa opioid receptor is only the eleventh published so far, but that number is rapidly changing. Last month, the Stevens laboratory published the structure of the S1P1 lipid receptor and the NMR characterization of the beta 2 adrenergic receptor, both in the journal Science.

"PSI:Biology promotes collaborative research between structural scientists and biologists to address important biological problems," said Jean Chin, PhD, who helps oversee PSI:Biology at the NIGMS. "The determination of the human kappa-opioid receptor structure bound to a compound with potential therapeutic value may lead to the design of more effective pain killers and anti-addiction medicines, demonstrating the value of these collaborations."

In addition to NIGMS and the NIH Common Fund, the study was supported by the National Institute of Mental Health Psychoactive Drug Screening Program in Chapel Hill, North Carolina, the National Institute of Drug Abuse (NIDA), and the NIDA Drug Supply Program for supplying opioid ligands.

In addition to Stevens, Roth, Wu, Cherezov, and Katrich, authors of the paper, "Structure of the human kappa opioid receptor in complex with JDTic," included Daniel Wacker, Mauro Mileni, Gye Won Han, Wei Liu, and Aaron A. Thompson of Scripps Research; Eyal Vardy and Xi-Ping Huang of Roth's laboratory at UNC; F. Ivy Carroll and S. Wayne Mascarella at the Research Triangle Institute in Research Triangle Park, NC; and Richard B. Westkaemper and Philip D. Mosier of Virginia Commonwealth University.

Almost all non-human mammals eat placenta for good reasons. Are we missing something? A paper by neuroscientists at the University at Buffalo and Buffalo State College suggests that ingestion of components of afterbirth or placenta — placentophagia — may offer benefits to human mothers and perhaps to non-mothers and males.

They say this possibility does not warrant the wholesale ingestion of afterbirth, for some very good reasons, but that it deserves further study.

Mark Kristal, PhD, professor of psychology and neuroscience at UB, directs the graduate program in behavioral neuroscience, and has studied placentophagia for more than 40 years. He is recognized as a principle expert in the field.

Kristal's article "Placentophagia in Human and Nonhuman Mammals: Causes and Consequences," will be published in the March 30 issue of the journal Ecology of Food and Nutrition, which will be devoted to the subject of placentophagia.

Kristal's co-authors are Jean M. DiPirro, PhD, associate professor, Department of Psychology, Buffalo State College, and Alexis C. Thompson, PhD, research associate professor, UB Department of Psychology and a research scientist in the UB Research Institute on Addictions.

They point out that the benefits of placenta ingestion (as well as the ingestion of amniotic fluid) by non-human mammalian mothers are significant. It provokes an increase in mother-infant interaction, for instance, and increases the effects of pregnancy-mediated analgesia in the delivering mother. It also potentiates opioid circuits in the maternal brain that facilitate the onset of caretaking behavior, and suppresses postpartum pseudopregnancy, thereby increasing the possibilities for fertilization.

"Human childbirth is fraught with additional problems for which there are no practical nonhuman animal models," says Kristal, citing postpartum depression, failure to bond and maternal hostility toward the infant.

He says ingested afterbirth may contain components that ameliorate these problems, but although there have been many anecdotal claims made for human placentophagia, the issue has not been tested empirically.

"If such studies are undertaken," he says, "the results, if positive, will be medically relevant. If the results are negative, speculations and recommendations will persist, as it is not possible to prove the negative."

Kristal says there is a current fad of ingesting encapsulated placenta, which mirrors unverified reports in the 1960s and 1970s of people in back-to-nature communes cooking and eating human placentas. The upsurge in recent anecdotal reports of the benefits of taking placenta by new mothers, irrespective of dose, method of preparation, or time course, suggests more of a placebo effect than a medicinal effect.

"People will do anything," Kristal says, "but we shouldn't read too much significance into reports of such exceptions, even if they are accurate, because they are neither reliable nor valid studies. My own studies found no evidence of the routine practice of placentophagia in other cultures, findings supported by a recent extensive study by anthropologists at the University of Nevada, Las Vegas.

"The more challenging anthropological question is," he says, "'Why don't humans engage in placentophagia as a biological imperative as so many other mammals apparently do?' because we clearly do not do this as a matter of course today and apparently never have. Perhaps for humans, there is a greater adaptive advantage to not eating the placenta." The paper discusses some possibilities in this regard.

"Whether or not we learn why humans do not do this, it is important for us to search for the medicinal or behavioral benefits of components of afterbirth for the same reasons that we search for plant-based medicinal substances," Kristal says.

"The outcome of such a quest need not be an exhortation for women to eat afterbirth, but for scientists to isolate and identify the molecule or molecules that produce the beneficial effect and use it to design pharmacological tools," he says.

He adds, "In the case of Placental Opioid-Enhancing Factor or POEF and enhanced opioid-mediated analgesia, for instance, we have determined through earlier studies that not only is the effect nonspecific in regard to species, but it is also nonspecific in regard to sex.

"That means that although males, who in all probability do not make the molecule, have the ability to respond to it," Kristal says.

An international team of researchers involving the University of Adelaide has made a major discovery that could lead to more effective treatment of severe pain using morphine.

Morphine is an extremely important drug for pain relief, but it can lead to a range of side-effects — such as patients developing tolerance to morphine and increased sensitivity to pain. Until now, how this occurs has remained a mystery.

The team from the University of Colorado and University of Adelaide has shown for the first time how opioid drugs, such as morphine, create an inflammatory response in the brain — by activating an immune receptor in the brain.

They have also demonstrated how this brain immune receptor can be blocked, laying the groundwork for the development of new therapeutic drugs that improve the effectiveness of morphine while reducing many of its problematic side effects.

The results of this research are published April 2 in the Proceedings of the National Academy of Sciences (PNAS).

"Because morphine is considered to be such an important drug in the management of moderate to severe pain in patients right around the world, we believe these results will have far-reaching benefits," says study co-author Dr Mark Hutchinson, ARC Research Fellow in the University of Adelaide's School of Medical Sciences.

Dr Hutchinson's team, including University of Adelaide colleague Professor Andrew Somogyi, conducted studies in mice to validate the work done at the University of Colorado by the teams of Assistant Professor Hubert Yin and Professor Linda Watkins.

"For some time it's been assumed that the inflammatory response from morphine was being caused via the classical opioid receptors," says Dr Hutchinson.

"However, we found instead that morphine binds to an immune receptor complex called toll-like receptor 4 (TLR4), and importantly this occurs in a very similar way to how this receptor detects bacteria.

"Our experiments in mice have shown that if this relationship with the immune receptor is disrupted, it will prevent the inflammatory response.

"This is an exciting result because it opens up possibilities for future drugs that promote the beneficial actions of morphine while negating some of the harmful side effects. This could lead to major advances in patient and palliative care," he says.

 A team of researchers at the MedUni Vienna's Department of Neurophysiology (Centre for Brain Research) has discovered a previously unknown effect of opioids: the study, which has now been published in the journal Science and was led by Ruth Drdla-Schutting and Jürgen Sandkühler, shows that opioids not only temporarily relieve pain, but at the right dose can also erase memory traces of pain in the spinal cord and therefore eliminate a key cause of chronic pain.

The scientists recreated a surgical procedure in vivo in which pain fibres were stimulated under controlled conditions.

Says Sandkühler: "Although deep anaesthesia prevents any sensations of pain, we were able to reserve long-term synaptic potentiation in the spinal cord. Despite anaesthesia, there appears to be a memory trace for pain and a pain amplifier has engaged." High doses of intravenous opioids over the course of an hour — normally opioids are delivered at moderate doses over a longer period — were able to completely resolve the potentiation. Says Sandkühler: "The memory trace for pain was therefore deleted again and the pain amplifier switched off."

The memory trace, as it is termed, is triggered by a variety of mechanisms, including the potentiation of signal transmission at the contact points (synapses) between the nerve cells. This is known as long-term synaptic potentiation. This pain memory can result in the sensation of amplified pain lasting much longer than the actual cause of the pain, even leading to a condition known as chronic pain syndrome.

A paradigm shift in pain therapy?

The project, which is sponsored by the Vienna Fund for Science, Research and Technology (WWTF), is currently investigating how this discovery can be put to use in clinical settings. To this end, test subjects or patients with pain syndrome are being given a high dose of an opioid over a period of 60 minutes.

"If our approach turns out to be effective under clinical conditions, this would herald a paradigm shift in pain therapy. It would mean moving away from the temporary, purely symptom-based pain therapy to a long-term removal of the cause of pain based on pain mechanisms using opioids."

The effect of opioids (morphine or morphine-like substances) is based on their ability to bind to specific binding sites, known as µ-opiate receptors (MOR) which are found on nerve cells and which process pain-related information. Until now, it has been assumed that opioids are only able to alleviate pain while they are bound to the MOR and therefore suppress stimulation in the pain-processing system. Says Drdla-Schutting: "As soon as the medication is stopped, the pain-relieving effect disappears too." In clinical practice, opioids are therefore given continuously in moderate doses in order to achieve permanent binding to the MOR. This may relieve pain very effectively, but its cause cannot be eliminated. The new, high-dose, short-term therapy with opioids, on the other hand, causes a reversal of cellular changes that play an important role in pain memories, therefore possibly eliminating one of the causes of chronic pain.

Journal Reference:

1. R. Drdla-Schutting, J. Benrath, G. Wunderbaldinger, J. Sandkuhler. Erasure of a Spinal Memory Trace of Pain by a Brief, High-Dose Opioid Administration. Science, 2012; 335 (6065): 235 DOI: 10.1126/science.1211726

— Drinking alcohol leads to the release of endorphins in areas of the brain that produce feelings of pleasure and reward, according to a study led by researchers at the Ernest Gallo Clinic and Research Center at the University of California, San Francisco (UCSF).

The finding marks the first time that endorphin release in the nucleus accumbens and orbitofrontal cortex in response to alcohol consumption has been directly observed in humans.

Endorphins are small proteins with opiate-like effects that are produced naturally in the brain.

"This is something that we've speculated about for 30 years, based on animal studies, but haven't observed in humans until now," said lead author Jennifer Mitchell, PhD, clinical project director at the Gallo Center and an adjunct assistant professor of neurology at UCSF. "It provides the first direct evidence of how alcohol makes people feel good."

The discovery of the precise locations in the brain where endorphins are released provides a possible target for the development of more effective drugs for the treatment of alcohol abuse, said senior author Howard L. Fields, MD, PhD, a professor of neurology and Endowed Chair in Pharmacology of Addiction in Neurology at UCSF and director of human clinical research at the Gallo Center.

The study appears on January 11, 2012, in Science Translational Medicine.

The researchers used positron emission tomography, or PET imaging, to observe the immediate effects of alcohol in the brains of 13 heavy drinkers and 12 matched "control" subjects who were not heavy drinkers.

In all of the subjects, alcohol intake led to a release of endorphins. And, in all of the subjects, the more endorphins released in the nucleus accumbens, the greater the feelings of pleasure reported by each drinker.

In addition, the more endorphins released in the orbitofrontal cortex, the greater the feelings of intoxication in the heavy drinkers, but not in the control subjects.

"This indicates that the brains of heavy or problem drinkers are changed in a way that makes them more likely to find alcohol pleasant, and may be a clue to how problem drinking develops in the first place," said Mitchell. "That greater feeling of reward might cause them to drink too much."

Results Suggest Possible Approach to Treat Alcohol Abuse

Before drinking, the subjects were given injections of radioactively tagged carfentanil, an opiate-like drug that selectively binds to sites in the brain called opioid receptors, where endorphins also bind. As the radioactive carfentanil was bound and emitted radiation, the receptor sites "lit up" on PET imaging, allowing the researchers to map their exact locations.

The subjects were then each given a drink of alcohol, followed by a second injection of radioactive carfentanil, and scanned again with PET imaging. As the natural endorphins released by drinking were bound to the opioid receptor sites, they prevented the carfentanil from being bound. By comparing areas of radioactivity in the first and second PET images, the researchers were able to map the exact locations — areas of lower radioactivity — where endorphins were released in response to drinking.

The researchers found that endorphins released in response to drinking bind to a specific type of opioid receptor, the Mu receptor.

This result suggests a possible approach to improving the efficacy of treatment for alcohol abuse through the design of better medications than naltrexone, said Fields, who collaborated with Mitchell in the design and analysis of the study.

Fields explained that naltrexone, which prevents binding at opioid receptor sites, is not widely accepted as a treatment for alcohol dependence — "not because it isn't effective at reducing drinking, but because some people stop taking it because they don't like the way it makes them feel," he said.

"Naltrexone blocks more than one opioid receptor, and we need to know which blocking action reduces drinking and which causes the unwanted side effects," he said. "If we better understand how endorphins control drinking, we will have a better chance of creating more targeted therapies for substance addiction. This paper is a significant step in that direction because it specifically implicates the Mu opioid receptor in alcohol reward in humans."

Co-authors of the study are James P. O'Neill and Mustafa Janabi of Lawrence Berkeley Laboratory and Shawn M. Marks and William J. Jagust, MD, of LBL and the University of California, Berkeley.

The study was supported by funds from the Department of Defense and by State of California Funds for Research on Drug and Alcohol Abuse.

Journal Reference:

1. J. M. Mitchell, J. P. O'Neil, M. Janabi, S. M. Marks, W. J. Jagust, H. L. Fields. Alcohol Consumption Induces Endogenous Opioid Release in the Human Orbitofrontal Cortex and Nucleus Accumbens. Science Translational Medicine, 2012; 4 (116): 116ra6 DOI: 10.1126/scitranslmed.3002902

Drinking alcohol leads to the release of endorphins in areas of the brain that produce feelings of pleasure and reward, according to a study led by researchers at the Ernest Gallo Clinic and Research Center at the University of California, San Francisco (UCSF).

The finding marks the first time that endorphin release in the nucleus accumbens and orbitofrontal cortex in response to alcohol consumption has been directly observed in humans.

Endorphins are small proteins with opiate-like effects that are produced naturally in the brain.

"This is something that we've speculated about for 30 years, based on animal studies, but haven't observed in humans until now," said lead author Jennifer Mitchell, PhD, clinical project director at the Gallo Center and an adjunct assistant professor of neurology at UCSF. "It provides the first direct evidence of how alcohol makes people feel good."

The discovery of the precise locations in the brain where endorphins are released provides a possible target for the development of more effective drugs for the treatment of alcohol abuse, said senior author Howard L. Fields, MD, PhD, a professor of neurology and Endowed Chair in Pharmacology of Addiction in Neurology at UCSF and director of human clinical research at the Gallo Center.

The study appears on January 11, 2012, in Science Translational Medicine.

The researchers used positron emission tomography, or PET imaging, to observe the immediate effects of alcohol in the brains of 13 heavy drinkers and 12 matched "control" subjects who were not heavy drinkers.

In all of the subjects, alcohol intake led to a release of endorphins. And, in all of the subjects, the more endorphins released in the nucleus accumbens, the greater the feelings of pleasure reported by each drinker.

In addition, the more endorphins released in the orbitofrontal cortex, the greater the feelings of intoxication in the heavy drinkers, but not in the control subjects.

"This indicates that the brains of heavy or problem drinkers are changed in a way that makes them more likely to find alcohol pleasant, and may be a clue to how problem drinking develops in the first place," said Mitchell. "That greater feeling of reward might cause them to drink too much."

Results Suggest Possible Approach to Treat Alcohol Abuse

Before drinking, the subjects were given injections of radioactively tagged carfentanil, an opiate-like drug that selectively binds to sites in the brain called opioid receptors, where endorphins also bind. As the radioactive carfentanil was bound and emitted radiation, the receptor sites "lit up" on PET imaging, allowing the researchers to map their exact locations.

The subjects were then each given a drink of alcohol, followed by a second injection of radioactive carfentanil, and scanned again with PET imaging. As the natural endorphins released by drinking were bound to the opioid receptor sites, they prevented the carfentanil from being bound. By comparing areas of radioactivity in the first and second PET images, the researchers were able to map the exact locations — areas of lower radioactivity — where endorphins were released in response to drinking.

The researchers found that endorphins released in response to drinking bind to a specific type of opioid receptor, the Mu receptor.

This result suggests a possible approach to improving the efficacy of treatment for alcohol abuse through the design of better medications than naltrexone, said Fields, who collaborated with Mitchell in the design and analysis of the study.

Fields explained that naltrexone, which prevents binding at opioid receptor sites, is not widely accepted as a treatment for alcohol dependence — "not because it isn't effective at reducing drinking, but because some people stop taking it because they don't like the way it makes them feel," he said.

"Naltrexone blocks more than one opioid receptor, and we need to know which blocking action reduces drinking and which causes the unwanted side effects," he said. "If we better understand how endorphins control drinking, we will have a better chance of creating more targeted therapies for substance addiction. This paper is a significant step in that direction because it specifically implicates the Mu opioid receptor in alcohol reward in humans."

Co-authors of the study are James P. O'Neill and Mustafa Janabi of Lawrence Berkeley Laboratory and Shawn M. Marks and William J. Jagust, MD, of LBL and the University of California, Berkeley.

The study was supported by funds from the Department of Defense and by State of California Funds for Research on Drug and Alcohol Abuse.

Journal Reference:

1. J. M. Mitchell, J. P. O'Neil, M. Janabi, S. M. Marks, W. J. Jagust, H. L. Fields. Alcohol Consumption Induces Endogenous Opioid Release in the Human Orbitofrontal Cortex and Nucleus Accumbens. Science Translational Medicine, 2012; 4 (116): 116ra6 DOI: 10.1126/scitranslmed.3002902

NewsPsychology (Dec. 7, 2011) — An attentive, nurturing mother may be able to help her children better resist the temptations of drug use later in life, according to a study in rats conducted by Duke University and the University of Adelaide in Australia.

A rat mother’s attention in early childhood actually changes the immune response in the brains of her pups by permanently altering genetic activity, according to Staci Bilbo, an assistant professor of psychology and neuroscience at Duke, who led the research. High-touch mothering increased the brain’s production of an immune system molecule called Interleukin-10, leaving these rats better able to resist the temptation of a dose of morphine much later in life.

This is the first study to show how morphine causes a molecular response in the glial cells of the brain’s reward centers, which had only recently been identified as part of drug addiction’s circuitry. “We set out to find out what that response looks like,” Bilbo said.

To program some of the rat pups to produce more IL-10, the researchers used an established technique called the “handling paradigm,” in which very young rat pups are removed from their mother’s cage for 15 minutes and then returned. “As soon as they’re returned, she checks them out vigorously,” grooming the pups and cleaning them, Bilbo said. For a control group, another set of pups were never removed. Some of them had more attentive mothers than others, just by natural variation.

The animals then were put through a test called the “place preference chamber,” a two-roomed cage in which they would be given a dose of morphine if they entered one side, or a dose of saline on the other. Over the next four weeks, the rats were returned to the two-sided chamber three times a week for five minutes, but were never given another dose of morphine. Initially, they all showed a preference for the morphine side, but over time, the handled rats showed little preference, which indicated their craving had been “extinguished,” Bilbo said.

About 8 weeks after their first exposure to morphine, the animals were each given a very small dose of morphine to prime craving and then returned to the 2-sided chamber. The non-handled control rats preferred spending time in the morphine chamber; the handled rats still showed no clear preference.

Morphine activates the glial cells of the brain to produce inflammatory molecules which signal a reward center of the brain called the nucleus accumbens. But IL-10 works against that inflammation and reward. The more IL-10 the brain produces, the less likely morphine would cause an increase in craving or relapse weeks after the initial experience with the drug.

The brains of the rat pups who experienced high-touch mothering were found to have more active genes for producing IL-10 in the microglial cells of the brain, which apparently “completely knocked out this drug-seeking behavior,” Bilbo said. They were producing about four times as much IL-10 as the control animals. “The nurturing moms can profoundly change outcomes,” Bilbo said.

This is a change not of the genes themselves, but of the way they are controlled by something called methylation, which can keep a gene’s activity suppressed. High-touch mothering removed methylation on the IL-10 gene, making these rats produce more of the anti-inflammatory molecule.

To further prove that IL-10 levels were key to the craving, the researchers used a drug called ibudilast to artificially increase IL-10 production in a group of control rats. These rats experience craving extinction much the same as the high-touch rats.

“Two exciting things have been uncovered by this groundbreaking research,” said coauthor Mark Hutchinson, a research fellow at the University of Adelaide. “One, we have proven a mother’s touch changes brain function and two, we have demonstrated an exciting way to intervene in the cycle of drug abuse.”

It’s important to note that the genetic modification created by the mothering didn’t change the initial rewarding effect of the morphine, it altered the craving for that reward much later, Bilbo said.

Bilbo said her team next wants to look at the long-term effects of maternal stress on the brain’s immune response. They’ll be working with the Children’s Environmental Health Initiative at Duke, which examines real-world environmental health effects in Durham, NC in collaboration with the US Environmental Protection Agency.

Recommend this story on Facebook, Twitter,
and Google +1:

Other bookmarking and sharing tools:

Story Source:

The above story is reprinted from materials provided by Duke University.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

1. J. M. Schwarz, M. R. Hutchinson, S. D. Bilbo. Early-Life Experience Decreases Drug-Induced Reinstatement of Morphine CPP in Adulthood via Microglial-Specific Epigenetic Programming of Anti-Inflammatory IL-10 Expression. Journal of Neuroscience, 2011; 31 (49): 17835 DOI: 10.1523/JNEUROSCI.3297-11.2011

NewsPsychology (Sep. 22, 2011) — Opioids — a class of medicines commonly given for pain — were associated with a higher risk of pneumonia in a study of 3,061 adults, aged 65 to 94, e-published in advance of publication in the Journal of the American Geriatrics Society. The study from researchers at Group Health Research Institute and the University of Washington (UW) also found that benzodiazepines, which are drugs generally given for insomnia and anxiety, did not affect pneumonia risk.

“Pneumonia is a common infection that can have serious consequences in older adults,” said study leader Sascha Dublin, MD, Ph.D, a Group Health Research Institute assistant investigator and Group Health primary care physician.

“Opioids and benzodiazepines work in different ways, but both can decrease the breathing rate. Both are also sedatives, which can increase the risk of aspiration.” Aspiration is inhaling material (including saliva or food particles) from the mouth into the lungs, which can lead to pneumonia.

A 2009 study estimated that two million Americans age 65 and older received long-term opioid treatment for non-cancer pain. Prescription opioid use has been on the rise in the United States. In earlier Group Health research, the use of chronic opioid therapy for chronic non-cancer pain doubled in the prior decade. And a 1998 report found that one in 10 older Americans used benzodiazepines.

“In animal studies, some opioids — including morphine, codeine, and fentanyl — harm the immune system, which also might contribute to pneumonia,” said Dr. Dublin. She and her research team hypothesized that risk of pneumonia would be higher in people using opioids or benzodiazepines than in people not using these medications, and would be highest for opioids that suppress the immune system. Study subjects were members of Group Health Cooperative, a nonprofit health care system with extensive computerized pharmacy, laboratory, and medical records that were used in the analysis.

Dublin and colleagues conducted a “case-control study,” matching patients who had pneumonia during the study period of 2000 to 2003 (“cases”) with similar patients who did not have pneumonia (“controls”). All were living in the community, not hospitalized or in nursing homes, and the researchers excluded people whose immune systems were suppressed.

The researchers measured whether people with pneumonia were more likely than controls to have taken opioids or benzodiazepines before the start of their illness. Among pneumonia cases, 13.9 percent were using opioids and 8.4 percent were using benzodiazepines. In subjects without pneumonia, 8.0 percent were using opioids and 4.6 percent were using benzodiazepines.

Statistical analysis by the researchers showed that:

• Patients taking long-acting opioids such as sustained-release morphine were more than three times as likely to get pneumonia as were those not taking opioids.
• Recently starting use was a risk factor: During their first 14 days of use, patients who took opioids were more than three times as likely to get pneumonia as were those not taking opioids.
• Patients using immunosuppressing opioids were nearly 1.9 times as likely to get pneumonia as were those not using opioids.
• Use of opioids for a longer time period, defined as three months or more before getting pneumonia, was not associated with infection.
• Taking benzodiazepines did not affect the risk of getting pneumonia.

This was the first large epidemiological study to look at how opioid use affects the risk of getting pneumonia in a general population. It lays the foundation for research on additional questions about the safety of opioid drugs in older Americans.

“Benzodiazepines don’t seem to be associated with increased risk of pneumonia,” said Dr. Dublin. “But our results mean that it is crucial to look more closely at opioid prescriptions and infections.”

Dr. Dublin was funded by a Paul Beeson Career Development Award from the National Institute on Aging, by the Branta Foundation, and by Group Health Research Institute internal funds. The Beeson award is also supported by the Hartford and Starr Foundations and Atlantic Philanthropies. The work was also funded in part by the National Institute on Drug Abuse.

Recommend this story on Facebook, Twitter,
and Google +1:

Other bookmarking and sharing tools:

Story Source:

The above story is reprinted (with editorial adaptations by UnknownBody.com staff) from materials provided by Group Health Research Institute, via EurekAlert!, a service of AAAS.

Journal Reference:

1. Sascha Dublin, Rod L. Walker, Michael L. Jackson, Jennifer C. Nelson, Noel S. Weiss, Michael Korff, Lisa A. Jackson. Use of Opioids or Benzodiazepines and Risk of Pneumonia in Older Adults: A Population-Based Case-Control Study. Journal of the American Geriatrics Society, 2011; DOI: 10.1111/j.1532-5415.2011.03586.x