A path to lower-risk painkillers: Newly-discovered drug target paves way for alternatives to morphine

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    New findings provide vital step towards exploring pain medications that may
    lower risks of prescription drug abuse and side effects of painkillers

    ANN ARBOR, Mich. ‹ For patients managing cancer and other chronic health
    issues, painkillers such as morphine and Vicodin are often essential for
    pain relief. The body¹s natural tendency to develop tolerance to these
    medications, however, often requires patients to take higher doses ­
    increasing risks of harmful side effects and dependency.

    Now, new research from the University of Michigan Health System and a major
    pharmaceutical company has identified a novel approach to moderate and
    severe pain therapy that paves the way for lower dosage painkillers. The
    findings appear in Proceedings of the National Academy of Sciences of the
    United States of America.

    Drugs such as hydrocodone (the main ingredient of Vicodin) and oxycodone
    (Oxycontin) are often the best options for the treatment of moderate to
    severe pain for patients facing medical conditions ranging from a wisdom
    tooth extraction to cancer. The drugs bind to specific molecules (opioid
    receptors) on nerve cells in the brain and spinal cord to prevent the
    feeling of pain.

    ³We have for the first time discovered compounds that bind to an alternative
    site on the nerve opioid receptors and that have significant potential to
    enhance the drug¹s positive impact without increasing negative side
    effects,² says co-author John Traynor, Ph.D., professor of pharmacology at
    the U-M Medical School.

    ³We are still in the very early stages of this research with a long way to
    go, but we believe identifying these compounds is a key step in
    revolutionizing the treatment of pain. This opens the door to developing
    pain relief medications that require lower doses to be effective, helping
    address the serious issues of tolerance and dependence that we see with
    conventional pain therapy.²

    Conventional drug treatments for pain work by targeting the so-called
    orthosteric site of the opioid receptor that provides pain relief. Targeting
    this site, however, is a double-edged sword because it is also responsible
    for all of the drug¹s unwanted side effects, such as constipation and
    respiratory depression. Tolerance also limits chronic use of the drugs
    because higher doses are required to maintain the same effect.

    Using cell systems and mouse brain membranes, researchers have identified
    compounds that bind to a physically distinct and previously unknown
    ³allosteric² site on the opioid receptor- a site that fine-tunes the
    activity of the receptor. Not only do these compounds act at a location that
    hasn¹t been studied as a drug target before but they bind to the receptor in
    a new way to enhance the actions of morphine ­ which means lower doses can
    have the same impact.

    ³The newly-discovered compounds bind to the same receptor as morphine but
    appear to act at a separate novel site on the receptor and therefore can
    produce different effects. What¹s particularly exciting is that these
    compounds could potentially work with the body¹s own natural painkillers to
    manage pain,² Traynor says.

    ³We know that conventional strong pain medications ultimately increase the
    risk of withdrawal symptoms and addiction, which is an especially serious
    issue with the current prescription drug abuse epidemic in our country. The
    implications of this work, if it translates to animal studies and then to
    humans, are highly significant to this area of study.²

    Additional authors: Andrew Alt, Ph.D., Neil Burford Ph.D., Mary J Clark
    M.A., Samuel Gerritz Ph.D, Martyn Banks Ph.D., Jonathan O¹Connell Ph.D., Tom
    Wehrman, Ph.D.

    Funding: Partially supported by National Institutes of Health grant MH083754

    Disclosures: None

    Reference: ³Discovery of Positive Allosteric Modulators and Silent
    Allosteric Modulators of the Mu Opioid Receptor,² Proceedings of the
    National Academy of Sciences of the United States of America.
     

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