For millions of people coping with the acute pain of surgery, serious illness, or injury, opioid drugs provide effective pain relief. Though these drugs are beneficial for many, they carry a powerful potential for tolerance, abuse and addiction that makes them less effective in the treatment of chronic pain. When developing a tolerance to a certain substance, the patient must ingest increasingly higher doses of the drug in order to feel its effect, and the risk of addiction rises in turn. We have written about past developments in the search for a non-addictive painkiller, and a new study has furthered our understanding of mechanisms that may contribute to the addictive quality of opioids. Using mice treated with morphine, researchers from the University of California, San Francisco identified a genetic modification that may diminish a patient's risk for dependency.
Neurons respond differently to morphine than they do to endorphins and other natural painkillers produced by the body, and this is a key aspect of the study, which was published in Current Biology. When endorphins bind to receptors, they cause the receptors to move from the surface of the cell to the cell's interior, a process known as endocytosis. As the receptor leaves the cell's surface, fewer endorphins are able to bind to it, and the receptor cycles between being "on" and being "off." This cycling allows for the regulation of endorphin intake. Morphine, however, does not cause endocytosis. Rather than cycling between "on" and "off," receptors that bind to morphine are continually "on." The researchers believed that because the intake of morphine is not controlled via endocytosis, the nervous system becomes tolerant of the drug and addiction becomes more likely.
To test their idea, the researchers genetically engineered the receptor cells of mice to undergo endocytosis in response to morphine. Unaltered mice developed tolerance or dependence after several days of treatment with morphine. Genetically altered mice, on the other hand, did not develop signs of tolerance or dependence during the study. For these mice, morphine remained an effective painkiller without leading to addiction.
Tolerance is complex and is most likely influenced by numerous factors. The results of this study point toward one potential mechanism involved in drug tolerance and indicate ways in which we may be able to develop more effective drugs. A drug that acts like morphine while facilitating endocytosis could carry a reduced risk for tolerance and dependence, and a drug like this may hold great benefits, especially for victims of chronic pain.
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