The effects on the brain may also contribute to better understanding of drug addiction.
The study, published in the September 22 issue of the Journal of Neuroscience, was the first to show that chronic opiate use disrupts the stress response of nerve cells in the noradrenergic system. This system, using a neurotransmitter called norepinephrine, influences the brain's arousal and attention levels when a stressful event occurs.
The researchers observed that the norepinephrine neurons of rats that had received morphine infusions for a week discharged more frequently in response to a stressor, compared to neurons of rats that had not received morphine. "The increase in neuron firing indicated the neurons were more sensitive to stress, and we also found this sensitization translated into behavioral changes--as shown in the rats' swimming behavior," said study leader Rita J. Valentino, Ph.D., a behavioral neuroscientist at The Children's Hospital of Philadelphia.
The researchers used a swim stress test that involved placing rats into glass containers of water. The opiate-treated rats tried to climb the chamber walls, in contrast to untreated rats, which exerted only the effort needed to float. "The climbing behavior reflected a higher activity level in the rats whose brains had been sensitized by the opiates," added Dr. Valentino.
In both humans and rats, a stressful event, such as blood loss, causes one part of the brain to release a hormone called corticotropin-releasing factor (CRF). CRF in turn stimulates neurons in a portion of the brain called the locus ceruleus. Cells in the locus release the neurotransmitter norepinephrine, which activates the area of the brain governing arousal responses (part of the "fight or flight" response to an attack).
The current study found that chronic exposure to the opiate drug morphine made locus ceruleus neurons more sensitive to CRF than they had been previously. If this process occurs similarly in humans, it could have practical implications for hospital patients receiving morphine or similar opiate drugs. "Based on these findings, we would predict that patients will have an increased sensitivity to stress," said Dr. Valentino. Jittery patients might suffer disrupted sleep patterns, increased anxiety and other symptoms, many of them similar to those found in people with post-traumatic stress disorder (PTSD).
Researchers have previously noted sleep disturbances and a higher incidence of PTSD symptoms among opiate users, added Dr. Valentino. Her current study suggests that the opiate-induced sensitivity to stress may play a role in the cycle of addiction that causes drug abusers to continue seeking drugs. However, she added, the role of the norepinephrine system in opiate-seeking behavior remains controversial, and further studies are needed.
As a practical matter, physicians and family members of patients who are taking opiates should be aware of the potential for increased stress symptoms, explained Dr. Valentino. Both children and adults may receive opiates as painkillers in the hospital, and one concern is that young children are particularly vulnerable to the effects of stress because their brains are developing. "As research advances in this field, we may be able to find other opiate medications that do not sensitize neurons to the same degree," she added.
Dr. Valentino's co-authors on this study were Guang-Ping Xu and Thelma Bethea, also of The Children's Hospital of Philadelphia, and Elisabeth Van Bockstaele, Ph.D., and Beverly Reyes, of Jefferson Medical College of Thomas Jefferson University. Support for the study came from The National Institute of Drug Abuse and the National Institute of Mental Health, along with the National Alliance for Research on Schizophrenia and Depression.
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