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Opioid pain relievers may prolong pain

Pain can help protect the body after an injury or infection. It serves as a warning system to rest or avoid certain activities. But sometimes, pain may become chronic. This can happen when nerve cells that detect something harmful alter the electrical or molecular signals they send to the spinal cord. This can trigger the production of chemicals in spinal cord neurons that make pain persist beyond the healing period.

Opioids, such as morphine, are often used to treat pain from a nervous system injury. These drugs activate opioid receptors and mimic the effects of natural chemicals produced by the body that both inhibit pain signals and produce a euphoric feeling.

To investigate the long-term effects of using opioids for pain relief, a team led by Drs. Peter Grace and Linda Watkins at the University of Colorado, Boulder, studied morphine treatment in rats with nerve injuries. The research was funded in part by NIH's National Institute of Drug Abuse (NIDA) and other NIH Institutes. Results were published on June 14 in the Proceedings of the National Academy of Sciences.

After a nerve injury, a non-painful stimulus, such as a light touch, can cause pain or an unpleasant sensation. The researchers tested rats for increased sensitivity to non-painful stimulation following a sciatic nerve injury or sham surgery. Rats were treated with either morphine or saline twice a day for 5 days beginning 10 days after surgery. Those with a nerve injury were more sensitive to touch on their hindpaws than the sham controls. Injured rats treated with morphine were sensitive for longer and to a higher degree; lighter touches caused them to withdraw their paws from the stimulus more often than saline-treated animals.

Experiments showed that the morphine-induced sensitivity wasn't mediated through opioid receptors. Morphine is also known to activate inflammation-inducing molecules, called cytokines. Blocking cytokine IL-1? or associated cytokines prevented the prolonged sensitivity when given with the morphine treatment. When delivered after morphine treatment, cytokine inhibition dampened the prolonged sensitivity.

Cytokine IL-1?'s activity is regulated by a molecular complex called the inflammasome, which helps trigger the inflammatory process in immune cells. Rats with the morphine-induced sensitivity showed increased expression of inflammasomes within specialized central nervous system immune cells called microglia. Experiments revealed that the morphine-induced pain sensitivity depended on the activation of an inflammasome protein called NLRP3 in microglia. These results suggest that interfering with the cytokine pathway could prevent opioid-induced prolonged chronic pain without hindering the painkilling properties.

"We are showing for the first time that even a brief exposure to opioids can have long-term negative effects on pain," Grace says. "We found the treatment was contributing to the problem."

Future studies will be needed to confirm whether these effects have clinical relevance.

-by Tianna Hicklin, Ph.D.

--From the National Institute of Health

For further information on this and other health topics, visit the web site of the National Institute of Health at

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