June 21, 2016

Opioid pain relievers may prolong pain

At a Glance

  • Short morphine treatments heightened and prolonged pain in rats with nerve injuries.
  • Researchers identified the specific molecular pathway responsible.
  • The findings suggest a strategy for intervening in this persistent pain effect without affecting the painkilling properties of opioid drugs.
Neurons firing Research into the cellular and molecular effects of opioid use may lead to better ways to treat chronic pain. GuidoVrola/iStock/Thinkstock

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, 2016, 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-1β 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-1β’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.

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Reference: Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Grace PM, Strand KA, Galer EL, Urban DJ, Wang X, Baratta MV, Fabisiak TJ, Anderson ND, Cheng K, Greene LI, Berkelhammer D, Zhang Y, Ellis AL, Yin HH, Campeau S, Rice KC, Roth BL, Maier SF, Watkins LR. Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):E3441-50. doi: 10.1073/pnas.1602070113. Epub 2016 May 31. PMID: 27247388.

Funding: NIH’s National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute of Dental and Craniofacial Research (NIDCR), and National Institute of General Medical Sciences (NIGMS); American Pain Society; Australia’s National Health and Medical Research Council; American Australian Association; National Natural Science Foundation of China; and Natural Science Foundation of Jilin Province.