Terminally ill patients often receive morphine to help them cope with severe pain. Yet chronic use of morphine and other opioids can backfire: not only can the drug’s effectiveness wane over time, but some patients find repeated doses make the pain feel even worse. Finding a way to block these long-term complications of morphine use would offer a major step forward in pain management, but the molecular mechanisms involved have been hard to unravel.

Now, researchers led by Wen-Li Mi at Fudan University in Shanghai have identified a cell-signaling sequence involved in both the tolerance and increased pain sensitivity (hyperalgesia) brought on by regular morphine use in mice. Suppressing this pathway in the animals turned off both side effects, raising the prospect that the same could be done in people, the researchers report September 7 in Science Signaling.

Venetia Zachariou, a neuroscientist and pharmacologist at the Icahn School of Medicine at Mount Sinai in New York who was not involved in the work, says the study offers one of the clearest views yet of how morphine affects cell behavior. “Here we have the specific molecules and pathways and the exact time course of events that leads to hyperalgesia. So the study is quite novel in this regard.”

The research focused on cells called astrocytes and oligodendrocytes in the spine. Both are glial cells, which support the nervous system. When the mice were exposed to morphine, these cells responded by increasing expression of a signaling protein called interleukin 33 (IL-33) as well as its receptor, ST2. IL-33 is known play a key role in the immune system and often triggers cells to increase the production of other signaling molecules called cytokines. In the new study, the researchers found that through ST2, IL-33 activated the production and release of a cytokine called CXCL12 from the astrocytes.

To test how the increased IL-33 and ST2 alter morphine’s effects on the mice’s pain response, the researchers used knockout mice that were missing the relevant genes, introduced inhibitory RNAs that wiped out the genes’ expression in wildtype mice, or injected antibodies into wildtype mice to reduce their influence. When these treated or modified animals were given morphine over time, they showed more reliable tolerance of pain than control mice, as indicated by behavioral tests that track when the animals move their paws and tails in response to heat. The researchers found similar results when they reduced CXCL12 expression or blocked its receptor in mice. 

“Collectively, these behavioral data demonstrated that spinal IL-33–ST2 signaling contributes to [morphine-induced hyperalgesia] and analgesic tolerance,” the authors conclude in the paper. They go on to suggest that injecting antibodies that target IL-33 or ST2 into a person’s cerebrospinal fluid “could be potentially used to prevent and/or treat the side effects caused by repeated opioid treatments.”  

“This study shows an important role of astrocytes in opioid-induced hyperalgesia and tolerance,” neurobiologist Ru-Rong Ji, director of the Center for Translational Pain Medicine at Duke University Medical Center, tells The Scientist in an email. The findings are clinically relevant, he adds, “But there is long way to go. This study did not test clinically relevant drugs.”

Zachariou similarly cautions that, while the animals are a good model to explore the physiological response to morphine, “mice cannot tell you they feel worse or that they have muscle aches.” 

She adds that this is probably one of several pathways that can drive tolerance to morphine and hyperalgesia. Environmental and genetic factors could also contribute, as well as other molecular interactions beyond the spine. “If the interventions in this particular pathway that the study identifies are sufficient, then we have a good target. But definitely there are additional and complementary pathways that one can think of.”