 It may be surprising to learn that drugs like morphine can actually make it harder to heal from injuries, including surgery. Researchers report that using opioids to manage this type of acute pain can make the pain last longer, potentially drawing out the need for pain relief. Although it's unclear exactly why this happens, scientists are beginning to uncover some of the physiological causes of this delayed healing, and they think it has something to do with the brain's immune system. That conclusion comes from an in-depth look at how morphine affects recovery in mice. Using a mouse model of orthopedic surgery, researchers looked at the consequences of post-operative morphine use. Mice were subjected to tibial fracture and repair and given a seven-day course of either morphine or an inactive vehicle. Some mice underwent a sham operation. They were anesthetized and received skin incisions, but no bone fracture, followed by the same treatment regimen. The setup helped narrow down the specific effects of opioid use in the setting of trauma. Intriguingly, morphine lowered the animal's pain threshold. The drug also made it take longer for them to regain a normal pain threshold. Mice receiving morphine for their fractures also had a much harder time walking normally than untreated animals. They were uncoordinated and continued to have problems stabilizing the affected limb a month after surgery. So what was causing these differences? The scientists discovered that animals treated with morphine for their fractures had significantly higher levels of toll like receptor 4, a protein with a key role in the immune system. Samples of spinal cord tissue revealed that microglia were the main source of this extra TLR4. These specialized cells normally clear damaged cells and infectious agents from the central nervous system to keep things in good working order. But activated microglia also contribute to many types of chronic pain. The TLR4 rich microglia were indeed activated, suggesting the animals were experiencing neuro inflammation. Curiously, morphine alone didn't activate the microglia. It was the combination of morphine and physical trauma that did it. It seems the relationship between pain and opioid use is a complex one. More work is needed to translate the importance of these findings into the clinical setting. But the study reveals some key considerations for managing pain.