Grant: Project Grant

Pain is one of the major complaints of patients suffering from various neurological and non- neurological conditions, such as autoimmune diseases, tissue infection, and injury. Current therapies for pain caused by inflammation, such as after surgical wound or bacterial infection, include NSAIDs and acetaminophen. These drugs often provide inadequate pain relief and are accompanied by serious gastrointestinal and cardiovascular side effects. Opioids are more effective pain-killers but carry a heavy burden to both the patient and society. While treatments targeting the spinal cord or brain can be challenging and carry risks of unwanted side effects, modulating the inflammation that occurs at the site of injury may be more amenable to treatment. Recent work from our lab has found that dendritic cells in the skin, which act as sentinels to injury and infection, secrete specific immune mediators after injury that can directly activate sensory neurons to cause pain. In preliminary studies, we discovered that tissue injury activates a specific molecule (the chemokine CCL22) in dendritic cells located at the site of tissue injury. We also discovered that blocking its receptor, CCR4, substantially reduces pain. Our work also suggests that pain-sensing neurons control the activation state of dendritic cells in response to injury, and may function in a feedback loop. This proposal will examine how these immune cells communicate with pain-sensing neurons to mediate pain, and whether the neurons themselves can alter the dendritic cell response. Understanding why and how pain occurs during inflammation will enable us to develop new health care strategies to prevent or treat pain in patients with bacterial infection and tissue injury.