Pain and the Immune System: A Novel Therapeutic Approach
Abstract
Chronic pain is a significant problem for tens of millions of Americans. The most widely used pain medications for moderate to severe pain are opioids, which carry significant side effects including risk of addiction and death. New therapies are urgently needed to alleviate the suffering from chronic pain. Stress including post-traumatic stress disorder (PTSD) is a contributing factor to several types of chronic pain, including inflammatory pain following an injury, neuropathic pain from nerve damage due to injury or disease (e.g., diabetic neuropathy) and so-called functional pain with no known cause (e.g., migraine, irritable bowel syndrome, fibromyalgia). Several types of pain result from an interaction between the immune system and the nervous system. Stress or injury result in release from damaged cells of damage-associated molecular patterns (DAMPs) that activate immune cells (cells that protect from infection), which also contribute to chronic pain. Toll-like receptors (TLRs), including TLR4, recognize invading pathogens and initiate an immune response that includes expression of cytokines and inflammation at the site of infection. Normally this is beneficial to the individual since it fights off the infection. Additionally, TLR4 recognizes DAMPs resulting in increased cytokine expression and an inflammatory response. When this inflammatory process fails to resolve, the increased expression of cytokines can lead to pain. TLR4 and its downstream signaling pathway including TNFalpha have been shown to underlie many types of chronic pain. Commonly prescribed drugs (biologics, e.g., Humira) that block TLR4 or TNF-alpha signaling are used to treat several types of chronic pain including arthritis and inflammatory bowel disease. However, a serious side effect of taking these drugs is an increased risk of infection including tuberculosis and fungal infections. Our group has invented a way to produce a new drug called ALT that mildly stimulates TLR4 rather than blocking it. ALT has the pain-fighting properties of the TLR4/TNF inhibitors but maintains protection from infection. Our proposal will test this hypothesis using two pain models in mice: hindpaw inflammation following stress modeling injury in battle (a stressful situation) and stress-induced visceral hypersensitivity, modeling abdominal pain characteristic of irritable bowel syndrome, a condition experienced by returning Veterans, especially those with PTSD. We will determine whether a single injection of ALT or chronic administration for 2 weeks can reduce or prevent pain in these models. We will determine if under these same conditions, the mice can fight off infection, which will differentiate ALT from the TLR4/TNF inhibitors. Since the ALT molecule is generated by bacteria, we will orally administer the bacteria to mice to determine if the bacteria can colonize in the mouse gastrointestinal tract, protect against pain and infection, and thereby be used as a probiotic. Finally, we are developing mice that express the human form of TLR4 (differs slightly from mice) and will test if it provides the same level of pain and infection protection, furthering its move to clinical testing.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110595
Entities
People
- Richard J. Traub
Organizations
- United States Army
- University of Maryland, Baltimore