A new clue to pain DMS researchers find link to immune system
Dartmouth Medical School (DMS) researchers have demonstrated that a receptor in central nervous system immune cells plays a critical role in triggering neuropathic pain, debilitating nerve pain that often defies relief from standard therapies.
The DMS team L-R of Flobert Tanga, Joyce DeLeo and Nancy Nutile-McMenemy demonstrated that a receptor in central nervous system immune cells plays a critical role in triggering debiliating pain. (photo by Barbara Atherton)
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Their study, published in the Apr. 19 issue of the Proceedings of the National Academy of Sciences (PNAS), could help pave the way for new approaches to alleviate chronic and agonizing pain due to nerve damage.
"The results of this study are significant," said Joyce DeLeo, Professor of Anesthesiology and Pharmacology at DMS and Director of Dartmouth's Neuroscience Center, "because they demonstrate the potential for very novel drug targets, related to innate immunity, to be effective for the treatment and/or prevention of chronic pain." DeLeo headed the study. "Our next steps are to carefully dissect out the components of this system to determine the magnitude of the effects and the ability to modify other parts of this pathway."
Building on prior research suggesting overlap between the immune and central nervous sytems (CNS), the research team discovered how a Toll-like receptor 4 (TLR4) induces neuropathic pain. TLR4 is expressed exclusively by microglia, CNS immune cells that become activated soon after an injury. Micoglia mobilize still other immune cells via protein messengers called cytokines, which have multiple and complex functions. TLR4 has been implicated in behavioral hypersensitivity in rodent models of neuropathy that mimic heightened human responses to temperature or touch after injury.
DeLeo, with research assistants Flobert Tanga and Nancy Nutile-McMenemy, manipulated a nerve in the lower back of mice that lacked a functional TLR4 receptor. Then they asessed how the TLR4-deficient mice responded when their hindpaws were touched or exposed to heat. Hypersensitivity was reduced and expression of cytokines and markers for activated microglia was decreased, the scientists found.
These results demonstrate that TLR4 helps to initiate a CNS immune response, leading to cytokine release and hypersensitivity. Further understanding of the ability of TLR4 to stimulate hypersensitivity may provide an opportunity to regulate microglial activation and block persistent chronic pain.
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