Role of extracellular damage-associated molecular pattern molecules (DAMPs) as mediators of persistent pain

Damage-associated molecular pattern molecules (DAMPs) are endogenous molecules that are constitutively expressed and released upon tissue damage, resulting in activation of the immune system. In the absence of injury or infection, DAMPs play important intracellular roles. However, once released subsequent to cell damage or cell stress, DAMPs promote activation of innate immune cells and recruitment and activation of antigen-presenting cells engaged in host defense and tissue repair. This process involves pattern recognition receptors, such as the Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE). Several of the TLRs and RAGE have been implicated to play key roles not only in the detection of injury but also in pain signaling. Pain-like behavior is reduced in TLR2- and TLR4-deficient mice, and after injection of TLR2-, TLR4-, and RAGE antagonists in experimental models of nerve injury, arthritis, and bone cancer pain. This suggests that the pathological processes in these models are associated with release of endogenous TLR and RAGE ligands, and further that DAMPs play an important role in persistent pain. There is now a rapidly growing list of DAMPs in the literature and here we give an overview of DAMPs that have been associated with nociceptive signaling.