Damage of peripheral nerves and surrounding tissues cause pain enhancement in humans. Such damage can arise for a variety of reasons: trauma, inflammation, infection, and drug neurotoxicities. One aim of our ongoing studies of pain dysregulation is to understand how infection, inflammation, toxicity and trauma of peripheral tissues and peripheral nerves leads to amplification of pain. The focus here is on immune activation: identifying what activated immune cells are key players in this process, identifying the sites along the pain pathway where they amplify pain, understanding the impact these immune products have on pain transmission, and identifying novel strategies for controlling the negative effects that immune activation has on pain.