The core idea of this proposal is that, while mediators released by activated immune cells are adaptive when directed against microbes, these same mediators can be pathological when they act on neurons. It is clear from animal studies that """"""""innocent bystander"""""""" damage can occur from immune activation near, but not directed at, peripheral nerves. Indeed, most human neuropathies are associated with immune activation rather than by physical (mechanical) trauma. These inflammatory neuropathies involve damage of peripheral nerves by immune cells and chronic pain. The overall goal of this proposal is to understand low-threshold mechanical allodynia (lowering of response threshold to mechanical stimuli) induced by immune activation and release of immune cells products in and around one healthy sciatic nerve (sciatic inflammatory neuritis (SIN). Unilateral and bilateral allodynia are rapidly induced by 4 and 160 ug peri-sciatic zymosan, respectively. We propose that SIN triggers a linear chain of events, resulting in allodynia: immune cells (activated by zymosan) release substances that alter peripheral nerve function, which in turn alters spinal cord function. Using a multidisciplinary approach, we will examine the basic elements of this chain of events & see how they interact to produce unilateral & bilateral allodynias. We will test peri-sciatically & intrathecally administered antagonists on behavioral indices of mechanical allodynia. We will then examine levels of SIN-induced pain enhancing endproducts from immune cells & spinal cord (measured by colorimetric assays & ELISAs), immunohistochemical expression of these endproducts in immune cells, sciatic nerve & spinal cord (by double-label immunohistochemistry & FACS flow cytometry), & changes in messenger RNA for these same endproducts in immune cells & spinal cord. Thus, this multidisciplinary approach will be used to examine the potential mediators of allodynia at the level of the immune cells (Specific Aim I), at the level of the sciatic nerve (Specific Aim II), & at the level of the spinal cord (Specific Aim III).
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