Abstract
Chronic neuroinflammation mediated by activated immune cells is important for the pathogenesis of neuropathic pain. Increasing evidence suggests that matrix metalloproteases (MMPs), which are proteases for degradation of extracellular matrix, may involve in neuroinflammation through induction of cytokines and chemokines. In this study, we focused on the function of MMP12 in peripheral nerve injury–induced neuropathic pain. Neuropathic pain model mice were produced by partial sciatic nerve ligation (PSL). After PSL, the gene expression of MMP12 was increased in the injured sciatic nerve (SCN). By immunohistochemistry, MMP12 protein was also up–regulated and localized on infiltrating macrophages in the injured SCN after PSL. By fluorescent dye, DiI, for labeling peripheral blood vessels, angiogenesis and vascularization were observed in the injured SCN, and DiI leaked into the surrounding tissue, indicating the enhancement of vascular permeability. Macrophages accumulated around DiI labeled peripher al vessels in the injured site of SCN after PSL. To determine the source of MMP12, EGFP+ chimeric mice were produced by bone marrow transplantation (BMT). After BMT, EGFP+ cells migrated around the SCN after PSL, but not in BMT–subjected sham. Moreover, MMP12 was localized on EGFP+ cells. Furthermore, the perineural injection of MMP408 (10 ng ⁄ 10 µl), MMP12 specific inhibitor, suppressed PSL–induced thermal hyper algesia and tactile allodynia, which were evaluated by Hargreaves test and von Frey test, respectively. These results suggest that MMP12, which was produced by bone marrow derived macrophages, acts as an exacerbating factor of neuropathic pain. Taken together, MMP12 may be a novel molecule for the treatment of neuropathic pain.
