High-mobility group box-1 (HMGB1) has been shown to be critical in the modulation of nociceptive transduction following a peripheral neuropathy. However, the precise role of peripherally expressed HMGB1 in neuropathic pain has yet to be fully elaborated. Following a partial sciatic nerve ligation (PSNL) in mice, a persistent ipsilateral up-regulation of HMGB1 was observed from 3 to 21 days after PSNL, in paralleled with a robust ipsilateral hind paw mechanical hypersensitivity. Increased HMGB1 was detected in both infiltrating macrophages and proliferating Schwann cells in the ipsilateral nerve 14 days following PSNL. Repeated perineural treatment with anti-HMGB1 antibody significantly ameliorated PSNL-induced mechanical hypersensitivity. Several pronoci-ceptive molecules, including matrix metalloprotease-9 (MMP-9), tumor necrosis factor-a, interleukin-1b (IL-1b), and cyclooxygenase-2, were up-regulated in injured sciatic nerve 14 days following PSNL. Repeated perineural treatment with an anti-HMGB1 antibody significantly suppressed expression of MMP-9, but not other pronociceptive molecules. Perineural treatment with a selective MMP-9 inhibitor ameliorated PSNL-induced mechanical hypersensitivity. The current findings demonstrate that the maintenance of the neuropathic state following an injured nerve is dependent on the up-regulation of HMGB1 and MMP-9. Thus, blocking HMGB1 function in sciatic nerve could be a potent therapeutic strategy for the treatment of neuropathic pain. Abbreviations used: COX-2, cyclooxygenase-2; DRG, dorsal root ganglion; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMGB1, high-mobility group box-1; IL-1b, interleukin-1b; IL-6, interleukin-6; iNOS, inducible nitric oxide; MBP, myelin basic protein; MMP-2, matrix metalloprotease-2; MMP-9, matrix metalloprotease-9; PSNL, partial sciatic nerve ligation; RAGE, receptor for advanced glycation end-products; SDS, sodium dodecyl sulfate; TIMP-1, tissue inhibitor of metalloproteinase 1; TLR, toll-like receptor; TNF-a, tumor necrosis factor-a.