High mobility box 1 (
HMGB1), a damage-associated molecular pattern, has crucial roles in induction of
neuropathic pain. Upregulation of
HMGB1 around the injured sciatic nerve contributes to mechanical
hypersensitivity following partial sciatic nerve
ligation (PSNL) of mice. However, central mechanisms mediating perineural HMGB1-induced nociceptive
hypersensitivity, especially within the spinal dorsal horn, have not been determined. The current study shows that perineural treatment of naïve mice with recombinant
HMGB1, which mimics increased
HMGB1 around the injured sciatic nerve of PSNL mice, significantly induced activation of microglia, but not astrocytes, in the spinal dorsal horn.
Intraperitoneal injection of
minocycline, a microglial inhibitor, ameliorated perineural rHMGB1-induced mechanical
hypersensitivity. In addition, blockade of spinal
N-methyl-D-aspartate (
NMDA) receptors significantly prevented perineural rHMGB1-induced mechanical
hypersensitivity and microglial activation. In contrast, non-
NMDA receptors,
neurokinin 1 receptor,
colony-stimulating factor 1 receptor and P2Y12 receptor were not involved in perineural rHMGB1-induced mechanical
hypersensitivity. Furthermore, repeated perineural treatment with an anti-HMGB1 antibody blocked activation of spinal microglia in PSNL mice. Collectively, the current findings demonstrate that increased
HMGB1 around injured sciatic nerve might induce nociceptive
hypersensitivity through activation of spinal microglia. Thus, HMGB1-dependent mechanisms between the injured sciatic nerve and spinal dorsal horn could be crucial in induction of
neuropathic pain.