Intrathecal treatment with recombinant high-mobility group box-1 (rHMGB1) in naïve mice leads to a persistent and significantly decreased hind paw withdrawal threshold to mechanical stimuli, suggesting that spinal
HMGB1 evokes abnormal
pain processing. By contrast, repeated intrathecal treatment with anti-HMGB1 antibody significantly reverses hind paw mechano-
hypersensitivity in mice with a partial sciatic nerve
ligation (PSNL). By contrast, the cellular mechanism by which spinal
HMGB1 induces
neuropathic pain has yet to be fully elaborated. The current study tested the hypothesis that spinal
HMGB1 could induce mechanical
hypersensitivity through the activation of specific receptor in glial cells. Intrathecal pretreatment with
toll-like receptor (TLR) 4 inhibitors, but not
TLR5, receptor for
advanced glycation end-products and
C-X-C chemokine receptor type 4 inhibitors, prevented rHMGB1-evoked mechanical
hypersensitivity. Activation of spinal astrocytes appears to be crucial for the mechanism of action of rHMGB1 in naïve mice, as intrathecal pretreatment with astrocytic inhibitors prevented the rHMGB1-induced mechanical
hypersensitivity. Interleukin-1β (IL-1β) was up-regulated within activated astrocytes and block of TLR4 prevented the upregulation of IL-1β. Interleukin-1β appears to be secreted by activated astrocytes, as IL-1β
neutralizing antibody prevented rHMGB1-induced mechanical
hypersensitivity. Furthermore, intrathecal pretreatment with either
MK801 or
gabapentin prevented the rHMGB1-induced mechanical
hypersensitivity, suggesting roles for spinal
glutamate and the
N-methyl-d-aspartate receptor in the mediation of rHMGB1-induced mechanical
hypersensitivity. Thus, the current findings suggest that spinal
HMGB1 upregulates IL-1β in spinal astrocytes through a TLR4-dependent pathway and increases glutamatergic nociceptive transduction. These spinal mechanisms could be key steps that maintain
neuropathic pain.