Molecular mechanisms underlying
bone cancer pain are poorly understood. Recently,
p38 mitogen-activated protein kinase (MAPK) activation was shown to play a major role not only in the production of proinflammatory
cytokines but also in the progression of inflammatory and
neuropathic pain. We have demonstrated that
tactile allodynia and spontaneous
pain of female rats with tibia
tumors were correlated with the increase of both phosphorylated-p38MAPK (p-p38MAPK) and proinflammatory
cytokines (IL-1beta and TNF-alpha) in the spinal cord 6 days after Walker 256 cells' inoculation. This change was specific to
bone cancer pain because rats without tibia
tumors failed to show such an increase. On the other hand, a 3-day administration [4 microg/rat/day, intrathecally (i.t.)] of 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (
SB203580), an inhibitor of p38MAPK, could suppress
tactile allodynia and spontaneous
pain of the
bone cancer pain rats and decrease the phosphorylation of p38 as well as the expression of IL-1beta and
TNF-alpha. To characterize the cellular events upstream of p38MAPK, we have examined the role of the
toll-like receptor 4 (TLR4), which had been suggested to be involved in
pain hypersensitivity. We found that prolonged knockdown of TLR4 during the 3-day administration of TLR4
small interfering RNA (
siRNA; 2 microg/rat/day, i.t.) could attenuate
hyperalgesia developed by Walker 256 cells' inoculation and decrease the phosphorylation of p38 as well as the increase of IL-1beta and
TNF-alpha expression. These results demonstrate that TLR4-dependent phosphorylation of p38MAPK in spinal cord of rats might contribute to the development and maintenance of
bone cancer pain, and p38MAPK and TLR4 would possibly be the potential targets for
pain therapy.