Tibia tumor-induced cancer pain involves spinal p38 mitogen-activated protein kinase activation via TLR4-dependent mechanisms.
ABSTRACT 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.
Article: Intrathecal siRNA against Toll-like receptor 4 reduces nociception in a rat model of neuropathic pain.[show abstract] [hide abstract]
ABSTRACT: Neuropathic pain is characterized by hyperalgesia, allodynia and spontaneous pain. It often occurs as a result of injury to peripheral nerves, dorsal root ganglions (DRG), spinal cord, or brain. Recent studies have suggested that Toll-like receptor 4 (TLR4) might play a role in neuropathic pain. In this study, we investigated the role of TLR4 in a rat chronic constriction injury (CCI) model and explored the feasibility of treating neuropathic pain by inhibiting TLR4. Our results demonstrated that intrathecal siRNA-mediated suppression of TLR4 attenuated CCI-induced mechanical allodynia and thermal hyperalgesia through inhibiting the activation of NF-kappaB p65 and production of proinflammatory cytokines (e.g., TNF-alpha and IL-1 beta). These findings suggest that suppression of TLR4 mediated by intrathecally administered siRNA may be a new strategy for the treatment of neuropathic pain.International journal of medical sciences 01/2010; 7(5):251-9. · 2.24 Impact Factor
Article: Cancer-induced bone pain sequentially activates the ERK/MAPK pathway in different cell types in the rat spinal cord.[show abstract] [hide abstract]
ABSTRACT: Previous studies have demonstrates that, after nerve injury, extracellular signal-regulated protein kinase (ERK) activation in the spinal cord-initially in neurons, then microglia, and finally astrocytes. In addition, phosphorylation of ERK (p-ERK) contributes to nociceptive responses following inflammation and/or nerve injury. However, the role of spinal cells and the ERK/MAPK pathway in cancer-induced bone pain (CIBP) remains poorly understood. The present study analyzed activation of spinal cells and the ERK/MAPK pathway in a rat model of bone cancer pain. A Sprague Dawley rat model of bone cancer pain was established and the model was evaluated by a series of tests. Moreover, fluorocitrate (reversible glial metabolic inhibitor) and U0126 (a MEK inhibitor) was administered intrathecally. Western blots and double immunofluorescence were used to detect the expression and location of phosphorylation of ERK (p-ERK). Our studies on pain behavior show that the time between day 6 and day 18 is a reasonable period ("time window" as the remaining stages) to investigate bone cancer pain mechanisms and to research analgesic drugs. Double-labeling immunofluorescence revealed that p-ERK was sequentially expressed in neurons, microglia, and astrocytes in the L4-5 superficial spinal cord following inoculation of Walker 256 cells. Phosphorylation of ERK (p-ERK) and the transcription factor cAMP response element-binding protein (p-CREB) increased in the spinal cord of CIBP rats, which was attenuated by intrathecal injection of fluorocitrate or U0126. The ERK inhibitors could have a useful role in CIBP management, because the same target is expressed in various cells at different times.Molecular Pain 07/2011; 7:48. · 3.53 Impact Factor