Tibia tumor-induced cancer pain involves spinal p38 mitogen-activated protein kinase activation via TLR4-dependent mechanisms.
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.
Liu
Silan
S
Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
Yang
Jianping
J
Wang
Lina
L
Jiang
Miao
M
Qiu
Qiaocheng
Q
Ma
Zhenni
Z
Liu
Lei
L
Li
Caifang
C
Ren
Chunguang
C
Zhou
Jin
J
Li
Wei
W
D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology; D002279:Carcinoma 256, Walker / Q000473:pathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D007150:Immunohistochemistry; D007278:Injections, Spinal; D053583:Interleukin-1beta / Q000378:metabolism; D009368:Neoplasm Transplantation; D010148:Intractable Pain / Q000209:etiology* / Q000378:metabolism*; D010812:Physical Stimulation; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000378:metabolism; D013977:Tibia / Q000000981:diagnostic imaging / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D053583:Interleukin-1beta; D011725:Pyridines; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580