The influence of p38 mitogen-activated protein kinase inhibitor on synthesis of inflammatory cytokine tumor necrosis factor alpha in spinal cord of rats with chronic constriction injury.
BACKGROUND
Tumor necrosis factor alpha (TNF-alpha) could trigger p38 mitogen-activated protein kinase (MAPK) activation. Conversely phosphorylated p38 (p-p38) could induce the upregulation of TNF-alpha. In this study, we examined the hypothesis that chronic constrictive injury (CCI) of the sciatic nerve could promote spinal cord release of TNF-alpha and produce allodynia via the p38 MAPK pathway.


METHODS
Sprague-Dawley rats were divided into five groups: 1) naïve control rats, 2) sham surgery rats, 3) CCI surgery rats without treatment, 4) CCI surgery rats with saline (0.9%) treatment, and 5) CCI surgery rats with the p38 MAPK inhibitor SB203580 treatment. In treatment groups, saline or SB203580 (2 microg, twice a day) was given intrathecally starting 1 day before or 1 day or 7 days after CCI. All rats were killed at different times after surgery to examine p38 MAPK activity and TNF-alpha levels in the spinal cord by Western blot analysis or immunohistochemistry. Mechanical allodynia was tested by a series of von Frey hairs 3, 7, and 14 days after surgery.


RESULTS
p-p38 MAPK was significantly increased at 3, 7, and 14 days after CCI surgery compared with time-matched shams (P < 0.05). Peripheral nerve injury induced mechanical allodynia and enhanced spinal concentrations of TNF-alpha (P < 0.05). Pretreatment or early treatment with SB203580 inhibited p38 MAPK activity, resulting in reduction of TNF-alpha synthesis and attenuation of mechanical allodynia (P < 0.05).


CONCLUSIONS
p38 MAPK activation is one aspect of the signaling cascade that culminates in TNF-alpha synthesis and contributes to mechanical allodynia after peripheral nerve injury.
Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China.
Li
L
Xu
Yuguang
Y
Huang
Xuerong
X
Yu
Jianying
J
Yue
Nan
N
Yang
Pingping
P
Zuo
D000818:Animals; D002908:Chronic Disease; D003251:Constriction, Pathologic; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D016207:Cytokines; D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580