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.
Xu
Li
L
Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China.
Huang
Yuguang
Y
Yu
Xuerong
X
Yue
Jianying
J
Yang
Nan
N
Zuo
Pingping
P
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