p38 activation in uninjured primary afferent neurons and in spinal microglia contributes to the development of neuropathic pain induced by selective motor fiber injury.
Compelling evidence shows that the adjacent uninjured primary afferents play an important role in the development of neuropathic pain after nerve injury. The underlying mechanisms, however, are largely unknown. In the present study, the selective motor fiber injury was performed by L5 ventral root transection (L5 VRT), and p38 activation in dorsal root ganglia (DRG) and L5 spinal dorsal horn was examined. The results showed that phospho-p38 immunoreactivity (p-p38-IR) was increased in both L4 and L5 DRGs, starting on day 1 and persisting for nearly 3 weeks (P<0.05) following L5 VRT and that the activated p38 was confined in neurons, especially in IB4 positive C-type neurons. L5 VRT also induced p38 activation in L5 spinal dorsal horn, occurred at the first day after the lesion and lasted for 2 weeks (P<0.05). The activated p38 is restricted entirely in spinal microglia. In contrast, selective injury of sensory neurons by L5 dorsal root transection (L5 DRT) failed to induce behavioral signs of neuropathic pain and activated p38 only in L5 DRG but not in L4 DRG and L5 spinal dorsal horn. Intraperitoneal injection of thalidomide, an inhibitor of TNF-alpha synthesis, prevented p38 activation in DRG and spinal cord. Intrathecal injection of p38 inhibitor SB203580, starting before L5 VRT, inhibited the abnormal pain behaviors. Post-treatment with SB203580 performed at the 1st day or at the 8th day after surgery also reduced established neuropathic pain. These data suggest that p38 activation in uninjured DRGs neurons and in spinal microglia is necessary for the initiation and maintenance of neuropathic pain induced by L5 VRT.
Xu
Ji-Tian
JT
Pain Research Center, Zhongshan Medical School of Sun Yat-sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, PR China.
Xin
Wen-Jun
WJ
Wei
Xu-Hong
XH
Wu
Chang-You
CY
Ge
Yu-Xing
YX
Liu
Yan-Ling
YL
Zang
Ying
Y
Zhang
Tong
T
Li
Yong-Yong
YY
Liu
Xian-Guo
XG
D000818:Animals; D003714:Denervation; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000201:enzymology; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology; D006987:Hypesthesia / Q000209:etiology / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D008161:Lumbosacral Region; D008297:Male; D017628:Microglia / Q000201:enzymology*; D009046:Motor Neurons / Q000473:pathology; D009412:Nerve Fibers / Q000473:pathology; D009437:Neuralgia / Q000209:etiology* / Q000503:physiopathology / Q000523:psychology; D009475:Neurons, Afferent / Q000201:enzymology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology*; D013126:Spinal Nerve Roots / Q000293:injuries* / Q000473:pathology; D013792:Thalidomide / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580