Activation of extracellular signal-regulated protein kinases 5 in the spinal cord contributes to the neuropathic pain behaviors induced by CCI in rats.
OBJECTIVE
To investigate whether activation and translocation of extracellular signal-regulated kinase 5 (ERK5) is involved in the induction and maintenance of neuropathic pain and observe the effects of activation and translocation of ERK5 on the expression of phosphorylated cAMP response element binding (pCREB) in the chronic neuropathic pain.


METHODS
Lumbar intrathecal catheters were chronically implanted in male Sprague-Dawley rats. The left sciatic nerve was loosely ligated proximal to the sciatica's trifurcation at approximately 1.0 mm intervals with 4-0 silk sutures. The phosphorothioate-modified antisense oligonucleotides (AS-ODNs) were intrathecally administered every 12 hours, 1 day pre-chronic constriction injury (CCI) and 3 day post-CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal latency to a radiant heat and von Frey filaments. Expressions of phosphorylated ERK5 (pERK5), pCREB, were assessed by both Western blotting and immunohistochemical analysis.


RESULTS
Intrathecal injection of ERK5 AS-ODN significantly attenuated CCI-induced mechanical allodynia and thermal hyperalgesia. CCI significantly increased the expression of pERK5 neurons in the ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. The time courses of pERK5 expression showed that the levels of both cytosol and nuclear pERK5 were increased at all points after CCI and reached a peak level on post-operative day 5. CCI significantly increased the expression of pERK5 neurons in the laminae I and II of ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. Phospho-CREB-positive neurons were distributed in all laminae of the bilateral spinal cord. Intrathecal injection AS-ODN markedly suppressed the increase of CCI-induced pERK5, pCREB expression in the spinal cord.


CONCLUSIONS
The activation of ERK5 pathways contributes to neuropathic pain in CCI rats, and the function of pERK5 may partly be accomplished via the CREB protein-dependent gene expression.
Zhang
Lin
L
Department of Anesthesia, The First Affiliated Hospital, Medical College of Qingdao University, Qingdao, China.
Xiao
Chun
C
Wang
Jun-Ke
JK
Zhang
Li-Cai
LC
Zeng
Yin-Ming
YM
D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D002408:Catheters, Indwelling; D003080:Cold Temperature; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism / Q000503:physiopathology; D020319:Oligodeoxyribonucleotides, Antisense; D010146:Pain / Q000209:etiology / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold; D010766:Phosphorylation; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism / Q000503:physiopathology; D020426:Sciatic Neuropathy / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D013116:Spinal Cord / Q000378:metabolism* / Q000503:physiopathology
D017362:Cyclic AMP Response Element-Binding Protein; D020319:Oligodeoxyribonucleotides, Antisense; D048054:Mitogen-Activated Protein Kinase 7