title: NF-κB, ERK, p38 MAPK and JNK contribute to the initiation and/or maintenance of mechanical allodynia induced by tumor necrosis factor-alpha in the red nucleus.
abstract: Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-α) in the red nucleus (RN) plays facilitated roles in the development of abnormal pain. Here, the roles of nuclear factor-kappa B (NF-κB), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) in TNF-α-evoked mechanical allodynia were investigated. Repeated microinjection of recombinant rat TNF-α (20 ng daily for 3 days) into the unilateral RN of normal rats induced a significant mechanical allodynia in the contralateral but not ipsilateral hind paw at the fifth day and disappeared 24h later. Re-injection of a single bolus of 20 ng TNF-α into the same RN reproduced this mechanical allodynia within 30 min, which was used as a pain model for further experiments. Immunohistochemistry demonstrated that NF-κB, phospho-ERK (p-ERK) and p-p38 MAPK in the RN were significantly up-regulated at 1h after TNF-α microinjection, the up-regulations of NF-κB and p-ERK but not p-p38 MAPK remained at high levels till 4h later. A significant up-regulation of p-JNK occurred at 4h (but not 1h) after TNF-α microinjection, which was later than those of NF-κB, p-ERK and p-p38 MAPK. Pre-treatment with NF-κB inhibitor PDTC, ERK inhibitor PD98059 or p38 MAPK inhibitor SB203580 at 30 min before TNF-α microinjected into the RN completely prevented TNF-α-evoked mechanical allodynia. Pre-treatment with JNK inhibitor SP600125 did not prevent but reversed TNF-α-evoked mechanical allodynia during the subsequent detection time. Post-treatment with PDTC, PD98059 or SP600125 (but not SB203580) at 4h after TNF-α microinjected into the RN significantly reversed TNF-α-evoked mechanical allodynia. These results further prove that TNF-α in the RN plays a crucial role in the development of abnormal pain, and the algesic effect of TNF-α is initiated through activating NF-κB, ERK and p38 MAPK. The later maintenance of TNF-α-evoked mechanical allodynia mainly relies on the activation of NF-κB, ERK and JNK, but not p38 MAPK.
authors.affiliation: Department of Immunology and Pathogenic Biology, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, China; Department of Pathogenic Biology and Immunology, Qinghai University College of Medicine, Xining, Qinghai 810016, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Mei-Ting
authors.initials: MT
authors.lastname: Duan
authors.forename: Shui-Ping
authors.initials: SP
authors.lastname: Han
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zeng
authors.forename: Jun-Yang
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004334:Drug Administration Schedule; D048049:Extracellular Signal-Regulated MAP Kinases; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012012:Red Nucleus / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: DRG; ERK; IL; JNK; LTP; Mitogen-activated protein kinase; NF-κB; NGF; Nuclear factor-kappa B; PDTC; PWT; RN; RVM; Rat; Red nucleus; SNI; TNF-α; Tumor necrosis factor-alpha; c-Jun N-terminal kinase; dorsal root ganglia; extracellular signal-regulated kinase; interleukin; long-term potentiation; nerve growth factor; nuclear factor-kappa B; p38 MAPK; p38 mitogen-activated protein kinase; paw withdrawal threshold; pyrrolidine dithiocarbamate; red nucleus; rostral ventromedial medulla; spared nerve injury; tumor necrosis factor-alpha