Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury.
Mitogen-activated protein kinase (MAPK) plays an important role in the induction and maintenance of neuropathic pain. Transforming growth factor-activated kinase 1 (TAK1), a member of the MAPK kinase kinase family, is indispensable for the activation of c-Jun N-terminal kinase (JNK) and p38 MAPK. We now show that TAK1 induced in spinal cord astrocytes is crucial for mechanical hypersensitivity after peripheral nerve injury. Nerve injury induced a striking increase in the expression of TAK1 in the ipsilateral dorsal horn, and TAK1 was increased in hyperactive astrocytes, but not in neurons or microglia. Intrathecal administration of TAK1 antisense oligodeoxynucleotide (AS-ODN) prevented and reversed nerve injury-induced mechanical, but not heat hypersensitivity. Furthermore, TAK1 AS-ODN suppressed the activation of JNK1, but not p38 MAPK, in spinal astrocytes. In contrast, there was no change in TAK1 expression in primary sensory neurons, and TAK1 AS-ODN did not attenuate the induction of transient receptor potential ion channel TRPV1 in sensory neurons. Taken together, these results demonstrate that TAK1 upregulation in spinal astrocytes has a substantial role in the development and maintenance of mechanical hypersensitivity through the JNK1 pathway. Thus, preventing the TAK1/JNK1 signaling cascade in astrocytes might provide a fruitful strategy for treating intractable neuropathic pain.
Katsura
Hirokazu
H
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Obata
Koichi
K
Miyoshi
Kan
K
Kondo
Takashi
T
Yamanaka
Hiroki
H
Kobayashi
Kimiko
K
Dai
Yi
Y
Fukuoka
Tetsuo
T
Sakagami
Masafumi
M
Noguchi
Koichi
K
D000818:Animals; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D006614:Hindlimb; D007700:Kinetics; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense; D051381:Rats; D017207:Rats, Sprague-Dawley; D012684:Sensory Thresholds; D013116:Spinal Cord / Q000201:enzymology*; D013119:Spinal Cord Injuries / Q000201:enzymology*; D013127:Spinal Nerves / Q000502:physiology / Q000503:physiopathology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020319:Oligodeoxyribonucleotides, Antisense; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7