A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance

Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GF...

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Published in:The Journal of neuroscience 2006-03, Vol.26 (13), p.3551-3560
Main Authors: Zhuang, Zhi-Ye, Wen, Yeong-Ray, Zhang, De-Ren, Borsello, Tiziana, Bonny, Christophe, Strichartz, Gary R, Decosterd, Isabelle, Ji, Ru-Rong
Format: Article
Language:English
Subjects:
Animals
Astrocytes - drug effects
Astrocytes - enzymology
Enzyme Activation - drug effects
Ganglia, Spinal - drug effects
Ganglia, Spinal - enzymology
Hyperalgesia - complications
Hyperalgesia - enzymology
Hyperalgesia - prevention & control
Male
MAP Kinase Kinase 4 - antagonists & inhibitors
MAP Kinase Kinase 4 - metabolism
Neuralgia - complications
Neuralgia - enzymology
Neuralgia - prevention & control
Neurons, Afferent - drug effects
Neurons, Afferent - enzymology
Peptides - administration & dosage
Rats
Rats, Sprague-Dawley
Spinal Nerves - drug effects
Spinal Nerves - injuries
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Summary:Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast, p38 mitogen-activated protein kinase activation was found in spinal microglia after SNL, which had fallen to near basal level by 21 d. Intrathecal infusion of a JNK peptide inhibitor, D-JNKI-1, did not affect normal pain responses but potently prevented and reversed SNL-induced mechanical allodynia, a major symptom of neuropathic pain. Intrathecal D-JNKI-1 also suppressed SNL-induced phosphorylation of the JNK substrate, c-Jun, in spinal astrocytes. However, SNL-induced upregulation of GFAP was not attenuated by spinal D-JNKI-1 infusion. Furthermore, SNL induced a rapid (
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.5290-05.2006