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

Details

Serval ID
serval:BIB_73E7157F5634
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
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
Journal
Journal of Neuroscience
Author(s)
Zhuang  Z. Y., Wen  Y. R., Zhang  D. R., Borsello  T., Bonny  C., Strichartz  G. R., Decosterd  I., Ji  R. R.
ISSN
1529-2401 (Electronic)
Publication state
Published
Issued date
03/2006
Volume
26
Number
13
Pages
3551-60
Notes
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't --- Old month value: Mar 29
Abstract
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 (<12 h) but transient activation of JNK in the L5 (injured) but not L4 (intact) DRG. JNK activation in the DRG was mainly found in small-sized C-fiber neurons. Infusion of D-JNKI-1 into the L5 DRG prevented but did not reverse SNL-induced mechanical allodynia. Finally, intrathecal administration of an astroglial toxin, l-alpha-aminoadipate, reversed mechanical allodynia. Our data suggest that JNK activation in the DRG and spinal cord play distinct roles in regulating the development and maintenance of neuropathic pain, respectively, and that spinal astrocytes contribute importantly to the persistence of mechanical allodynia. Targeting the JNK pathway in spinal astroglia may present a new and efficient way to treat neuropathic pain symptoms.
Keywords
Animals Astrocytes/drug effects/*enzymology Enzyme Activation/drug effects Ganglia, Spinal/drug effects/*enzymology Hyperalgesia/complications/*enzymology/prevention & control MAP Kinase Kinase 4/antagonists & inhibitors/*metabolism Male Neuralgia/complications/*enzymology/prevention & control Neurons, Afferent/drug effects/*enzymology Peptides/*administration & dosage Rats Rats, Sprague-Dawley Spinal Nerves/drug effects/injuries
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 15:19
Last modification date
20/08/2019 15:31
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