Pain control: c-Jun N-terminal kinase (JNK) for neuropathic pain

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J Neurosci. 2006 Mar 29;26(13):3551-60.

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.

Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR,

Decosterd I, Ji RR.

Department of Anesthesiology, Pain Research Center, Brigham and

Women's Hospital, Harvard Medical School, Boston, Massachusetts

02115, USA.

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.