c-Jun N-terminal kinase activation in dorsal root ganglion contributes to pain hypersensitivity

doi:10.1016/j.bbrc.2005.07.055

Biochemical and Biophysical Research Communications

Volume 335, Issue 1, 16 September 2005, Pages 132-138

https://doi.org/10.1016/j.bbrc.2005.07.055 Get rights and content

Abstract

Inflammatory pain, characterized by a decrease in the nociceptive threshold, arises through the actions of inflammatory mediators. Mitogen-activated protein kinase cascades participate in peripheral nociceptive sensitization. We examined the involvement of c-Jun N-terminal kinase (JNK) in the dorsal root ganglion (DRG) in the early phase of inflammation-induced hyperalgesia. An intra-plantar (i.pl.) injection of complete Freund’s adjuvant induced the activation of JNK in DRG neurons within 30 min. Pre-treatment as well as post-treatment of rats with a JNK inhibitor, SP600125, significantly attenuated thermal hyperalgesia, as assessed by paw-withdrawal latency, and the upregulation of c-fos immunoreactivity in dorsal horn neurons. An i.pl. injection of nerve growth factor (NGF) also induced the phosphorylation of JNK as well as thermal hyperalgesia, and SP600125 improved hyperalgesia. Inhibitor experiments suggest that JNK and extracellular signal-regulated protein kinase act on primary nociceptive neurons synergistically. These findings demonstrate that JNK is a therapeutic target for treating inflammation-induced pain hypersensitivity.

Section snippets

Materials and methods

Animals. Adult male Sprague–Dawley rats (200–250 g) were used according to Chiba University Animal Care Institutional Guidelines following the National Institute of Health Guidelines for the Care and Use of Laboratory Animals (1996 revision).

Surgical procedures. All procedures were performed under 3% halothane anesthesia in 50% O₂. Complete Freund’s adjuvant (50 μ; CFA; Calbiochem, La Jolla, CA) was i.pl. injected into the ipsilateral hind paw 60 min after SP600125 (5 mg/kg) (n = 7) or DMSO (100 μl) (n

Localized peripheral inflammation activates JNK

Experimental inflammation produced by an i.pl. injection of CFA results in local sensory hypersensitivity. To test if localized peripheral inflammation activates JNK in the DRG, CFA was injected into the plantar surface of the left hind paw. This injection induces localized inflammation that develops over minutes, lasts more than a week, and is associated with swelling and erythema, as well as thermal and mechanical pain hypersensitivity [18]. CFA-induced inflammation produced an increase in

Discussion

In this study, we employed a rat model of hyperalgesia induced by CFA or NGF to address whether JNK is involved in inflammation-induced nociceptor sensitization, and demonstrated that an i.pl. injection of CFA or NGF-activated JNK in the DRG. Some signals for p-JNK were found in small-to-medium-diameter neurons in the DRG, whereas some large neurons were also immunopositive for p-JNK. JNK activation is involved in CFA- or NGF-induced hyperalgesia, as the specific inhibitor of JNK was effective

Acknowledgments

This work was supported by the Research Grant from the Inamori Foundation and the Research Grant (15A-2) for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare.

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c-Jun N-terminal kinase activation in dorsal root ganglion contributes to pain hypersensitivity

Abstract

Section snippets

Materials and methods

Localized peripheral inflammation activates JNK

Discussion

Acknowledgments

Brain Res.

Neuroscience

Neuron

Neuron

Int. J. Dev. Neurosci.

Neuron

Pain

Pain

Curr. Opin. Neurobol.

Evidence for a central component of post-injury pain hypersensitivity

Nature

Neuronal plasticity: increasing the gain in pain

Science

Expression of mu-, delta-, and kappa-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation

J. Neurosci.

Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors

J. Neurosci.

Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition

Nature

Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurons

Nature

Nociceptor sensitization by extracellular signal-regulated kinases

J. Neurosci.