CCL-1 in the spinal cord contributes to neuropathic pain induced by nerve injury

N. Akimoto, K. Honda, D. Uta, K. Beppu, Y. Ushijima, Y. Matsuzaki, S. Nakashima, M. A. Kido, K. Imoto, Y. Takano, M. Noda

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Cytokines such as interleukins are known to be involved in the development of neuropathic pain through activation of neuroglia. However, the role of chemokine (C-C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, in the nociceptive transmission remains unclear. We found that CCL-1 was upregulated in the spinal dorsal horn after partial sciatic nerve ligation. Therefore, we examined actions of recombinant CCL-1 on behavioural pain score, synaptic transmission, glial cell function and cytokine production in the spinal dorsal horn. Here we show that CCL-1 is one of the key mediators involved in the development of neuropathic pain. Expression of CCL-1 mRNA was mainly detected in the ipsilateral dorsal root ganglion, and the expression of specific CCL-1 receptor CCR-8 was upregulated in the superficial dorsal horn. Increased expression of CCR-8 was observed not only in neurons but also in microglia and astrocytes in the ipsilateral side. Recombinant CCL-1 injected intrathecally (i.t.) to naive mice induced allodynia, which was prevented by the supplemental addition of N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. Patch-clamp recordings from spinal cord slices revealed that application of CCL-1 transiently enhanced excitatory synaptic transmission in the substantia gelatinosa (lamina II). In the long term, i.t. injection of CCL-1 induced phosphorylation of NMDA receptor subunit, NR1 and NR2B, in the spinal cord. Injection of CCL-1 also upregulated mRNA level of glial cell markers and proinflammatory cytokines (IL-1b, TNF-a and IL-6). The tactile allodynia induced by nerve ligation was attenuated by prophylactic and chronic administration of neutralizing antibody against CCL-1 and by knocking down of CCR-8. Our results indicate that CCL-1 is one of the key molecules in pathogenesis, and CCL-1/CCR-8 signaling system can be a potential target for drug development in the treatment for neuropathic pain.

Original languageEnglish
Article numbere679
JournalCell Death and Disease
Volume4
Issue number6
DOIs
Publication statusPublished - Jun 1 2013

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Neuralgia
Spinal Cord
Ligands
Wounds and Injuries
Substantia Gelatinosa
Neuroglia
Hyperalgesia
Cytokines
N-Methyl-D-Aspartate Receptors
Synaptic Transmission
Ligation
CCR Receptors
CC Chemokines
Messenger RNA
Injections
Dizocilpine Maleate
Interleukins
Spinal Ganglia
Microglia
Sciatic Nerve

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

CCL-1 in the spinal cord contributes to neuropathic pain induced by nerve injury. / Akimoto, N.; Honda, K.; Uta, D.; Beppu, K.; Ushijima, Y.; Matsuzaki, Y.; Nakashima, S.; Kido, M. A.; Imoto, K.; Takano, Y.; Noda, M.

In: Cell Death and Disease, Vol. 4, No. 6, e679, 01.06.2013.

Research output: Contribution to journalArticle

Akimoto, N, Honda, K, Uta, D, Beppu, K, Ushijima, Y, Matsuzaki, Y, Nakashima, S, Kido, MA, Imoto, K, Takano, Y & Noda, M 2013, 'CCL-1 in the spinal cord contributes to neuropathic pain induced by nerve injury', Cell Death and Disease, vol. 4, no. 6, e679. https://doi.org/10.1038/cddis.2013.198
Akimoto N, Honda K, Uta D, Beppu K, Ushijima Y, Matsuzaki Y et al. CCL-1 in the spinal cord contributes to neuropathic pain induced by nerve injury. Cell Death and Disease. 2013 Jun 1;4(6). e679. https://doi.org/10.1038/cddis.2013.198
Akimoto, N. ; Honda, K. ; Uta, D. ; Beppu, K. ; Ushijima, Y. ; Matsuzaki, Y. ; Nakashima, S. ; Kido, M. A. ; Imoto, K. ; Takano, Y. ; Noda, M. / CCL-1 in the spinal cord contributes to neuropathic pain induced by nerve injury. In: Cell Death and Disease. 2013 ; Vol. 4, No. 6.
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