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

被引：63

作者：

Akimoto, N. ^{[1
,2
,5
]}

Honda, K. ^{[2
]}

Uta, D. ^{[3
]}

Beppu, K. ^{[1
]}

Ushijima, Y. ^{[2
]}

Matsuzaki, Y. ^{[2
]}

Nakashima, S. ^{[2
]}

Kido, M. A. ^{[4
]}

Imoto, K. ^{[3
]}

Takano, Y. ^{[2
]}

Noda, M. ^{[1
]}

机构：

[1] Kyushu Univ, Lab Pathophysiol, Grad Sch Pharmaceut Sci, Higashi Ku, Fukuoka 8128582, Japan

[2] Fukuoka Univ, Dept Physiol & Pharmacol, Fac Pharmaceut Sci, Fukuoka 8140180, Japan

[3] Natl Inst Physiol Sci, Dept Informat Physiol, Div Neural Signaling, Okazaki, Aichi 4448787, Japan

[4] Kyushu Univ, Dept Mol Cell Biol & Oral Anat, Grad Sch Dent Sci, Higashi Ku, Fukuoka 8128582, Japan

[5] Japan Soc Promot Sci, Tokyo, Japan

来源：

CELL DEATH & DISEASE | 2013年 / 4卷

关键词：

CCL-1; neuropathic pain; glutamate; spinal cord; NMDA receptor; SUBSTANTIA-GELATINOSA NEURONS; NMDA-RECEPTOR PHOSPHORYLATION; INFLAMMATORY HYPERALGESIA; TACTILE ALLODYNIA; CLAMP RECORDINGS; NR2B SUBUNIT; IMMUNE CELLS; DORSAL-HORN; MICROGLIA; RAT;

D O I：

10.1038/cddis.2013.198

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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-1 beta, TNF-alpha 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.

引用

页码：e679 / e679

页数：13

共 59 条

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