title: CCL-1 in the spinal cord contributes to neuropathic pain induced by nerve injury.
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-1β, TNF-α 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.
authors.affiliation: Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Akimoto
authors.forename: K
authors.initials: K
authors.lastname: Honda
authors.forename: D
authors.initials: D
authors.lastname: Uta
authors.forename: K
authors.initials: K
authors.lastname: Beppu
authors.forename: Y
authors.initials: Y
authors.lastname: Ushijima
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: S
authors.initials: S
authors.lastname: Nakashima
authors.forename: M A
authors.initials: MA
authors.lastname: Kido
authors.forename: K
authors.initials: K
authors.lastname: Imoto
authors.forename: Y
authors.initials: Y
authors.lastname: Takano
authors.forename: M
authors.initials: M
authors.lastname: Noda
mesh_terms: D000700:Analgesics / Q000008:administration & dosage; D000818:Animals; D002478:Cells, Cultured; D054402:Chemokine CCL1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D005727:Ganglia, Spinal / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid; D006930:Hyperalgesia / Q000188:drug therapy; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D059225:Nociception; D059348:Peripheral Nerve Injuries / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics; D054401:Receptors, CCR8 / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000700:Analgesics; C502258:Ccl1 protein, mouse; C489319:Ccr8 protein, mouse; D054402:Chemokine CCL1; D034741:RNA, Small Interfering; D054401:Receptors, CCR8; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016291:Dizocilpine Maleate