Involvement of the chemokine CCL3 and the purinoceptor P2X7 in the spinal cord in paclitaxel-induced mechanical allodynia

Molecular Pain

Kazuhide Inoue¹  Makoto Tsuda¹  Hidetoshi Tozaki-Saitoh¹  Tomoyuki Inoue¹  Kenichiro Nagata¹  Ryutaro Ochi-ishi¹ 

[1] Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 MaidashiHigashi-ku, Fukuoka 812-8582, Japan

关键词: Rats;    Allodynia;    Spinal cord;    Chemokines;    Microglia;    Paclitaxel;   

Others  :  1138502
DOI  :  10.1186/1744-8069-10-53

 received in 2014-05-07, accepted in 2014-08-11,  发布年份 2014

【 摘 要 】

Background

Paclitaxel is an effective chemotherapeutic agent widely used for the treatment of solid tumors. The major dose-limiting toxicity of paclitaxel is peripheral neuropathy. The mechanisms underlying the development and maintenance of paclitaxel-induced peripheral neuropathy are still unclear, and there are no currently established effective treatments. Accumulating evidence in models of neuropathic pain in which peripheral nerves are lesioned has implicated spinal microglia and chemokines in pain hypersensitivity, but little is know about their roles in chemotherapy-induced peripheral neuropathy. In the present study, we investigated the role of CC-chemokine ligand 3 (CCL3) in the spinal cord in the development and maintenance of mechanical allodynia using a rat model of paclitaxel-induced neuropathy.

Findings

Repeated intravenous administration of paclitaxel induced a marked decrease in paw withdrawal threshold in response to mechanical stimulation (mechanical allodynia). In these rats, the number of microglia in the spinal dorsal horn (SDH) was significantly increased. Paclitaxel-treated rats showed a significant increase in the expression of mRNAs for CCL3 and its receptor CCR5 in the SDH. Intrathecal administration of a CCL3-neutralizing antibody not only attenuated the development of paclitaxel-induced mechanical allodynia but also reversed its maintenance. Paclitaxel also upregulated expression of purinoceptor P2X7 receptors (P2X7Rs), which have been implicated in the release of CCL3 from microglia, in the SDH. The selective P2X7R antagonist A438079 had preventive and reversal effects on paclitaxel-induced allodynia.

Conclusions

Our findings suggest a contribution of CCL3 and P2X7Rs in the SDH to paclitaxel-induced allodynia and may provide new therapeutic targets for paclitaxel-induced painful neuropathy.

【 授权许可】

   
2014 Ochi-ishi et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Scripture CD, Figg WD, Sparreboom A: Peripheral neuropathy induced by paclitaxel: recent insights and future perspectives. Curr Neuropharmacol 2006, 4:165-172.
• [2]Argyriou AA, Koltzenburg M, Polychronopoulos P, Papapetropoulos S, Kalofonos HP: Peripheral nerve damage associated with administration of taxanes in patients with cancer. Crit Rev Oncol Hematol 2008, 66:218-228.
• [3]Tanabe Y, Hashimoto K, Shimizu C, Hirakawa A, Harano K, Yunokawa M, Yonemori K, Katsumata N, Tamura K, Ando M, Kinoshita T, Fujiwara Y: Paclitaxel-induced peripheral neuropathy in patients receiving adjuvant chemotherapy for breast cancer. Int J Clin Oncol 2013, 18:132-138.
• [4]Scholz J, Woolf CJ: The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007, 10:1361-1368.
• [5]Inoue K, Tsuda M: Microglia and neuropathic pain. Glia 2009, 57:1469-1479.
• [6]Tsuda M, Masuda T, Tozaki-Saitoh H, Inoue K: P2X4 receptors and neuropathic pain. Front Cell Neurosci 2013, 7:191.
• [7]White FA, Jung H, Miller RJ: Chemokines and the pathophysiology of neuropathic pain. Proc Natl Acad Sci U S A 2007, 104:20151-20158.
• [8]Kuner R: Central mechanisms of pathological pain. Nat Med 2010, 16:1258-1266.
• [9]Peters CM, Jimenez-Andrade JM, Jonas BM, Sevcik MA, Koewler NJ, Ghilardi JR, Wong GY, Mantyh PW: Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells. Exp Neurol 2007, 203:42-54.
• [10]Cata JP, Weng HR, Dougherty PM: The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats. Brain Res 2008, 1229:100-110.
• [11]Kataoka A, Tozaki-Saitoh H, Koga Y, Tsuda M, Inoue K: Activation of P2X7 receptors induces CCL3 production in microglial cells through transcription factor NFAT. J Neurochem 2009, 108:115-125.
• [12]Matsushita K, Tozaki-Saitoh H, Kojima C, Masuda T, Tsuda M, Inoue K, Hoka S: Chemokine (C-C motif) receptor 5 is an important pathological regulator in the development and maintenance of neuropathic pain. Anesthesiology 2014, 120:1491-1503.
• [13]Kiguchi N, Kobayashi Y, Maeda T, Saika F, Kishioka S: CC-chemokine MIP-1alpha in the spinal cord contributes to nerve injury-induced neuropathic pain. Neurosci Lett 2010, 484:17-21.
• [14]Maurer M, von Stebut E: Macrophage inflammatory protein-1. Int J Biochem Cell Biol 2004, 36:1882-1886.
• [15]Padi SS, Shi XQ, Zhao YQ, Ruff MR, Baichoo N, Pert CB, Zhang J: Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation. Pain 2012, 153:95-106.
• [16]Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53:55-63.
• [17]McGaraughty S, Chu KL, Namovic MT, Donnelly-Roberts DL, Harris RR, Zhang XF, Shieh CC, Wismer CT, Zhu CZ, Gauvin DM, Fabiyi AC, Honore P, Gregg RJ, Kort ME, Nelson DW, Carroll WA, Marsh K, Faltynek CR, Jarvis MF: P2X7-related modulation of pathological nociception in rats. Neuroscience 2007, 146:1817-1828.
• [18]Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H: Purinergic signalling in the nervous system: an overview. Trends Neurosci 2009, 32:19-29.
• [19]Okamura T, Katayama T, Obinata C, Iso Y, Chiba Y, Kobayashi H, Yamada Y, Harashima H, Minami M: Neuronal injury induces microglial production of macrophage inflammatory protein-1alpha in rat corticostriatal slice cultures. J Neurosci Res 2012, 90:2127-2133.
• [20]Kobayashi K, Takahashi E, Miyagawa Y, Yamanaka H, Noguchi K: Induction of the P2X7 receptor in spinal microglia in a neuropathic pain model. Neurosci Lett 2011, 504:57-61.
• [21]He WJ, Cui J, Du L, Zhao YD, Burnstock G, Zhou HD, Ruan HZ: Spinal P2X(7) receptor mediates microglia activation-induced neuropathic pain in the sciatic nerve injury rat model. Behav Brain Res 2012, 226:163-170.
• [22]Kim B, Jeong HK, Kim JH, Lee SY, Jou I, Joe EH: Uridine 5'-diphosphate induces chemokine expression in microglia and astrocytes through activation of the P2Y6 receptor. J Immunol 2011, 186:3701-3709.
• [23]Yoon SY, Robinson CR, Zhang H, Dougherty PM: Spinal astrocyte gap junctions contribute to oxaliplatin-induced mechanical hypersensitivity. J Pain 2013, 14:205-214.
• [24]Ji XT, Qian NS, Zhang T, Li JM, Li XK, Wang P, Zhao DS, Huang G, Zhang L, Fei Z, Jia D, Niu L: Spinal astrocytic activation contributes to mechanical allodynia in a rat chemotherapy-induced neuropathic pain model. PLoS One 2013, 8:e60733.
• [25]Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S: Macrophage inflammatory protein-1alpha mediates the development of neuropathic pain following peripheral nerve injury through interleukin-1beta up-regulation. Pain 2010, 149:305-315.
• [26]Gamo K, Kiryu-Seo S, Konishi H, Aoki S, Matsushima K, Wada K, Kiyama H: G-protein-coupled receptor screen reveals a role for chemokine receptor CCR5 in suppressing microglial neurotoxicity. J Neurosci 2008, 28:11980-11988.
• [27]Jo YH, Schlichter R: Synaptic corelease of ATP and GABA in cultured spinal neurons. Nat Neurosci 1999, 2:241-245.
• [28]Fam SR, Gallagher CJ, Salter MW: P2Y(1) purinoceptor-mediated Ca(2+) signaling and Ca2+ wave propagation in dorsal spinal cord astrocytes. J Neurosci 2000, 20:2800-2808.
• [29]Pevida M, Lastra A, Hidalgo A, Baamonde A, Menendez L: Spinal CCL2 and microglial activation are involved in paclitaxel-evoked cold hyperalgesia. Brain Res Bull 2013, 95:21-27.