CCL2 Released from Neuronal Synaptic Vesicles in the Spinal Cord Is a Major Mediator of Local Inflammation and Pain after Peripheral Nerve Injury

被引:163
作者
Van Steenwinckel, Juliette
Reaux-Le Goazigo, Annabelle
Pommier, Blandine
Mauborgne, Annie
Dansereau, Marc-Andre [2 ]
Kitabgi, Patrick
Sarret, Philippe [2 ]
Pohl, Michel
Parsadaniantz, Stephane Melik [1 ]
机构
[1] Univ Paris 06, Inst Cerveau & Moelle Epiniere,Pain Grp, INSERM,CNRS,UMR 7225,Fac Med Pitie Salpetriere, Ctr Rech,Unite Mixte Rech Sante 975,Equipe Douleu, F-75013 Paris, France
[2] Univ Sherbrooke, Fac Med & Hlth Sci, Dept Physiol & Biophys, Sherbrooke, PQ J1H 5N4, Canada
基金
加拿大健康研究院;
关键词
MONOCYTE CHEMOATTRACTANT PROTEIN-1; DORSAL-ROOT GANGLIA; SUBSTANCE-P-LIKE; GENE-RELATED PEPTIDE; LAMINAE-I-III; NEUROPATHIC PAIN; INVITRO RELEASE; CENTRAL SENSITIZATION; CHEMOKINE RECEPTOR; TACTILE ALLODYNIA;
D O I
10.1523/JNEUROSCI.5986-10.2011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
CCL2 chemokine and its receptor CCR2 may contribute to neuropathic pain development. We tested the hypothesis that injury to peripheral nerves triggers CCL2 release from afferents in the dorsal horn spinal cord (DHSC), leading to pronociceptive effects, involving the production of proinflammatory factors, in particular. Consistent with the release of CCL2 from primary afferents, electron microscopy showed the CCL2 immunoreactivity in glomerular boutons and secretory vesicles in the DHSC of naive rats. Through the ex vivo superfusion of DHSC slices, we demonstrated that the rate of CCL2 secretion was much lower in neonatal capsaicin-treated rats than in controls. Thus, much of the CCL2 released in the DHSC originates from nociceptive fibers bearing TRPV1 (transient receptor potential vanilloid 1). In contrast, high levels of CCL2 released from the DHSC were observed in neuropathic pain animal model induced by chronic constriction of the sciatic nerve (SN-CCI). The upregulated expression of proinflammatory markers and extracellular signal-regulated kinase (ERK) 1/2 pathway activation (ERK1/2 phosphorylation) in the DHSC of SN-CCI animals were reversed by intrathecal administration of the CCR2 antagonist INCB3344 (N-[2-[[(3S, 4S)-1-E4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexyl]-4-ethoxy-3-pyrrolidinyl]amino]-2-oxoethyl]-3-(trifluoromethyl) benzamide). These pathological pain-associated changes in the DHSC were mimicked by the intrathecal injection of exogenous CCL2 in naive rats and were prevented by the administration of INCB3344 or ERK inhibitor (PD98059). Finally, mechanical allodynia, which was fully developed 2 weeks after SN-CCI in rats, was attenuated by the intrathecal injection of INCB3344. Our data demonstrate that CCL2 has the typical characteristics of a neuronal mediator involved in nociceptive signal processing and that antagonists of its receptor are promising agents from treating neuropathic pain.
引用
收藏
页码:5865 / 5875
页数:11
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