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|Title:||IMPLICATION OF THE CHEMOKINE MCP-1/CCL2 IN
SPINAL NOCICEPTIVE NEUROTRANSMISSION
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|Authors/Affiliations:||4 Marc-André Dansereau*; 3 Romain Gosselin; 2 Michel Pohl; 3 Blandine Pommier; 3 William Rostene; 3 Patrick Kitabgi; 1 Nicolas Beaudet; 3 Stéphane Mélik-Parsadaniantz, 1 P.Sarret |
1 ; 2 Unité mixte 713 INSERM-UPMC, Faculté de Médecine Pitié-Salpêtrière, Paris, France; 3 Unité mixte 732 INSERM-UPMC, Hôpital Saint-Antoine, Paris, France; 4 Université de Sherbrooke; QC, Canada
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|Content:||Objectives: Chemokines are secreted proteins classically implicated in immune and inflammatory functions. However, growing evidences reveal that chemokines are also produced in the central and peripheral nervous systems and play an important role in pain modulation. The aim of the present study was therefore to investigate whether the Monocyte Chemoattractant Protein-1 (MCP-1)/CCL2 is directly involved in pain transmission at the spinal level in rats. |
Methods and Results: We first established, using immunoblotting and immunohistochemical techniques, that MCP-1 was extensively associated with spinal nociceptive pathways, both in the dorsal root ganglia (DRGs) and in the superficial layers of the dorsal horn of the spinal cord. Accordingly, potassium-triggered depolarization evoked calcium-dependent release of MCP-1 from DRGs and spinal explants. We then examined the effects of intrathecal (i.t.) administration of MCP-1 on acute thermal pain and on the nociceptive response to tactile stimuli. I.t. administration of MCP-1 at a dose of 1µg produced a significant hyperalgesic effect in the hot-plate test, decreasing by 56% the response latency after 2 hours. At the same time, i.t injection of MCP-1 progressively induced mechanical allodynia, lowering the paw-withdrawal threshold to von Frey filament from 47g to 32g. Changes in non-noxious tactile threshold were maintained over 4 days after MCP-1 treatment. The enrichment of MCP-1 in vesicular fractions containing substance P and CGRP, further supported the pro-nociceptive role of MCP-1. To assess whether the MCP-1 effects were attributable to a selective stimulation of CCR2 receptors, rats were concomitantly treated with MCP-1 and the CCR2 antagonist INCB-3344. A single injection of 1 mM INCB-3344 completely prevented MCP-1-induced hyperalgesia and blocked the development of allodynia up to the third day.
Conclusions: Altogether, these results demonstrate that MCP-1 is constitutively expressed by ascending nociceptive structures and is directly implicated in the neurotransmission of painful stimuli, probably by its binding to CCR2 receptors. Supported by CIHR, FRSQ, ANR and INSERM.
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