title: CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury.
abstract: 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.
authors.affiliation: Pain Group, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Université Pierre et Marie Curie, Inserm Unité Mixte de Recherche en Santé 975, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, 75013 Paris, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Van Steenwinckel
authors.forename: Annabelle
authors.initials: A
authors.lastname: Reaux-Le Goazigo
authors.forename: Blandine
authors.initials: B
authors.lastname: Pommier
authors.forename: Annie
authors.initials: A
authors.lastname: Mauborgne
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Dansereau
authors.forename: Patrick
authors.initials: P
authors.lastname: Kitabgi
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.forename: Michel
authors.initials: M
authors.lastname: Pohl
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mélik Parsadaniantz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002908:Chronic Disease; D003251:Constriction, Pathologic; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005455:Fluorescent Antibody Technique; D006930:Hyperalgesia / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D008297:Male; D008854:Microscopy, Electron; D009437:Neuralgia / Q000473:pathology*; D009474:Neurons / Q000378:metabolism*; D059348:Peripheral Nerve Injuries; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000293:injuries / Q000473:pathology; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; C505875:INCB3344; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D012333:RNA, Messenger; D054390:Receptors, CCR2; D048049:Extracellular Signal-Regulated MAP Kinases