%0 Journal Article %1 van_steenwinckel_ccl2_2011 %A Steenwinckel, Juliette Van %A Goazigo, Annabelle Reaux-Le %A Pommier, Blandine %A Mauborgne, Annie %A Dansereau, Marc-André %A Kitabgi, Patrick %A Sarret, Philippe %A Pohl, Michel %A Parsadaniantz, Stéphane Mélik %D 2011 %J The Journal of Neuroscience: The Official Journal of the Society for Neuroscience %K Animals Blotting Chemokine_{CCL2} Chronic_Disease Constriction Electron Extracellular_{Signal-Regulated}_{MAP}_Kinases Fluorescent_Antibody_Technique Hyperalgesia Immunohistochemistry Inflammation Male Messenger Microscopy Neuralgia Neurons Newborn Pathologic Peripheral_Nerves Protein_Kinase_Inhibitors Pyrrolidines Rats Receptors Reverse_Transcriptase_Polymerase_Chain_Reaction Sciatic_Nerve Spinal_Cord Synaptic_Vesicles Western {CCR2} {Enzyme-Linked}_Immunosorbent_Assay {RNA} {Sprague-Dawley} %N 15 %P 5865--5875 %R 10.1523/JNEUROSCI.5986-10.2011 %T CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury %U http://www.ncbi.nlm.nih.gov/pubmed/21490228 %V 31 %X 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-pyrrolidinylamino-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.

@article{van_steenwinckel_ccl2_2011, 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.}, added-at = {2011-08-03T17:38:07.000+0200}, author = {Steenwinckel, Juliette Van and Goazigo, Annabelle {Reaux-Le} and Pommier, Blandine and Mauborgne, Annie and Dansereau, {Marc-André} and Kitabgi, Patrick and Sarret, Philippe and Pohl, Michel and Parsadaniantz, Stéphane Mélik}, biburl = {https://www.bibsonomy.org/bibtex/264e5f21598e7ea9f03892679599c8333/crc_chus}, doi = {10.1523/JNEUROSCI.5986-10.2011}, interhash = {9330039ffa7cb6996e699ee312af943a}, intrahash = {64e5f21598e7ea9f03892679599c8333}, issn = {1529-2401}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, keywords = {Animals Blotting Chemokine_{CCL2} Chronic_Disease Constriction Electron Extracellular_{Signal-Regulated}_{MAP}_Kinases Fluorescent_Antibody_Technique Hyperalgesia Immunohistochemistry Inflammation Male Messenger Microscopy Neuralgia Neurons Newborn Pathologic Peripheral_Nerves Protein_Kinase_Inhibitors Pyrrolidines Rats Receptors Reverse_Transcriptase_Polymerase_Chain_Reaction Sciatic_Nerve Spinal_Cord Synaptic_Vesicles Western {CCR2} {Enzyme-Linked}_Immunosorbent_Assay {RNA} {Sprague-Dawley}}, month = apr, note = {{PMID:} 21490228}, number = 15, pages = {5865--5875}, timestamp = {2011-08-03T20:51:54.000+0200}, title = {{CCL2} released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury}, url = {http://www.ncbi.nlm.nih.gov/pubmed/21490228}, volume = 31, year = 2011 }