title: Analgesic effects evoked by a CCR2 antagonist or an anti-CCL2 antibody in inflamed mice.
abstract: Chemokine CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a molecule that in addition to its well-established role in chemotaxis can also act as nociceptor sensitizer. The upregulation of this chemokine in inflamed tissues could suggest its involvement in inflammatory hypernociception. Thus, we have measured CCL2 levels in mice with acute or chronic inflammation due to the intraplantar (i.pl.) injection of carrageenan or complete Freund's adjuvant (CFA), respectively, and we have studied whether inflammatory hyperalgesia or allodynia could be attenuated by blocking CCR2 receptors or neutralizing CCL2 with an anti-CCL2 antibody. A remarkable increase in CCL2 concentration was detected by ELISA in paw homogenates coming from carrageenan- or CFA-inflamed mice, being its expression mainly localized in macrophages, as shown by immunohistochemical assays. The s.c. (0.3-3 mg/kg) or i.pl. (0.3-3 μg) administration of the CCR2 antagonist, RS 504393, dose dependently inhibited thermal hyperalgesia measured in acutely or chronically inflamed mice, whereas s.c. administration of this drug did not reduce inflammatory mechanical allodynia. Furthermore, the inhibition of inflammatory hyperalgesia after the administration of an anti-CCL2 antibody (0.1-1 μg; i.pl.) suggests that CCL2 could be the endogenous chemokine responsible for CCR2-mediated hyperalgesic effects. Besides, the acute administration of the highest antihyperalgesic dose of RS 504393 assayed did not reduce paw tumefaction or modify the presence of inflammatory cells. These results indicate that the blockade of the CCL2/CCR2 system can counteract inflammatory hyperalgesia, being this antinociceptive effect unrelated to a decrease in the inflammatory reaction.
authors.affiliation: Facultad de Medicina, Laboratorio de Farmacología, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/Julián Clavería 6, 33006, Oviedo, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Llorián-Salvador
authors.affiliation: Facultad de Medicina, Laboratorio de Farmacología, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/Julián Clavería 6, 33006, Oviedo, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pevida
authors.affiliation: Facultad de Medicina, Laboratorio de Farmacología, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/Julián Clavería 6, 33006, Oviedo, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: González-Rodríguez
authors.affiliation: Facultad de Medicina, Laboratorio de Farmacología, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/Julián Clavería 6, 33006, Oviedo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Lastra
authors.affiliation: Unidad de Histopatología Molecular en Modelos Animales de Cáncer, IUOPA, Universidad de Oviedo, C/Julián Clavería 6, 33006, Oviedo, Spain.
authors.forename: María-Teresa
authors.initials: MT
authors.lastname: Fernández-García
authors.affiliation: Facultad de Medicina, Laboratorio de Farmacología, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/Julián Clavería 6, 33006, Oviedo, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Hidalgo
authors.affiliation: Facultad de Medicina, Laboratorio de Farmacología, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/Julián Clavería 6, 33006, Oviedo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Baamonde
authors.affiliation: Facultad de Medicina, Laboratorio de Farmacología, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/Julián Clavería 6, 33006, Oviedo, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Menéndez
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D048588:Benzoxazines; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C579117:RS 504393; D054390:Receptors, CCR2; D013141:Spiro Compounds
keywords: CCL2; CCR2; carrageenan; chemokines; complete Freund's adjuvant; inflammation; mouse