title: Hyperalgesic and hypoalgesic mechanisms evoked by the acute administration of CCL5 in mice.
abstract: We show here that the intraplantar administration of CCL5 in mice produces hyperalgesia at low doses but activates compensatory antinociceptive mechanisms at doses slightly higher. Thus, the injection of 3-10ng of CCL5 evoked thermal hyperalgesia through the activation of CCR1 and CCR5 receptors, as demonstrated by the inhibitory effect exerted by the selective antagonists J113863 (0.01-0.1μg) and DAPTA (0.3-3μg), respectively. The prevention of this hyperalgesia by diclofenac (1-10μg), the inhibitors of COX-1 SC-560 (0.1-1μg) or COX-2 celecoxib (1-5μg), the TRPV1 antagonist capsazepine (0.03-0.3μg) or the TRPA1 antagonist HC030031 (10-50μg) demonstrates the involvement of prostaglandin synthesis and TRP sensitization in CCL5-evoked hyperalgesia. Doses of CCL5 higher than 17μg did not evoke hyperalgesia. However, this effect was restored by the administration of naloxone-methiodide (5μg), nor-binaltorphimine (10mg/kg) or an anti-dynorphin A antibody (0.62-2.5ng). The administration of 30ng of CCL5 also induced hyperalgesia in mice with reduced number of circulating white blood cells in response to cyclophosphamide or with selective neutrophil depletion induced by an anti-Ly6G antibody. In fact, the number of neutrophils present in paws treated with 30ng of CCL5 was greater than in paws receiving the administration of the hyperalgesic dose of 10ng. Finally, the expression of the endogenous opioid peptide dynorphin A was demonstrated by double immunofluorescence assays in these neutrophils attracted by CCL5. These results support previous data describing the hyperalgesic properties of CCL5 and constitute the first indication that a chemokine of the CC group can activate endogenous analgesic mechanisms.
authors.affiliation: Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/ Julián Clavería 6, 33006 Oviedo, Asturias, Spain; Current address S.G-R: Instituto de Biología Molecular y Celular (IBMC), Av. de la Universidad s/n, Edif, Torregaitán, E-03202 Elche, Alicante, Spain. Electronic address: sara.gonzalezr@umh.es.
authors.forename: Sara
authors.initials: S
authors.lastname: González-Rodríguez
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33006 Oviedo, Asturias, Spain. Electronic address: miguelga_92@hotmail.com.
authors.forename: Miguel G
authors.initials: MG
authors.lastname: Álvarez
authors.affiliation: Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/ Julián Clavería 6, 33006 Oviedo, Asturias, Spain. Electronic address: UO201540@uniovi.es.
authors.forename: Mario
authors.initials: M
authors.lastname: García-Domínguez
authors.affiliation: Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/ Julián Clavería 6, 33006 Oviedo, Asturias, Spain. Electronic address: analas2006@hotmail.com.
authors.forename: Ana
authors.initials: A
authors.lastname: Lastra
authors.affiliation: Área de Biología Celular, Departamento de Morfología y Biología Celular, Universidad de Oviedo, INEUROPA (Instituto De Neurociencias Del Principado De Asturias), C/ Julián Clavería 6, 33006 Oviedo, Asturias, Spain. Electronic address: rcernuda@uniovi.es.
authors.forename: Rafael
authors.initials: R
authors.lastname: Cernuda-Cernuda
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, 33006 Oviedo, Asturias, Spain. Electronic address: arfolgueras@uniovi.es.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Folgueras
authors.affiliation: Unidad de Histopatología Molecular en Modelos Animales de Cáncer, IUOPA, Universidad de Oviedo, C/ Julián Clavería 6, 33006 Oviedo, Asturias, Spain. Electronic address: fernandezgarteresa@uniovi.es.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Fernández-García
authors.affiliation: Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/ Julián Clavería 6, 33006 Oviedo, Asturias, Spain. Electronic address: hidalgo@uniovi.es.
authors.forename: Agustín
authors.initials: A
authors.lastname: Hidalgo
authors.affiliation: Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/ Julián Clavería 6, 33006 Oviedo, Asturias, Spain. Electronic address: arbaiza@uniovi.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Baamonde
authors.affiliation: Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/ Julián Clavería 6, 33006 Oviedo, Asturias, Spain. Electronic address: luismen@uniovi.es.
authors.forename: Luis
authors.initials: L
authors.lastname: Menéndez
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D000068579:Celecoxib / Q000008:administration & dosage / Q000627:therapeutic use; D018946:Chemokine CCL5; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D004008:Diclofenac / Q000008:administration & dosage / Q000627:therapeutic use; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D054389:Receptors, CCR1 / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C000592874:CCR5 protein, mouse; C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; D052246:Cyclooxygenase 2 Inhibitors; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D004008:Diclofenac; D000068579:Celecoxib
keywords: Antinociception; CCL5; Cyclooxygenase; Dynorphin A; Hyperalgesia; Kappa-opioid receptors; Mouse; Neutrophils; TRPA1; TRPV1