title: Granulocyte-colony stimulating factor (G-CSF) induces mechanical hyperalgesia via spinal activation of MAP kinases and PI3K in mice.
abstract: Granulocyte-colony stimulating factor (G-CSF) is a current pharmacological approach to increase peripheral neutrophil counts after anti-tumor therapies. Pain is most relevant side effect of G-CSF in healthy volunteers and cancer patients. Therefore, the mechanisms of G-CSF-induced hyperalgesia were investigated focusing on the role of spinal mitogen-activated protein (MAP) kinases ERK (extracellular signal-regulated kinase), JNK (Jun N-terminal Kinase) and p38, and PI(3)K (phosphatidylinositol 3-kinase). G-CSF induced dose (30-300 ng/paw)-dependent mechanical hyperalgesia, which was inhibited by local post-treatment with morphine. This effect of morphine was reversed by naloxone (opioid receptor antagonist). Furthermore, G-CSF-induced hyperalgesia was inhibited in a dose-dependent manner by intrathecal pre-treatment with ERK (PD98059), JNK (SB600125), p38 (SB202190) or PI(3)K (wortmanin) inhibitors. The co-treatment with MAP kinase and PI(3)K inhibitors, at doses that were ineffective as single treatment, significantly inhibited G-CSF-induced hyperalgesia. Concluding, in addition to systemic opioids, peripheral opioids as well as spinal treatment with MAP kinases and PI(3)K inhibitors also reduce G-CSF-induced pain.
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM480 PR445, CEP 86051-990, Cx Postal 6001, Londrina, Paraná, Brazil.
authors.forename: Thacyana T
authors.initials: TT
authors.lastname: Carvalho
authors.forename: Tamires
authors.initials: T
authors.lastname: Flauzino
authors.forename: Eliane S
authors.initials: ES
authors.lastname: Otaguiri
authors.forename: Ana P
authors.initials: AP
authors.lastname: Batistela
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Sérgio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011994:Recombinant Proteins; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D000730:Androstadienes; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D009020:Morphine; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin