title: Granulocyte-colony stimulating factor (G-CSF)-induced mechanical hyperalgesia in mice: Role for peripheral TNFα, IL-1β and IL-10.
abstract: Granulocyte-colony stimulating factor (G-CSF) is a therapeutic approach to increase peripheral neutrophil counts after anti-tumor therapies. Pain is the major side effect of G-CSF. Intraplantar administration of G-CSF in mice induces mechanical hyperalgesia. However, the peripheral mechanisms involved in this effect were not elucidated. Therefore, the participation of pronociceptive cytokines tumor necrosis factor (TNF) alpha (TNFα), interleukin (IL)-1 beta (IL-1β) and antinociceptive cytokine IL-10 in G-CSF-induced mechanical hyperalgesia in mice was investigated. G-CSF-induced mechanical hyperalgesia was inhibited by systemic and local treatment with etanercept and IL-1 receptor antagonist (IL-1ra) or TNF receptor 1 (TNFR1) deficiency and increased in IL-10 deficient mice. In agreement, G-CSF injection induced significant TNFα, IL-1β and IL-10 production in paw tissue. G-CSF-induced hyperalgesia was dose-dependently inhibited by thalidomide (5-45mg/kg) and pentoxifylline (0.5-13.5mg/kg), and treatment with these drugs inhibited G-CSF-induced TNFα, IL-1β and IL-10 production. The combined treatment with pentoxifylline or thalidomide with morphine, at doses that are ineffective as single treatment, diminished G-CSF-induced hyperalgesia through inhibiting cytokine production. Indomethacin also reduces G-CSF hyperalgesia alone or combined with pentoxifylline or thalidomide. Thus, G-CSF-induced hyperalgesia might be mediate by peripheral production of pronociceptive cytokines TNFα and IL-1β and down-regulated by IL-10. Systemic IL-1ra reduced G-CSF-induced increase of peripheral neutrophil counts. However, local treatment with morphine, IL-1ra or etanercept, and systemic treatment with indomethacin, etanercept, thalidomide and pentoxifylline did not alter G-CSF-induced mobilization of neutrophils. Therefore, this study advances in the understanding of G-CSF-induced hyperalgesia and suggests therapeutic approaches for its control.
authors.affiliation: Department of Pathology, Center of Biological Science, Londrina State University, Rod. Celso Garcia Cid KM480 PR445, CEP 86057-970, Cx Postal 10.011, Londrina, Paraná, Brazil. Electronic address: thacy_thacy@yahoo.com.br.
authors.forename: Thacyana T
authors.initials: TT
authors.lastname: Carvalho
authors.affiliation: Department of Pathology, Center of Biological Science, Londrina State University, Rod. Celso Garcia Cid KM480 PR445, CEP 86057-970, Cx Postal 10.011, Londrina, Paraná, Brazil. Electronic address: sergio_borghi@yahoo.com.br.
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Borghi
authors.affiliation: Department of Pathology, Center of Biological Science, Londrina State University, Rod. Celso Garcia Cid KM480 PR445, CEP 86057-970, Cx Postal 10.011, Londrina, Paraná, Brazil. Electronic address: pinho.fe@gmail.com.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Pinho-Ribeiro
authors.affiliation: Department of Pathology, Center of Biological Science, Londrina State University, Rod. Celso Garcia Cid KM480 PR445, CEP 86057-970, Cx Postal 10.011, Londrina, Paraná, Brazil. Electronic address: sandramizokami@hotmail.com.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Mizokami
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Avenida Bandeirantes, 3900, CEP 14049-900 Ribeirao Preto, Sao Paulo, Brazil. Electronic address: thicunha@usp.br.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Avenida Bandeirantes, 3900, CEP 14049-900 Ribeirao Preto, Sao Paulo, Brazil. Electronic address: shferrei@fmrp.usp.br.
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Avenida Bandeirantes, 3900, CEP 14049-900 Ribeirao Preto, Sao Paulo, Brazil. Electronic address: fdqcunha@fmrp.usp.br.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Department of Pharmaceutical Sciences, University Hospital (Health Science Centre), Londrina State University, Avenida Robert Koch, 60, Hospital Universitário, 86038-350 Londrina, Paraná, Brazil. Electronic address: rubiacasa@yahoo.com.br.
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.affiliation: Department of Pathology, Center of Biological Science, Londrina State University, Rod. Celso Garcia Cid KM480 PR445, CEP 86057-970, Cx Postal 10.011, Londrina, Paraná, Brazil. Electronic address: waldiceujr@yahoo.com.br.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000068800:Etanercept; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007074:Immunoglobulin G / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007958:Leukocyte Count; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D010431:Pentoxifylline / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013792:Thalidomide / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; C556062:IL10 protein, mouse; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; D013792:Thalidomide; D009020:Morphine; D000068800:Etanercept; D010431:Pentoxifylline
keywords: Cytokine; G-CSF; Morphine; Pain; Pentoxifylline; Thalidomide