Granulocyte-colony stimulating factor (G-CSF)-induced mechanical hyperalgesia in mice: Role for peripheral TNFα, IL-1β and IL-10

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 (TNF alpha), interleukin (IL)-1 beta (IL-1 beta) 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 TNF alpha, IL-1 beta 3 and IL 10 production in paw tissue. G-CSF-induced hyperalgesia was dose dependently inhibited by thalidomide (5-45 mg/kg) and pentoxifylline (0.5-13.5 mg/kg), and treatment with these drugs inhibited G-CSF-induced TNF alpha, IL-1 beta 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 cyrokines TNF alpha and IL1 beta 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. (C). 2015 Elsevier B.V. All rights reserved.