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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / administration & dosage
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Androstadienes / pharmacology
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Animals
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Flavonoids / administration & dosage
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Flavonoids / pharmacology
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Granulocyte Colony-Stimulating Factor / administration & dosage
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Granulocyte Colony-Stimulating Factor / toxicity*
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Humans
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Hyperalgesia / etiology*
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Hyperalgesia / physiopathology
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Hyperalgesia / prevention & control
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Imidazoles / administration & dosage
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Imidazoles / pharmacology
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Injections, Spinal
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Injections, Subcutaneous
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / physiology
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MAP Kinase Signaling System / drug effects*
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Male
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Mice
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Morphine / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism*
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Pyridines / administration & dosage
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Pyridines / pharmacology
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Recombinant Proteins
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Spinal Cord / drug effects
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Spinal Cord / physiopathology
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Wortmannin
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / physiology
Substances
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Androstadienes
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Flavonoids
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Imidazoles
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Pyridines
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Recombinant Proteins
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Granulocyte Colony-Stimulating Factor
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Morphine
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Phosphatidylinositol 3-Kinases
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Wortmannin