The granulopoietic cytokine granulocyte colony-stimulating factor (G-CSF) induces pain: analgesia by rutin.
Thacyana T CarvalhoSandra S MizokamiCamila R FerrazMarília F ManchopeSergio M BorghiVictor FattoriCassia Calixto-CamposDoumit Camilios-NetoRubia CasagrandeWaldiceu Aparecido VerriPublished in: Inflammopharmacology (2019)
Rutin is a glycone form of the flavonol quercetin and it reduces inflammatory pain in animal models. Therapy with granulocyte colony-stimulating factor (G-CSF) is known by the pain caused as its main side effect. The effect of rutin and its mechanisms of action were evaluated in a model of hyperalgesia induced by G-CSF in mice. The mechanical hyperalgesia induced by G-CSF was reduced by treatment with rutin in a dose-dependent manner. Treatment with both rutin + morphine or rutin + indomethacin, at doses that are ineffectual per se, significantly reduced the pain caused by G-CSF. The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)-ATP-sensitive potassium channel (KATP) signaling pathway activation is one of the analgesic mechanisms of rutin. Rutin also reduced the pro-hyperalgesic and increased anti-hyperalgesic cytokine production induced by G-CSF. Furthermore, rutin inhibited the activation of the nuclear factor kappa-light-chain enhancer of activated B cells (NFκB), which might explain the inhibition of the cytokine production. Treatment with rutin upregulated the decreased mRNA expression of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) combined with enhancement of the mRNA expression of the Nrf2 downstream target heme oxygenase (HO-1). Intraperitoneal (i.p.) treatment with rutin did not alter the mobilization of neutrophils induced by G-CSF. The analgesia by rutin can be explained by: NO-cGMP-PKG-KATP channel signaling activation, inhibition of NFκB and triggering the Nrf2/HO-1 pathway. The present study demonstrates rutin as a promising pharmacological approach to treat the pain induced by G-CSF without impairing its primary therapeutic benefit of mobilizing hematopoietic progenitor cells into the blood.
Keyphrases
- nuclear factor
- neuropathic pain
- chronic pain
- pain management
- nitric oxide
- signaling pathway
- oxidative stress
- toll like receptor
- pi k akt
- protein kinase
- type diabetes
- cerebrospinal fluid
- postoperative pain
- metabolic syndrome
- combination therapy
- epithelial mesenchymal transition
- spinal cord
- peripheral blood
- bone marrow
- transcription factor
- immune response
- mesenchymal stem cells
- skeletal muscle
- replacement therapy
- cell proliferation
- hydrogen peroxide
- insulin resistance
- high fat diet induced