Treatment with 5-fluoro-2-oxindole Increases the Antinociceptive Effects of Morphine and Inhibits Neuropathic Pain

The Antinociceptive, Antioxidant and Anti-Inflammatory Effects of 5-Fluoro-2-Oxindole during Inflammatory Pain

“…5-fluoro-2-oxindole ( Figure 1 ) with a 97% of purity was purchased in Sigma-Aldrich (St. Louis, MO, USA), dissolved in dimethylsulfoxide (1% in 0.9% of saline solution) and intraperitoneally administered in a final volume of 10 mL/kg, 1 h before testing, in conformity with a preceding study [ 8 ]. Morphine hydrochloride acquired from Alcaiber S.A. (Madrid, Spain) was dissolved in 0.9% saline solution and subplantarly administered, in a final volume of 30 μL, 30 min before doing the behavioral tests [ 11 , 19 ].…”

“…The antinociceptive actions of different oxindole alkaloids during acute inflammation or visceral pain have also been demonstrated [ 5 , 6 , 7 ]. A recent study further revealed the antinociceptive effects of 5-fluoro-2-oxindole in animals with chronic neuropathic pain [ 8 ]. Nonetheless, the potential pain-relieving action of 5-fluoro-2-oxindole in animals with chronic inflammatory pain has not yet been evaluated.…”

“…Peripheral inflammation also induced the activation of mitogen-activated protein kinase (MAPK)/NF-κB signaling pathways in the spinal cord and paw [ 11 ], whose inhibition is a mechanism of action of the oxindoles, RIN and IRN, for attenuating the inflammatory responses induced by lipopolysaccharide (LPS) in cell cultures [ 12 , 13 ]. The administration of 5-fluoro-2-oxindole also inhibits the spinal cord and hippocampal activation of microglia provoked by nerve injury [ 8 ]. Nonetheless, the regulatory effects of 5-fluoro-2-oxindole in MAPK phosphorylation, microglial activation and NOS2 overexpression in the spinal cord and/or paw tissues of mice with inflammatory pain have not been evaluated.…”

“…The antioxidant enzymes, NADPH quinone oxidoreductase1 (NQO1) and/or heme oxygenase 1 (HO-1), participate in the analgesic actions of several compounds such as sulforaphane, oltipraz and carbon monoxide-releasing molecules (CORM’s) during inflammatory and neuropathic pain [ 11 , 14 , 15 , 16 , 17 ]. Other works also proved that the analgesic effects of 5-fluoro-2-oxindole in animals with sciatic nerve injury-induced neuropathic pain are mediated via augmenting the Nrf2 transcription factor, NQO1 and HO-1 protein levels [ 8 ] and that the anti-inflammatory effects of IRN were produced via avoiding the down-regulation of the antioxidant proteins superoxide dismutase, glutathione peroxidase 1 and catalase [ 3 ]. The probable contribution of the Nrf2 transcription factor, NQO1 and HO-1 in the pain-relieving actions of 5-fluoro-2-oxindole, and the effects of this treatment in the levels of 4-hydroxy-2-nonenal (4-HNE)-positive proteins, an oxidative stress marker, during inflammatory pain were not identified.…”

“…Thus, the effectiveness of morphine increased in animals with inflammatory or neuropathic pain pre-treated with activators of Nrf2 (sulforaphane) or HO-1 (cobalt protoporphyrin IX (CoPP)) as well as with CORM’s [ 11 , 14 , 15 , 18 , 19 ]. 5-fluoro-2-oxindole also enhanced the antiallodynic and antihyperalgesic effects of morphine in sciatic nerve-injured animals [ 8 ], but its role in modulating the analgesic properties of morphine and MOR expression during inflammatory pain remains untested.…”