5-Fluoro-2-oxindole: Antinociceptive Effects in Neuropathic/Inflammatory Pain

5-Fluoro-2-oxindole is a benzene ring fused pyrrolidone (γ -lactam) with a fluorine substituent at 5-position. It has proven effectiveness on alleviating inflammatory pain and improving the analgesic effects of morphine. 5-Fluoro-2-oxindole inhibits the plasticity changes, oxidative stress, and inflammatory responses cause by peripheral inflammation.

5-fluoro-2-oxindole Increases the Antinociceptive Effects of Morphine

The management of neuropathic pain remains a challenge basically due to the low effectivity of the actual treatments and their undesirable effects (tolerance, sedation, respiratory depression). The treatment of the anxiety- and depressive-like behaviors accompanying neuropathic pain is also very troublesome since not all treatments inhibit both the nociceptive and emotional behaviors. We investigate the effectiveness of 5-fluoro-2-oxindole to inhibit neuropathic pain and mood disorders associated. The oxindoles, rhynchophylline and isorhynchophylline, attenuate the inflammatory and depressive-like behaviors through downregulating of mitogen-activated protein kinase/NF-κB and the PI3K/Akt signaling pathways, but little is known about the potential implication of microglia in the oxindole actions. Thus, the effects of 5-fluoro-2-oxindole in the expression of the microglial marker (CD11b/c) in the spinal cord and hippocampus of animals with sciatic nerve injury-induced neuropathic pain were examined. The administration of Nrf2 or HO-1 inducers, such as sulforaphane or cobalt protoporphyrin IX (CoPP), significantly increased the analgesic effects of morphine during inflammatory and neuropathic pain. In this study, we studied the antinociceptive, antidepressant and/or anxiolytic effects of the administration of 5-fluoro-2-oxindole in animals with neuropathic pain. The effects of this drug in the local antinociceptive actions of morphine and the mechanisms involved were also assessed.[1]

Our results show, for the first time, that the administration of 5-fluoro-2-oxindole inhibited the mechanical allodynia, thermal hyperalgesia and cold allodynia induced by sciatic nerve injury in a dose-dependent manner. Moreover, while one day of treatment with 40 mg/kg 5-fluoro-2-oxindole completely blocked the mechanical allodynia, thermal hyperalgesia and cold allodynia induced by sciatic nerve injury, eight days of treatment with 10 mg/kg of this drug are needed to completely reverse the mechanical allodynia and thermal hyperalgesia, and eleven days to block cold allodynia. In humans, chronic neuropathic pain is commonly accompanied with important emotional disorders. The present work confirmed the manifestation of depressive- and anxiety-like behaviors in animals with sciatic nerve injury-induced chronic neuropathic pain as has been reported by ours and other works. It’s interesting to highlight that while some treatments might alleviate the depressive-like behaviors or the anxiety-like comportments concomitant with chronic pain in an independent way such as, pregabalin or some hydrogen sulfide donors, only few drugs inhibit both affective disorders. In summary, this study reveals that the treatment with 5-fluoro-2-oxindole inhibits neuropathic pain and the emotional comorbidities associated, and further potentiates the local analgesic effects of morphine. This treatment also activates the antioxidant system, inhibits microglial activation and normalizes the expression of MOR in the spinal cord and/or hippocampus.

Effects of 5-Fluoro-2-Oxindole during Inflammatory Pain

Several studies showed the protective role played by numerous oxindole derivates such as isorhynchophylline (IRN) and rhynchophylline (RIN), versus diabetes, thrombosis, bacterial infection, asthma, cancer and inflammation. The antinociceptive actions of different oxindole alkaloids during acute inflammation or visceral pain have also been demonstrated. A recent study further revealed the antinociceptive effects of 5-fluoro-2-oxindole in animals with chronic neuropathic pain. Peripheral inflammation also induced the activation of mitogen-activated protein kinase (MAPK)/NF-κB signaling pathways in the spinal cord and paw, 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. In mice with chronic inflammatory pain generated with the subplantar injection of complete Freund’s adjuvant (CFA), we assessed the effects of 5-fluoro-2-oxindole in: (a) the mechanical allodynia and thermal hyperalgesia provoked by peripheral inflammation and the reversion of its effects with the administration of the HO-1 inhibitor, tin protoporphyrin IX (SnPP); (b) the protein levels of MAPK, Nrf2, HO-1 and NQO1, the oxidative stress (4-HNE) and inflammatory (NOS2, CD11b/c and IBA-1) markers as well as of MOR in the spinal cord and/or paw tissues; (c) the antinociceptive actions of locally administered morphine.[2]

The role of oxindoles in the modulation of chronic inflammatory pain has not been widely studied. Previous studies demonstrated that the administration of several oxindoles such as convolutamydine A (4,6-bromo-3-(2-oxopropyl)-3-hydroxy-2-oxindole), 3-(2-oxopropyl)-3-hydroxy-2-oxindole and 5-bromo-3-(2-oxopropyl)-3-hydroxy-2-oxindole inhibited visceral and acute inflammatory pain. A recent work evidenced the antinociceptive effects of 5-fluoro-2-oxindole in animals with chronic neuropathic pain. Even so, the likely analgesic effects of this oxindole during chronic inflammatory pain are unknown. Our results showed, for the first time, that the administration of 5 and 10 mg/kg 5-fluoro-2-oxindole inhibited the mechanical allodynia and thermal hyperalgesia induced by peripheral inflammation in a different effectiveness. Our results further reported that 5-fluoro-2-oxindole increased the protein levels of MOR in the paws of CFA-injected mice. The fact that this treatment also activated the HO-1 synthesis and this enzyme incited the upregulation of peripheral MOR in mice with inflammatory pain, allows us to theorize that the HO-1 signaling pathway activation might be implicated in the MOR overexpression induced by 5-fluoro-2-oxindole. Finally, and considering the enhanced paw expression of MOR induced by this drug, we evaluated the effects of this treatment on the antinociceptive actions produced by the local administration of morphine. These results agree with the potentiation of the antinociceptive effects of morphine induced by this treatment during neuropathic pain, as well as with the improvement in the peripheral antinociceptive actions of morphine generated by CoPP in animals with inflammatory and neuropathic pain.

References

[1]Ferreira-Chamorro P, Redondo A, Riego G, Pol O. Treatment with 5-fluoro-2-oxindole Increases the Antinociceptive Effects of Morphine and Inhibits Neuropathic Pain. Cell Mol Neurobiol. 2021 Jul;41(5):995-1008. doi: 10.1007/s10571-020-00952-w. Epub 2020 Sep 2. PMID: 32880099; PMCID: PMC11448661.

[2]Redondo A, Riego G, Pol O. The Antinociceptive, Antioxidant and Anti-Inflammatory Effects of 5-Fluoro-2-Oxindole during Inflammatory Pain. Antioxidants (Basel). 2020 Dec 9;9(12):1249. doi: 10.3390/antiox9121249. PMID: 33316895; PMCID: PMC7763029.