Treatment with 5-fluoro-2-oxindole Increases the Antinociceptive Effects of Morphine and Inhibits Neuropathic Pain
Por:
Ferreira-Chamorro, P, Redondo, A, Riego, G, Pol, O
Publicada:
1 jul 2021
Ahead of Print:
1 sep 2020
Resumen:
The efficacy of mu-opioid receptors (MOR) in neuropathic pain is low and with numerous side effects that limited their use. Chronic neuropathic pain is also linked with emotional disorders that aggravate the sensation of pain and which treatment has not been resolved. This study investigates whether the administration of an oxindole, 5-fluoro-2-oxindole, could inhibit the nociceptive and emotional behaviors and increase the effectiveness of morphine via modulating the microglia and activating the nuclear factor erythroid-2 related factor 2 (Nrf2) signaling pathway and MOR expression. In C57BL/6 mice with neuropathic pain provoked by the total constriction of sciatic nerve we studied the effects of 10 mg/kg 5-fluoro-2-oxindole in: (i) the allodynia and hyperalgesia caused by the injury; (ii) the anxiety- and depressive-like behaviors; (iii) the local antinociceptive actions of morphine; (iv) the expression of CD11b/c (a microglial marker), the antioxidant and detoxificant enzymes Nrf2, heme oxygenase 1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO1), and of MOR in the spinal cord and hippocampus. Results showed that the inhibition of the main nociceptive symptoms and the anxiety- and depressive-like behaviors induced by 5-fluoro-2-oxindole were accompanied with the suppression of microglial activation and the activation of Nrf2/HO-1/NQO1 signaling pathway in the spinal cord and/or hippocampus. This treatment also potentiated the pain-relieving activities of morphine by normalizing the reduced MOR expression. This work demonstrates the antinociceptive, anxiolytic and antidepressant effects of 5-fluoro-2-oxindole, suggests a new strategy to enhance the antinociceptive actions of morphine and proposes a new mechanism of action of oxindoles during chronic neuropathic pain.
Filiaciones:
Ferreira-Chamorro, P:
Inst Invest Biomed St Pau, Grp Neurofarmacol Mol, Barcelona 08041, Spain
Univ Autonoma Barcelona, Inst Neurociencies, Grp Neurofarmacol Mol, Barcelona 08193, Spain
Redondo, A:
Inst Invest Biomed St Pau, Grp Neurofarmacol Mol, Barcelona 08041, Spain
Univ Autonoma Barcelona, Inst Neurociencies, Grp Neurofarmacol Mol, Barcelona 08193, Spain
Riego, G:
Inst Invest Biomed St Pau, Grp Neurofarmacol Mol, Barcelona 08041, Spain
Univ Autonoma Barcelona, Inst Neurociencies, Grp Neurofarmacol Mol, Barcelona 08193, Spain
Pol, O:
Inst Invest Biomed St Pau, Grp Neurofarmacol Mol, Barcelona 08041, Spain
Univ Autonoma Barcelona, Inst Neurociencies, Grp Neurofarmacol Mol, Barcelona 08193, Spain
Univ Autonoma Barcelona, Inst Invest Biomed St Pau, Grp Neurofarmacol Mol, Edifici M2, Barcelona 08193, Spain
Univ Autonoma Barcelona, Inst Neurociencies, Fac Med, Edifici M2, Barcelona 08193, Spain
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