Treatment with 5-fluoro-2-oxindole Increases the Antinociceptive Effects of Morphine and Inhibits Neuropathic Pain
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ORIGINAL RESEARCH
Treatment with 5‑fluoro‑2‑oxindole Increases the Antinociceptive Effects of Morphine and Inhibits Neuropathic Pain Pablo Ferreira‑Chamorro1,2 · Alejandro Redondo1,2 · Gabriela Riego1,2 · Olga Pol1,2,3 Received: 1 May 2020 / Accepted: 20 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The efficacy of µ-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 painrelieving 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. Keywords Anxiety · Depression · Opioid receptors · Neuropathic pain · Oxidative stress · Oxindole
Introduction 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 Pablo Ferreira-Chamorro, Alejandro Redondo, Gabriela Riego have contributed equally to this work. * Olga Pol [email protected] 1
Grup de Neurofarmacologia Molecular, Institut D’Investigació Biomèdica Sant Pau, 08041 Barcelona, Spain
2
Grup de Neurofarmacologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
3
Grup de Neurofarmacologia Molecular, Institut D’Investigació Biomèdica Sant Pau & Institut de Neurociències, Facultat de Medicina. Edifici M2, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
depression) (Butler et al. 2004; Humo
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