Morphine and Fentanyl Repeated Administration Induces Different Levels of NLRP3-Dependent Pyroptosis in the Dorsal Raphe
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ORIGINAL RESEARCH
Morphine and Fentanyl Repeated Administration Induces Different Levels of NLRP3‑Dependent Pyroptosis in the Dorsal Raphe Nucleus of Male Rats via Cell‑Specific Activation of TLR4 and Opioid Receptors César J. Carranza‑Aguilar1 · Araceli Hernández‑Mendoza1 · Carlos Mejias‑Aponte2 · Kenner C. Rice3 · Marisela Morales2 · Claudia González‑Espinosa1 · Silvia L. Cruz1 Received: 19 March 2020 / Accepted: 30 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Morphine promotes neuroinflammation after NOD-like receptor protein 3 (NLRP3) oligomerization in glial cells, but the capacity of other opioids to induce neuroinflammation and its relationship to the development of analgesic tolerance is unknown. We studied the effects of morphine and fentanyl on NLRP3 inflammasome activation in glial and neuronal cells in the dorsal raphe nucleus (DRN), a region involved in pain regulation. Male Wistar rats received i.p. injections of morphine (10 mg/kg) or fentanyl (0.1 mg/kg) 3 × daily for 7 days and were tested for nociception. Two hours after the last (19th) administration, we analyzed NLRP3 oligomerization, caspase-1 activation and gasdermin D-N (GSDMD-N) expression in microglia (CD11b positive cells), astrocytes (GFAP-positive cells) and neurons (NeuN-positive cells). Tolerance developed to both opioids, but only fentanyl produced hyperalgesia. Morphine and fentanyl activated NLRP3 inflammasome in astrocytes and serotonergic (TPH-2-positive) neurons, but fentanyl effects were more pronounced. Both opioids increased GFAP and CD11b immunoreactivity, caspase-1 and GSDMD activation, indicating pyroptotic cell death. The opioid receptor antagonist (−)-naloxone, but not the TLR4 receptor antagonist (+)-naloxone, prevented microglia activation and NLRP3 oligomerization. Only (+)-naloxone prevented astrocytes’ activation. The anti-inflammatory agent minocycline and the NLRP3 inhibitor MCC950 delayed tolerance to morphine and fentanyl antinociception and prevented fentanyl-induced hyperalgesia. MCC950 also prevented opioid-induced NLRP3 oligomerization. In conclusion, morphine and fentanyl differentially induce cellspecific activation of NLRP3 inflammasome and pyroptosis in the DRN through TLR4 receptors in astrocytes and through opioid receptors in neurons, indicating that neuroinflammation is involved in opioid-induced analgesia and fentanyl-induced hyperalgesia after repeated administrations. Keywords NLRP3 · Opioids · Glia · TLR4 · NF-κB · Serotonin
Introduction Claudia González-Espinosa and Silvia L. Cruz have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10571-020-00957-5) contains supplementary material, which is available to authorized users. * Silvia L. Cruz [email protected] 1
Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (Cinvestav, IPN), Sede Sur, Calzada de los Tenorios No. 235, Col. Granjas
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