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 cell-specific 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.
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Authors wish to thank Mr. Abraham Contreras for animal care and technical assistance. This work is derived from César J. Carranza-Aguilar PhD dissertation.
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The research leading to these results received funding from Grant 101 SEP-Cinvestav (SLC and CJCA) and scholarship 338376 (CJCA) from the National Council of Science and Technology (Conacyt, México).
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Authors SLC, CGE and CJCA designed the study. Authors CJCA and AHM carried out the antinociceptive test, immunofluorescence, imaging and the analysis of data set. Authors AHM and CMA were involved in immunofluorescence experiments and images acquisition. Author KCR synthetized (+)-naloxone. Authors SLC, CGE and MM provided drugs, reagents, equipment and, contributed to interpretation of results. The draft manuscript was written by CJCA. All authors contributed to and approved the final manuscript.
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Carranza-Aguilar, C.J., Hernández-Mendoza, A., Mejias-Aponte, C. et al. 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. Cell Mol Neurobiol 42, 677–694 (2022). https://doi.org/10.1007/s10571-020-00957-5
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DOI: https://doi.org/10.1007/s10571-020-00957-5