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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Neuropharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1434295

Effect of NLRP3 inflammasome induced astrocyte phenotype alteration in morphine tolerance

Provisionally accepted
Zhenyu Yuan Zhenyu Yuan 1Boxuan Lu Boxuan Lu 1*Meiling Zhang Meiling Zhang 1*Yinxiao Lu Yinxiao Lu 1*Zhihui Wang Zhihui Wang 1*Wenhao Zhang Wenhao Zhang 1*Hao Cheng Hao Cheng 1Zhifang Wu Zhifang Wu 1*Qing Ji Qing Ji 2*
  • 1 Department of Anesthesiology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
  • 2 Affiliated Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China

The final, formatted version of the article will be published soon.

    Morphine is a commonly prescribed analgesic, but its prolonged use is frequently hindered by the development of tolerance. The NLRP3 inflammasome and reactive astrocytes play pivotal roles in the development of morphine tolerance. Reactive astrocytes can be categorized into A1 neurotoxic reactive astrocytes and A2 neuroprotective reactive astrocytes. This study delves into the involvement of the NLRP3 inflammasome and alterations in astrocyte phenotype in the progression of morphine tolerance. We established a morphine tolerance model by administering morphine intrathecally for seven consecutive days. To inhibit the activation of the NLRP3 inflammasome, we utilized MCC950, a specific inhibitor of NLRP3.Behavioral tests revealed that seven days of morphine administration led to the development of tolerance, accompanied by increased protein levels of GFAP, IL-18, NLRP3, and C3 (a specific marker for A1 astrocytes) in the spinal cord. Simultaneously, there was a decrease in the protein level of S100A10, a specific marker for A2 astrocytes. The coadministration of morphine and MCC950 not only significantly slowed the development of morphine tolerance but also reversed alterations in the levels of NLRP3, IL-18, GFAP, C3, and S100A10 proteins. In conclusion, our findings highlight a significant association between NLRP3 inflammasome activation and the emergence of morphine tolerance, underscoring its pivotal role in the transformation of astrocytes into the A1 phenotype. Moreover, suppressing the NLRP3 inflammasome has the potential to revert the changes in astrocyte phenotype, thereby mitigating the development of morphine tolerance.

    Keywords: NLRP3 inflammasome, Morphine tolerance, Reactive astrocytes, MCC950, astrocyte phenotype, neuroinflammation NLRP3, nucleotide-binding oligomerization domain-like receptor pyrin domaincontaining-3, ASC, apoptosis-associated speck-like protein containing a caspase-recruitment domain, TLR4, Toll-like receptor 4

    Received: 17 May 2024; Accepted: 31 Oct 2024.

    Copyright: © 2024 Yuan, Lu, Zhang, Lu, Wang, Zhang, Cheng, Wu and Ji. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Boxuan Lu, Department of Anesthesiology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
    Meiling Zhang, Department of Anesthesiology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
    Yinxiao Lu, Department of Anesthesiology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
    Zhihui Wang, Department of Anesthesiology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
    Wenhao Zhang, Department of Anesthesiology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
    Zhifang Wu, Department of Anesthesiology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
    Qing Ji, Affiliated Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210093, Jiangsu Province, China

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