2. Academic Validation
  3. Direct inhibition of microglial activation by a μ receptor selective agonist alleviates inflammatory-induced pain hypersensitivity

Direct inhibition of microglial activation by a μ receptor selective agonist alleviates inflammatory-induced pain hypersensitivity

  • Eur J Pharmacol. 2023 Nov 9:176182. doi: 10.1016/j.ejphar.2023.176182.
Jing Wang 1,  Qiao-Min Ru 1,  Xiao-Hui Yu 1,  Changlong Wang 1,  Kai Li 1,  Chao-Zhen-Yi Han 1,  Na Li 1,  Jing Zhao 2,  John N Wood 2,  Xin Liu 3,  Rui Wang 4,  Yuan Wang 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
  • 2 Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
  • 3 Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China. Electronic address: liuxinlz@lzu.edu.cn.
  • 4 Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, China. Electronic address: wangrui@lzu.edu.cn.
  • 5 Department of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China. Electronic address: yuanwang@lzu.edu.cn.
PMID: 37951488 DOI: 10.1016/j.ejphar.2023.176182
Abstract

Opioids are widely used in the treatment of moderate and severe pain. Nociceptive stimulation has been reported to potentially promote microglial activation and neuroinflammation, which also causes chronic pain sensitization. The aim of this study was to demonstrate whether the novel μ receptor agonist MEL-0614 could inhibit activated microglia directly and the associated signaling pathway. Mice were administered lipopolysaccharide and formalin to induce allodynia. Von Frey test was used to detect the anti-allodynia effect of MEL-0614 before and after LPS and formalin injection. In the spinal cord, the levels of proinflammatory cytokines and microglial activation were determined after MEL-0614 administration. BV2 and primary microglia were cultured to further explore the effect of MEL-0614 on LPS-induced microglial activation and key signaling pathways involved. MEL-0614 partially prevented and reversed allodynia induced by LPS and formalin in vivo, which was not inhibited by the μ receptor antagonist CTAP. Minocycline was effective in reversing the established allodynia. MEL-0614 also downregulated the activation of microglia and related proinflammatory cytokines in the spinal cord. Additionally, in BV2 and primary microglia, MEL-0614 inhibited the LPS-induced upregulation of proinflammatory factors, which was unaffected by CTAP. The NLR family pyrin domain containing 3 (NLRP3) related signaling pathway may be involved in the interaction between MEL-0614 and microglia. The opioid agonist MEL-0614 inhibited the activation of microglia and the subsequent upregulation of proinflammatory factors both in vivo and in vitro. Notably, this effect is partially mediated by the μ receptor.

Keywords

Analgesia; Microglia; Neuroinflammation; Opioid peptide; Pain.

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