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

Jing Wang1, Qiao-Min Ru1, Xiao-Hui Yu1

  • 1Department 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.

European Journal of Pharmacology
|November 11, 2023
PubMed

Insights

The novel opioid agonist MEL-0614 reduces pain sensitivity by inhibiting microglial activation and neuroinflammation. This effect, partially mediated by the μ receptor, offers a new therapeutic avenue for chronic pain management.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Immunology

Background:

  • Opioids are crucial for managing moderate to severe pain.
  • Neuroinflammation, driven by microglial activation, contributes to chronic pain sensitization.
  • Targeting neuroinflammation presents a potential strategy for pain relief.

Purpose of the Study:

  • To investigate the efficacy of a novel μ receptor agonist, MEL-0614, in inhibiting microglial activation and associated signaling pathways.
  • To determine if MEL-0614 possesses anti-allodynic effects in pain models.

Main Methods:

  • Induction of allodynia in mice using lipopolysaccharide (LPS) and formalin.
  • Assessment of MEL-0614's anti-allodynic effects using the Von Frey test.
  • Quantification of spinal cord microglial activation and proinflammatory cytokines.
  • In vitro studies using BV2 and primary microglia to examine MEL-0614's impact on LPS-induced activation and signaling pathways, including the NLRP3 inflammasome.

Main Results:

  • MEL-0614 demonstrated partial prevention and reversal of LPS- and formalin-induced allodynia in vivo.
  • The anti-allodynic effect of MEL-0614 was not blocked by the μ receptor antagonist CTAP, but minocycline showed efficacy.
  • MEL-0614 significantly downregulated microglial activation and proinflammatory cytokine levels in the spinal cord.
  • In vitro, MEL-0614 inhibited LPS-induced microglial activation and proinflammatory factor upregulation, an effect independent of the μ receptor antagonist CTAP.
  • The NLR family pyrin domain containing 3 (NLRP3) signaling pathway was implicated.

Conclusions:

  • The opioid agonist MEL-0614 effectively inhibits microglial activation and subsequent neuroinflammation, both in vivo and in vitro.
  • This inhibitory effect on neuroinflammation contributes to MEL-0614's anti-allodynic properties.
  • While partially mediated by the μ receptor, MEL-0614's neuroinflammatory effects suggest a complex mechanism of action potentially involving other pathways.
Keywords:
AnalgesiaMicrogliaNeuroinflammationOpioid peptidePain

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