μ-Opioid receptor attenuates Aβ oligomers-induced neurotoxicity through mTOR signaling

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• The mu-opioid receptor (OPRM1) is involved in neuroprotection and plasticity.
• OPRM1 activation can influence mechanistic/mammalian target of rapamycin (mTOR) signaling.
• The role of OPRM1 in protecting neurons against beta-amyloid (Aβ) peptide neurotoxicity via mTOR signaling remains unclear.

Purpose of the Study:

• To investigate whether OPRM1 activation protects neurons against Aβ neurotoxicity through mTOR signaling.
• To elucidate the molecular mechanisms underlying OPRM1-mediated neuroprotection in the context of Aβ toxicity.

Main Methods:

• Primary cultured cortical neurons were used to assess the effects of OPRM1 activation on Aβ oligomers-induced neurotoxicity.
• Cell viability and neurite outgrowth assays were performed.
• Phosphorylation status of mTOR, Akt, and p70 S6k was measured by immunoblotting to determine signaling pathway activity.

Main Results:

• Morphine, an OPRM1 activator, dose-dependently attenuated Aβ oligomers-induced neurotoxicity.
• Aβ oligomers downregulated mTOR signaling, while morphine rescued this effect by influencing Akt and p70 S6k.
• The neuroprotective effects of morphine were reversed by OPRM1 antagonists and inhibitors of the PI3K/Akt/mTOR pathway.
• Endogenous opioids (enkephalins) also demonstrated neuroprotective effects against Aβ toxicity.

Conclusions:

• OPRM1 activation attenuates Aβ oligomers-induced neurotoxicity by modulating the mTOR signaling pathway.
• These findings provide novel insights into Alzheimer's disease pathogenesis and suggest potential therapeutic targets for Aβ neurotoxicity.