Pharmacological and phosphoproteomic approaches to roles of protein kinase C in kappa opioid receptor-mediated effects in mice. (15th December 2020)

• Record Type: Journal Article
• Authors: Liu, Jeffrey J.; Chiu, Yi-Ting; Chen, Chongguang; Huang, Peng; Mann, Matthias; Liu-Chen, Lee-Yuan
• Is Part Of: Neuropharmacology. Volume 181(2020)
• Publication Date: 2020-12-15
• Subjects: κ opioid receptor -- Protein kinase C -- Phosphoproteomics -- Wnt -- mTOR -- CB1; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2020.108324
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Kappa opioid receptor (KOR) agonists possess adverse dysphoric and psychotomimetic effects, thus limiting their applications as non-addictive anti-pruritic and analgesic agents. Here, we showed that protein kinase C (PKC) inhibition preserved the beneficial antinociceptive and antipruritic effects of KOR agonists, but attenuated the adverse condition placed aversion (CPA), sedation, and motor incoordination in mice. Using a large-scale mass spectrometry-based phosphoproteomics of KOR-mediated signaling in the mouse brain, we observed PKC-dependent modulation of G protein-coupled receptor kinases and Wnt pathways at 5 min; stress signaling, cytoskeleton, mTOR signaling and receptor phosphorylation, including cannabinoid receptor CB1 at 30 min. We further demonstrated that inhibition of CB1 attenuated KOR-mediated CPA. Our results demonstrated the feasibility of in vivo biochemical dissection of signaling pathways that lead to side effects. Highlights: PKC participates in κ opioid receptor-mediated behavior responses and signaling in brains. PKC regulated GRK5/6 and Wnt signaling at early time for KOR activation. PKC mediated mTOR pathways and CB1 at the late time for KOR activation. CB1 is involved in U50, 488H-induced aversion effect in a PKC-dependent manner.