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Pharmacological and Phosphoproteomic Approaches to Roles of Protein Kinase C in Kappa Opioid Receptor-Mediated Effects in Mice

ABSTRACT: KOR agonists possess adverse dysphoric and psychotomimetic effects, thus limiting their applications as anti-pruritic and non-addictive analgesic agents. Here, we showed that protein kinase C (PKC) inhibition preserved the KOR agonist induced beneficial antinociceptive and antipruritic effects, and 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 brain, we observed at 5 minutes PKC-dependent modulation of G protein-coupled receptor kinases and Wnt pathways, and at 30 minutes modulation of stress signaling, cytoskeleton, mTOR signaling and receptor phosphorylation, including cannabinoid receptor CB1. 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Jeffrey Liu

LAB HEAD: Matthias Mann

PROVIDER: PXD018140 | Pride | 2020-09-28

REPOSITORIES: Pride

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			Action	DRS
	20160922_QEp6_JeLi_SA_L976_30min_CHLSal_ctx_1.raw	Raw
	20160922_QEp6_JeLi_SA_L976_30min_CHLSal_ctx_2.raw	Raw
	20160922_QEp6_JeLi_SA_L976_30min_CHLSal_ctx_3.raw	Raw
	20160922_QEp6_JeLi_SA_L976_30min_CHLSal_hippo_1.raw	Raw
	20160922_QEp6_JeLi_SA_L976_30min_CHLSal_hippo_2.raw	Raw

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Pharmacological and phosphoproteomic approaches to roles of protein kinase C in kappa opioid receptor-mediated effects in mice.

Liu Jeffrey J JJ Chiu Yi-Ting YT Chen Chongguang C Huang Peng P Mann Matthias M Liu-Chen Lee-Yuan LY

Neuropharmacology 20200922

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 si ...[more]

PMID: 32976891

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Project description:Inhibition of cannabinoid receptor 1 (CB1) has shown efficacy in reducing body weight and improving metabolic parameters, with the effects correlating with target engagement in the brain. Recently, the peripheral effects of inhibiting the CB1 receptor has been appreciated through studies in diet-induced obese and liver-specific CB1 KO mice. In this report, we systematically investigated gene expression changes in peripheral tissues of DIO mice treated with the CB1 inverse agonist AM251. CB1 receptor inhibition led to down-regulation of genes within the de novo fatty acid and cholesterol synthetic pathways, including SREBP-1 and -2, and their downstream targets in both liver and adipose tissue. In addition, genes involved in fatty acid Beta-oxidation were up-regulated with AM251 treatment, probably through the activation of PPARalpha. In adipose tissue, CB1 receptor inhibition led to the down-regulation of genes in the TNFalpha signal transduction pathway and possibly to the activation of PPARgamma, both of which would result in improved insulin sensitivity. CB1-/- mice were obtained from A. Zimmer (University of Bonn) (Zimmer et al., 1999) and back-crossed onto C57BL/6J genetic background for ten generations by A. Zimmer before homozygous CB1-/- mice were re-derived at Taconic Farms (German Town, NY) onto the C57BL/6N genetic background. Male CB1-/- mice and control littermates (n=5-7 in each group) at 2 months of age were fed with regular chow (Teklad 7012, 13 % kcal from fat, 3.41 kcal/g, Harlan Laboratories, Indianapolis, IN, USA) or high fat diet (S3282, 59.4% kcal from fat; 24.5% kcal from carbohydrate; 16.2% kcal from protein; 5.29 kcal/g, Bio-Serv, Frenchtown, NJ, USA) for 14 weeks, and were individually caged 1 week before drug treatment. Vehicle (0.5% methylcellulose) or AM251 (10 mg/kg, Sigma, St Louis, MO, USA) were dosed by oral gavage at 5:00 PM daily for 2 days. Body weight was measured at 5:00 PM on day 1 and 2, and at 10:00 AM on day 3 before tissue collection. Food was measured at 5:00 PM on day 1 and at 10:00 AM on day 3 before tissue collection. Food intake is calculated as the difference in food weight at the start minus at the end of the study. Mice were euthanized by CO2 asphyxiation at 10:00 AM following the second dose.