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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation

Authors: Yinbing Pan, Xiaodi Sun, Lai Jiang, Liang Hu, Hong Kong, Yuan Han, Cheng Qian, Chao Song, Yanning Qian, Wentao Liu

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Tolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.

Methods

The microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests.

Results

We found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.

Conclusions

Metformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.
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Literature
1.
Henderson G. The μ-opioid receptor: an electrophysiologist's perspective from the sharp end. Br J Pharmacol. 2015;172(2):260–7.CrossRefPubMed
2.
Iwai S, et al. Inhibition of morphine tolerance is mediated by painful stimuli via central mechanisms. Drug Discoveries Ther. 2012;6(1):31–7.
3.
Xu J-T, et al. Opioid receptor–triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia. J Clin Invest. 2014;124(2):592–603.CrossRefPubMedPubMedCentral
4.
5.
6.
Vacca V, et al. Botulinum toxin A increases analgesic effects of morphine, counters development of morphine tolerance and modulates glia activation and μ opioid receptor expression in neuropathic mice. Brain Behav Immun. 2013;32:40–50.CrossRefPubMed
7.
Eidson LN, Murphy AZ. Blockade of Toll-like receptor 4 attenuates morphine tolerance and facilitates the pain relieving properties of morphine. J Neurosci. 2013;33(40):15952–63.CrossRefPubMedPubMedCentral
8.
9.
Berta T, et al. Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice. Neuroscience. 2013;247:376–85.CrossRefPubMedPubMedCentral
10.
Taves S, Berta T, Chen G, Ji RR. Microglia and spinal cord synaptic plasticity in persistent pain. Neural Plast. 2013;2013:753656.PubMedPubMedCentral
11.
Lee YY, et al. Anti-inflammatory mechanism of ginseng saponin metabolite Rh3 in lipopolysaccharide-stimulated microglia: critical role of 5′-adenosine monophosphate-activated protein kinase signaling pathway. J Agric Food Chem. 2015;63(13):3472–80.CrossRefPubMed
12.
13.
O'Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493(7432):346–55.CrossRefPubMed
14.
Inoki K, Kim J, Guan K-L. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol. 2012;52:381–400.CrossRefPubMed
15.
Zong Y. Resveratrol inhibits LPS-induced MAPKs activation via activation of the phosphatidylinositol 3-kinase pathway in murine RAW 264.7 macrophage cells. PLoS One. 2012;7(8):e44107.CrossRefPubMedPubMedCentral
16.
Spencer JP, et al. Neuroinflammation: modulation by flavonoids and mechanisms of action. Mol Asp Med. 2012;33(1):83–97.CrossRef
17.
Han Y, et al. Resveratrol reduces morphine tolerance by inhibiting microglial activation via AMPK signalling. Eur J Pain. 2014;18(10):1458–70.CrossRefPubMed
18.
19.
Wen H, Lu Y, Yao H, Buch S. Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells: implication for vascular permeability. PLoS One. 2011;6:e21707.CrossRefPubMedPubMedCentral
20.
Mika J. Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep. 2008;60(3):297–307.PubMed
21.
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732–41.CrossRefPubMedPubMedCentral
22.
Johnston IN, et al. A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci. 2004;24(33):7353–65.CrossRefPubMed
23.
24.
Shen CH, et al. Etanercept restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in morphine-tolerant rats. Anesth Analg. 2011;112(2):454–9.CrossRefPubMed
25.
Luger NM, et al. Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs. inflammatory pain. Pain. 2002;99(3):397–406.CrossRefPubMed
26.
Bao YH, et al. Gabapentin enhances the morphine anti-nociceptive effect in neuropathic pain via the interleukin-10-heme oxygenase-1 signalling pathway in rats. J Mol Neurosci. 2014;54(1):137–46.CrossRefPubMedPubMedCentral
27.
Lantero A, et al. TGF-beta and opioid receptor signaling crosstalk results in improvement of endogenous and exogenous opioid analgesia under pathological pain conditions. J Neurosci. 2014;34(15):5385–95.CrossRefPubMed
28.
Khabbazi S, Goumon Y, Parat MO. Morphine modulates interleukin-4 or breast cancer cell-induced pro-metastatic activation of macrophages. Sci Rep. 2015;5:11389.CrossRefPubMedPubMedCentral
29.
30.
31.
Bode JG, et al. The inhibitory effect of IL-1 beta on IL-6-induced alpha 2-macroglobulin expression is due to activation of NF-kappa B. J Immunol. 2001;167(3):1469–81.CrossRefPubMed
32.
33.
Zhang X, et al. Involvement of p38/NF-kappaB signaling pathway in the nucleus accumbens in the rewarding effects of morphine in rats. Behav Brain Res. 2011;218(1):184–9.CrossRefPubMed
34.
Davis RL, et al. The opioid antagonist, beta-funaltrexamine, inhibits NF-kappaB signaling and chemokine expression in human astrocytes and in mice. Eur J Pharmacol. 2015;762:193–201.CrossRefPubMedPubMedCentral
35.
Chen Y, Sommer C. The role of mitogen-activated protein kinase (MAPK) in morphine tolerance and dependence. Mol Neurobiol. 2009;40(2):101–7.CrossRefPubMed
36.
Cui Y, et al. Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance. Brain Res. 2006;1069(1):235–43.CrossRefPubMed
37.
He GY, Yuan CG, Hao L, Xu Y, Zhang ZX. GBE50 Attenuates Inflammatory Response by Inhibiting the p38 MAPK and NF- kappa B Pathways in LPS-Stimulated Microglial Cells. Evid Based Complement Alternat Med. 2014;2014:368598.CrossRefPubMedPubMedCentral
38.
Mika J, Wawrzczak-Bargiela A, Osikowicz M, Makuch W, Przewlocka B. Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice. Brain Behav Immun. 2009;23:75–84.CrossRefPubMed
39.
Cui Y, Liao XX, Liu W, Guo RX, Wu ZZ, Zhao CM, et al. A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. Brain Behav Immun. 2008;22:114–23.CrossRefPubMed
40.
Wen H, et al. Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells: implication for vascular permeability. PLoS One. 2011;6(6):e21707.
41.
Farooqui M, et al. COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia. Br J Cancer. 2007;97(11):1523–31.CrossRefPubMedPubMedCentral
42.
Takagi N, et al. Metabotropic glutamate mGlu5 receptor-mediated serine phosphorylation of NMDA receptor subunit NR1 in hippocampal CA1 region after transient global ischemia in rats. Eur J Pharmacol. 2010;644(1):96–100.CrossRefPubMed
43.
Zeitz KP, et al. Reduced development of tolerance to the analgesic effects of morphine and clonidine in PKC gamma mutant mice. Pain. 2001;94(3):245–53.CrossRefPubMed
44.
Yan H, Yu L-C. Expression of calcitonin gene-related peptide receptor subunits in cultured neurons following morphine treatment. Neurosci Lett. 2013;544:52–5.CrossRefPubMed
45.
Mattioli TA, et al. Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence. PLoS One. 2014;9(5):e97361.CrossRefPubMedPubMedCentral
46.
Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I: physiological pathways and pharmacological modalities. Can J Anaesth. 2001;48(10):1000–10.CrossRefPubMed
Metadata
Title
Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation
Authors
Yinbing Pan
Xiaodi Sun
Lai Jiang
Liang Hu
Hong Kong
Yuan Han
Cheng Qian
Chao Song
Yanning Qian
Wentao Liu
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0754-9

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