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Br J Pharmacol. 2016 Mar;173(5):856-69. doi: 10.1111/bph.13394. Epub 2016 Feb 4.

Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4.

Author information

1
Chemical Biology Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China.
2
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
3
Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, 80309, USA.
4
Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado at Boulder, Boulder, CO, 80309, USA.
5
Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA, 5005, Australia.
6
Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20892, USA.

Abstract

BACKGROUND AND PURPOSE:

The toll-like receptor TLR4 is involved in neuropathic pain and in drug reward and reinforcement. The opioid inactive isomers (+)-naltrexone and (+)-naloxone act as TLR4 antagonists, reversing neuropathic pain and reducing opioid and cocaine reward and reinforcement. However, how these agents modulate TLR4 signalling is not clear. Here, we have elucidated the molecular mechanism of (+)-naltrexone and (+)-naloxone on TLR4 signalling.

EXPERIMENTAL APPROACH:

BV-2 mouse microglial cell line, primary rat microglia and primary rat peritoneal macrophages were treated with LPS and TLR4 signalling inhibitors. Effects were measured using Western blotting, luciferase reporter assays, fluorescence microscopy and ELISA KEY RESULTS: (+)-Naltrexone and (+)-naloxone were equi-potent inhibitors of the LPS-induced TLR4 downstream signalling and induction of the pro-inflammatory factors NO and TNF-α. Similarly, (+)-naltrexone or (+)-naloxone inhibited production of reactive oxygen species and increased microglial phagocytosis, induced by LPS. However, (+)-naltrexone and (+)-naloxone did not directly inhibit the increased production of IL-1β, induced by LPS. The drug interaction of (+)-naloxone and (+)-naltrexone was additive. (+)-Naltrexone or (+)-naloxone inhibited LPS-induced activation of IFN regulatory factor 3 and production of IFN-β. However, they did not inhibit TLR4 signalling via the activation of either NF-κB, p38 or JNK in these cellular models.

CONCLUSIONS AND IMPLICATIONS:

(+)-Naltrexone and (+)-naloxone were TRIF-IFN regulatory factor 3 axis-biased TLR4 antagonists. They blocked TLR4 downstream signalling leading to NO, TNF-α and reactive oxygen species. This pattern may explain, at least in part, the in vivo therapeutic effects of (+)-naltrexone and (+)-naloxone.

PMID:
26603732
PMCID:
PMC4761092
[Available on 2017-03-01]
DOI:
10.1111/bph.13394
[Indexed for MEDLINE]
Free PMC Article

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