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Br J Pharmacol. 2013 Mar;168(6):1421-9. doi: 10.1111/bph.12028.

Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4.

Author information

1
Department of Pharmacology and Physiology, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107, USA. cw.stevens@okstate.edu

Abstract

BACKGROUND AND PURPOSE:

Previous work in our laboratory showed opioid agents inhibit cytokine expression in astrocytes. Recently, Watkins and colleagues hypothesized that opioid agonists activate toll-like receptor 4 (TLR4) signalling, which leads to neuroinflammation. To test this hypothesis, we characterized LPS and opioid effects on TLR4 signalling in reporter cells.

EXPERIMENTAL APPROACH:

NF-κB reporter cells expressing high levels of TLR4 were used to compare LPS and opioid effects on NF-κB activation, a pathway activated by TLR4 stimulation.

KEY RESULTS:

LPS increased TLR4 signalling in a concentration-dependent manner and was antagonized by LPS antagonist (LPS-RS, from Rhodobacter sphaeroides). A concentration ratio analysis showed that LPS-RS was a competitive antagonist. The opioid agonists, morphine and fentanyl, produced minor activation of TLR4 signalling when given alone. When tested following LPS stimulation, opioid agonists inhibited NF-κB activation but this inhibition was not blocked by the general opioid antagonist, naloxone, nor by the selective μ opioid receptor antagonist, β-FNA. Indeed, both naloxone and β-FNA also inhibited NF-κB activation in reporter cells. Further examination of fentanyl and β-FNA effects revealed that both opioid agents inhibited LPS signalling in a non-competitive fashion.

CONCLUSIONS AND IMPLICATIONS:

These results show that LPS-RS is a competitive antagonist at the TLR4 complex, and that both opioid agonists and antagonists inhibit LPS signalling in a non-competitive fashion through a non-GPCR, opioid site(s) in the TLR4 signalling pathway. If confirmed, existing opioid agents or other drug molecules more selective at this novel site may provide a new therapeutic approach to the treatment of neuroinflammation.

PMID:
23083095
PMCID:
PMC3596647
DOI:
10.1111/bph.12028
[Indexed for MEDLINE]
Free PMC Article

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