Toll like Receptor (TLR)-4 as a Regulator of Peripheral Endogenous Opioid-Mediated Analgesia in Inflammation

Background: Leukocytes containing opioid peptides locally control inflammatory pain. In the early phase of complete Freund's adjuvant (CFA)-induced hind paw inflammation, formyl peptides (derived e.g. from Mycobacterium butyricum) trigger the release of opioid peptides from neutrophils contribu...

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Bibliographic Details
Published in:	Molecular pain Vol. 10; no. 1; p. 10
Main Authors:	Sauer, Reine-Solange, Hackel, Dagmar, Morschel, Laura, Sahlbach, Henrike, Wang, Ying, Mousa, Shaaban A, Roewer, Norbert, Brack, Alexander, Rittner, Heike L
Format:	Journal Article
Language:	English
Published:	Los Angeles, CA SAGE Publications 06-02-2014 BioMed Central Ltd Sage Publications Ltd BioMed Central
Subjects:	Analgesia Anesthesiology Animals Antagonists Beta-endorphin beta-Endorphin - metabolism Calcium (intracellular) Calcium - metabolism Calcium ionophores Care and treatment CD14 antigen CD16 antigen Cell activation Cell Differentiation - drug effects Cyclophosphamide Design Fc receptors Formyl peptides Freund's adjuvant Freund's Adjuvant - administration & dosage Freund's Adjuvant - pharmacology Genetic aspects Health aspects Humans Hyperalgesia - complications Hyperalgesia - metabolism Hyperalgesia - pathology Inflammation Inflammation - complications Inflammation - drug therapy Inflammation - metabolism Inflammation - pathology Intensive care Ionomycin Leukocytes (neutrophilic) Ligands Lipopolysaccharide Receptors - metabolism Lipopolysaccharides Lipopolysaccharides - pharmacology Macrophages Macrophages - drug effects Macrophages - metabolism Male Monocytes Monocytes - drug effects Monocytes - metabolism Mycobacterium Naloxone Narcotics Nociception - drug effects Opioid peptides Opioid Peptides - pharmacology Opioid Peptides - therapeutic use Opioid receptors Pain Pain perception Peptides Peripheral neuropathy Physiological aspects Rats Rats, Wistar Receptors, IgG - metabolism Receptors, Opioid - metabolism Rodents Sepsis Studies TLR4 protein Toll-Like Receptor 2 - metabolism Toll-Like Receptor 4 - metabolism Toll-like receptors Germany Analgesia Endogenous opioids Inflammatory pain Toll like receptors
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Summary:	Background: Leukocytes containing opioid peptides locally control inflammatory pain. In the early phase of complete Freund's adjuvant (CFA)-induced hind paw inflammation, formyl peptides (derived e.g. from Mycobacterium butyricum) trigger the release of opioid peptides from neutrophils contributing to tonic basal antinociception. In the later phase we hypothesized that toll-like-receptor-(TLR)-4 activation of monocytes/macrophages triggers opioid peptide release and thereby stimulates peripheral opioid-dependent antinociception. Results: In Wistar rats with CFA hind paw inflammation in the later inflammatory phase (48–96 h) systemic leukocyte depletion by cyclophosphamide (CTX) or locally injected naloxone (NLX) further decreased mechanical and thermal nociceptive thresholds. In vitro β-endorphin (β-END) content increased during human monocyte differentiation as well as in anti-inflammatory CD14+CD16- or non-classical M2 macrophages. Monocytes expressing TLR4 dose-dependently released β-END after stimulation with lipopolysaccharide (LPS) dependent on intracellular calcium. Despite TLR4 expression proinflammatory M1 and anti-inflammatory M2 macrophages only secreted opioid peptides in response to ionomycin, a calcium ionophore. Intraplantar injection of LPS as a TLR4 agonist into the inflamed paw elicited an immediate opioid- and dose-dependent antinociception, which was blocked by TAK-242, a small-molecule inhibitor of TLR4, or by peripheral applied NLX. In the later phase LPS lowered mechanical and thermal nociceptive thresholds. Furthermore, local peripheral TLR4 blockade worsened thermal and mechanical nociceptive pain thresholds in CFA inflammation. Conclusion: Endogenous opioids from monocytes/macrophages mediate endogenous antinociception in the late phase of inflammation. Peripheral TLR4 stimulation acts as a transient counter-regulatory mechanism for inflammatory pain in vivo, and increases the release of opioid peptides from monocytes in vitro. TLR4 antagonists as new treatments for sepsis and neuropathic pain might unexpectedly transiently enhance pain by impairing peripheral opioid analgesia.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1744-8069 1744-8069
DOI:	10.1186/1744-8069-10-10