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

作者：Reine‐Solange Sauer, Dagmar Hackel, Laura Morschel, Henrike Sahlbach, Ying Wang, Shaaban A. Mousa, Norbert Roewer, Alexander Brack, Heike Lydia Rittner · 发表于：Molecular Pain · 年份：2014 · DOI：10.1186/1744-8069-10-10 · 被引用次数：65 · 研究领域：Neuropeptides and Animal Physiology、Pain Mechanisms and Treatments、Immune Response and 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 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 LP...