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The selective mu opioid antagonist β‐funaltrexamine (β‐FNA) reduces toll‐like receptor‐4 signaling
Author(s) -
Stevens Craig W,
Aravind Shruthi,
Davis Randall L
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.583.4
Subject(s) - tlr4 , opioid , pharmacology , agonist , opioid receptor , chemistry , receptor , signal transduction , naltrexone , medicine , biochemistry
Recently published data from our labs showed that the selective mu opioid antagonist, β‐FNA (β‐funaltrexamine), inhibits the release of pro‐inflammatory cytokines and the expression of nitric oxide synthase (iNOS) in tumor necrosis factor alpha (TNFα)‐stimulated human astrocytes. The finding that the opioid agonists, morphine and fentanyl, also inhibited these pro‐inflammatory processes suggested that these opioid effects were not mediated at the classical mu opioid receptor. Other recent data primarily from Watkins’ research group, suggest that this non‐opioid receptor mediated effect of opioid agents on glial cell activation may be due to an interaction of opioids on the toll‐like receptor 4 (TLR4) signaling pathway. Thus, the present studies were undertaken to further investigate the effects of β‐FNA on the TLR4 signaling pathway using human astrocytes and a commercially available reporter cell line for TLR4 signaling called HEK‐Blue4 cells. We found that opioid agonists themselves produce a minor but significant stimulation of TLR4 signaling which is not blocked by the general opioid antagonist, naltrexone. When cells were treated with a specific TLR4 agonist, LPS‐EK, opioid agonists and antagonists both decreased TLR4 signaling. β‐FNA was the most potent agent in this regard. Given these preliminary data, β‐FNA may show promise as a new anti‐inflammatory agent. Supported by NIH grants DA12448 (CWS) and NS062664 (RLD).