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Nociceptin and the nociceptin receptor (NOP) have been described as targets for treatment of pain and inflammation, whereas toll-like receptors (TLRs) play key roles in inflammation and impact opioid receptors and endogenous opioids expression. In this study, interactions between the nociceptin and TLR systems were investigated. Human THP-1 cells were cultured with or without phorbol myristate acetate (PMA 5 ng/mL), agonists specific for TLR2 (lipoteichoic acid, LTA 10 µg/mL), TLR4 (lipopolysaccharide, LPS 100 ng/mL), TLR7 (imiquimod, IMQ 10 µg/mL), TLR9 (oligonucleotide (ODN) 2216 1 µM), PMA+TLR agonists, or nociceptin (0.01–100 nM). Prepronociceptin (<i>ppNOC</i>), <i>NOP</i>, and <i>TLR</i> mRNAs were quantified by RT-qPCR. Proteins were measured using flow cytometry. PMA upregulated <i>ppNOC</i> mRNA, intracellular nociceptin, and cell membrane NOP proteins (all <i>p</i> < 0.05). LTA and LPS prevented PMA’s upregulating effects on <i>ppNOC</i> mRNA and nociceptin protein (both <i>p</i> < 0.05). IMQ and ODN 2216 attenuated PMA’s effects on <i>ppNOC</i> mRNA. PMA, LPS, IMQ, and ODN 2216 increased NOP protein levels (all <i>p</i> < 0.05). PMA+TLR agonists had no effects on NOP compared to PMA controls. Nociceptin dose-dependently suppressed TLR2, TLR4, TLR7, and TLR9 proteins (all <i>p</i> < 0.01). Antagonistic effects observed between the nociceptin and TLR systems suggest that the nociceptin system plays an anti-inflammatory role in monocytes under inflammatory conditions.