Analgesic effects of chemically synthesized NOD1 and NOD2 agonists in mice

Abstract

Intracellular nucleotide-binding oligomerization domain (NOD)-like receptors, NOD1 and NOD2, recognize the diaminopimelic acid (DAP)-containing peptide moiety and muramyldipeptide (MDP) moiety of bacterial peptidoglycan, respectively. Muramyldipeptide has been reported to exert analgesic activity to decrease the frequency of acetic acid-induced writhing movements in mice. In this study, we demonstrated the analgesic activities of NOD1 as well as NOD2 agonists. Intravenous injection of NOD2-agonistic MDP, 6-O-stearoyl-MDP (L18-MDP), and MDP-Lys (L18) exhibited analgesic activity at 10, 50, and 2.0 µg/head, respectively, in BALB/c mice. NOD1-Agonistic FK156 (D-lactyl-L-Ala-D-Glu-meso-DAP-L-Gly) and FK565 (heptanoyl-D-Glu-meso-DAP-D-Ala) were also analgesic at 50 µg/head and 1.0 µg/head, respectively. The analgesic effect of FK565 appeared from 30 min, reached maximum activity at 8 h, and continued until 24 h. The FK565 exhibited activity by various administration routes; intravenous, intraperitoneal, intramuscular, sublingual (1.0 µg/head each), subcutaneous, intragastric (oral), intragingival (10 µg/ head each) and intracerebroventricular (0.01 µg/head). The analgesic activity of FK565 was observed even in tumor necrosis factor (TNF)-α knockout, interleukin (IL)-1α/β double knockout, and their triple knockout mice. Naloxane, a non-selective antagonist for the opioid receptor, completely inhibited the analgesic effect of FK565. These findings suggest that NOD1 and NOD2 activation induces an analgesic effect via opioid receptors in a TNF-α and IL-1α/β independent manner.

Synergistic effects of NOD1 or NOD2 and TLR4 activation on mouse sickness behavior in relation to immune and brain activity markers

“…In line with this contention, LPS has been shown to evoke acute pain ( Kamei et al, 2004 ) although it has also been reported to induce analgesia via activation of opioid receptors ( Yirmiya et al, 1994 ). Likewise, the cytokine-independent analgesic effect of MDP and FK565 is blocked by the opioid receptor antagonist naloxone ( Sato et al, 2010 ). It thus seems unlikely that the behavioral response to combined NLR and TLR4 agonism reflects hyperalgesia, but this issue needs further investigation.…”

Strategies for Using Muramyl Peptides - Modulators of Innate Immunity of Bacterial Origin - in Medicine

“…Later in 2011, the potentiating effect of romurtide was discovered: its co-administration with IFN-b promotes the maturation of dendritic cells and inhibits the growth of B16F10 melanoma, while muramyl peptide and IFN-b alone did not have a significant effect on tumor growth (89). In addition, through animal experiments, the Japanese researchers found the analgesic effect of romurtide: at doses of 10, 50, and 2.0 µg per mouse, a decrease in the frequency of convulsive movements caused by acetic acid was observed (90). Until 1998, the dosage form (DF) of romurtide was produced in the form of a lyophilisate of 200 mg in vials complete with water for preparing a solution for subcutaneous injection.…”