Analgesic effects of chemically synthesized NOD1 and NOD2 agonists in mice.
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.
Sato
Tadasu
T
Division of Oral Microbiology, Division of Oral Molecular Regulation, Division of Periodontology and Endodontology, Department of Oral Biology, Tohoku University Graduate School of Dentistry, Sendai, Japan.
Shikama
Yosuke
Y
Shimauchi
Hidetoshi
H
Endo
Yasuo
Y
Takada
Haruhiko
H
D019342:Acetic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D003960:Diaminopimelic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D004336:Drug Antagonism; D005260:Female; D007375:Interleukin-1 / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists* / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000819:agonists* / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control*; D010147:Pain Measurement; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000700:Analgesics; D007375:Interleukin-1; D009292:Narcotic Antagonists; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; D009270:Naloxone; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D003960:Diaminopimelic Acid; C035295:6-O-stearoyl-N-acetylmuramyl-alanylisoglutamine; C034330:FK 156; C039537:heptanoyl-gamma-D-glutamyl-L-meso-diaminopimelyl-D-alanine; D019342:Acetic Acid; C036866:romurtide