S-777469, a novel cannabinoid type 2 receptor agonist, suppresses itch-associated scratching behavior in rodents through inhibition of itch signal transmission

Pharmacology. 2015;95(1-2):95-103. doi: 10.1159/000371890.

Abstract

We have previously reported that S-777469 [1-([6-ethyl-1-(4-fluorobenzyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carbonyl]amino)-cyclohexanecarboxylic acid], a novel cannabinoid type 2 receptor (CB2) agonist, significantly suppressed compound 48/80-induced scratching behavior in mice in a dose-dependent manner when it was administered orally. Here, we demonstrated that the inhibitory effects of S-777469 on compound 48/80-induced scratching behavior are reversed by pretreatment with SR144528, a CB2-selective antagonist. In addition, we investigated the effects of S-777469 on itch-associated scratching behavior induced by several pruritogenic agents in mice and rats. S-777469 significantly suppressed scratching behavior induced by histamine or substance P in mice or by serotonin in rats. In contrast, the H1-antihistamine fexofenadine clearly inhibited histamine-induced scratching behavior but did not affect scratching behavior induced by substance P or serotonin. Moreover, S-777469 significantly inhibited histamine-induced peripheral nerve firing in mice. In conclusion, these results suggest that S-777469 produces its antipruritic effects by inhibiting itch signal transmission through CB2 agonism.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Female
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / metabolism
  • Histamine
  • Mice, Inbred ICR
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / physiology
  • Pruritus / chemically induced
  • Pruritus / drug therapy*
  • Pruritus / physiopathology
  • Pyridones / pharmacology*
  • Pyridones / therapeutic use*
  • Rats, Inbred F344
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Serotonin
  • Signal Transduction / drug effects
  • Substance P
  • p-Methoxy-N-methylphenethylamine

Substances

  • Pyridones
  • Receptor, Cannabinoid, CB2
  • S-777469
  • Serotonin
  • Substance P
  • p-Methoxy-N-methylphenethylamine
  • Histamine