Antinociceptive and desensitizing effects of systemically administered capsaicinoids (capsaicin and KR25018) were investigated in guinea pig. Nociceptive sensitivity to chemical stimulus was examined to test sensory function, and the content of substance P-like immunoreactivity (SP-LI) in bronchi was determined as a peripheral marker of capsaicin-sensitive primary afferent neurons. Guinea pigs were pretreated s.c. with several doses of capsaicin (1, 2.5, 5, 10 mg/kg) or KR25018 (1, 2.5, 5, 10 mg/kg) one week prior to the experiments. Frequency of eye wiping was significantly decreased by capsaicin and KR25018 in a pretreatment dose-dependent manner. In capsaicin- or KR25018-pretreated guinea pigs, there was a significant loss of SP-LI in bronchial tissue extracts. In summary, a newly synthesized capsaicin analogue KR25018 exhibited antinociceptive effect against chemical stimulus in guinea pig, with comparable potency to capsaicin. This desensitizing activity of capsaicin or KR25018 might be related to the loss of SP-LI in peripheral afferent nerves.