Nobuo Aikawa and Kenji Ohmori
Drug Development Research Laboratories, Pharmaceutical Research Institute,
Kyowa Hakko Kogyo Co., Ltd.,
1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411 - 8731, Japan
Abstract: Using distention of the small intestine as a visceral
pain model, we investigated the effect of zaldaride maleate (ZAL), a selective
inhibitor of calmodulin, on the depressor response. In pentobarbital-anesthetized
rats, small intestine distention was induced by rapid application of intraluminal
pressures of 40 cmH2O causing a reflex fall in arterial blood
pressure. The depressor response to intestinal distention was abolished
by intraperitoneal administration of capsaicin (5 mg/rat), which depletes
neuropeptides such as substance P from the sensory neurons, on the mesenteric
stalk and by neonatal pretreatment with capsaicin (50 mg/kg, s.c.). Morphine
(20 mg/kg, s.c.) reduced the depressor response following intestinal distention.
At doses of 3 mg/kg (i.v.) and higher, ZAL significantly reduced depressor
response. The effect of morphine was reversed by naloxone (5 mg/kg, i.v.);
the effect of ZAL was not affected. These results suggest that ZAL helps
reduce the visceral pain induced by noxious stimulus and that the antinociceptive
effect of ZAL is not mediated by opioid receptors.
Keywords: Zaldaride maleate, Visceral pain, Calmodulin, Intestinal distention