| Co-Investigator(Kenkyū-buntansha) |
WAKASA Yoshio ditto, 付属前臨床医学研究所・精神薬理部, 主任研究員 (60124278)
SHIMADA Akira Central Institute for Experimental Animals, Preclinical Research Laboratories, S, 付属前臨床医学研究所・薬理部, 主任研究員 (00124272)
津田 敏治 実験動物中央研究所, 薬理部, 主任研究員 (70172020)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1991: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1990: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1989: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
In assessment of the physical dependence potential of drugs, withdrawal signs are usually observed in whole animals, but establishment of alternative in vitro methods are needed since whole animal experiments may entail sow withdrawal discomfort if physical dependence develops. For this reason, an in vitro method of assessing the physical dependence potential of some opioid substances was sought by using isolated animal organs, and the following results were obtained.
1)A longitudinal muscle preparation of guinea pig ileum was suspended in Magnus bath and electrically stimulated. Morphine, pethidine, codeine, pentazocine, and ethyl-keto-cyclazocine(EKC)inhibited the contraction and IC50 values were obtained with these drugs. The effects of these drugs were antagonized by naloxone.
2)When the preparations were incubated with a test drug solution for 24 hrs, then suspended in the bath and naloxone was applied, the baseline of the contraction was elevated. The extent of this elevation paral
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leled the incubation time. When the preparations were not incubated but were pretreated with the drugs for 30 min in the bath, the elevation was obvious with morphine or codeine but unclear with the other drugs.
3)In deferent duct preparations of the rabbit none of the drugs, except EKC, inhibited the contraction, and with EKC no elevation of the baseline was observed with naloxone application, following 24 hr incubation.
4)In an in vivo experiment in rats, EKC was intravenously infused every hour for 72 hrs, then nalox one was subcutaneously administered and withdrawal signs were observed for lhr. The animals manifested appearent withdrawal signs such as hyperirritability, diarhea, and body weight loss, but the signs were weaker than those of pentazocine. The results were in agreement with those of the in vitro experiments.
Thus, the method of using isolated guinea pig ileum was found to have practical value for the assessment of physical dependence potential of opioid substances if applied in a stepwise fashion ; first to observe IC50, then to incubate the preparation with a test drug for 24 hrs at 1 to 5 multiple concentrations of IC50, and if the baseline elevation is observed to then pretreat the preparation with the test drug for 30 min in a bath prior to naloxone application. Less
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