Khotib Junaidi, Narita Minoru, Suzuki Masami, Yajima Yoshinori, Suzuki Tsutomu
Department of Toxicology, Hoshi University, School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-Ku, Tokyo 142-8501, Japan.
Neuropharmacology. 2004 Mar;46(4):531-40. doi: 10.1016/j.neuropharm.2003.11.003.
It has been widely accepted that repeated administration of kappa-opioid receptor agonists leads to the development of antinociceptive tolerance. The present study was designed to investigate the effect of repeated administration of a selective kappa-opioid receptor agonist (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride ((-)U-50,488H) on the mu- and delta-opioid receptor agonist-induced antinociception and G-protein activation in mice. The mice were injected either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) pretreated with saline or (-)U-50,488H once a day for seven consecutive days. Two hours after the last injection, the mice were challenged by either mu- or delta-opioid receptor agonist for the antinociceptive assay. Repeated treatment with (-)U-50,488H (s.c. or i.c.v.) significantly enhanced antinociceptive effect of both mu-opioid receptor agonist (morphine) and delta-opioid receptor agonists ([d-Ala2]deltorphin (DELT) and (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dime thyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80) compared to saline-treated groups. Under these conditions, repeated s.c. injection of (-)U-50,488H significantly enhanced both mu- and delta-opioid receptor agonist-stimulated [35S]GTPgammaS binding in the membrane of the thalamus. On the contrary, either repeated administration of morphine (s.c. or i.c.v.) or SNC-80 failed to affect the kappa-opioid receptor agonist-induced antinociception and G-protein activation. Taken together, these results suggest that repeated stimulation of kappa-opioid receptor markedly increases the functional mu- and delta-opioid receptors, whereas repeated stimulation of either mu- or delta-opioid receptor had no direct effect on kappa-opioidergic function in mice.
人们普遍认为，反复给予κ-阿片受体激动剂会导致抗伤害感受耐受性的产生。本研究旨在探讨反复给予选择性κ-阿片受体激动剂（1S-反式）-3,4-二氯-N-甲基-N-[2-(1-吡咯烷基)环己基]-苯乙酰胺盐酸盐（(-)U-50,488H）对μ-和δ-阿片受体激动剂诱导的小鼠抗伤害感受及G蛋白激活的影响。将小鼠连续7天每天皮下（s.c.）或脑室内（i.c.v.）注射生理盐水或(-)U-50,488H进行预处理。最后一次注射后2小时，用μ-或δ-阿片受体激动剂对小鼠进行抗伤害感受测定。与生理盐水处理组相比，(-)U-50,488H（s.c.或i.c.v.）反复处理显著增强了μ-阿片受体激动剂（吗啡）和δ-阿片受体激动剂（[d-Ala2]强啡肽（DELT）和(+)-4-[(αR)-α-((2S,5R)-4-烯丙基-2,5-二甲基-1-哌嗪基)-3-甲氧基苄基]-N,N-二乙苯甲酰胺（SNC-80）的抗伤害感受作用。在这些条件下，反复皮下注射(-)U-50,488H显著增强了μ-和δ-阿片受体激动剂刺激的丘脑膜中[35S]GTPγS结合。相反，反复给予吗啡（s.c.或i.c.v.）或SNC-80均未能影响κ-阿片受体激动剂诱导的抗伤害感受及G蛋白激活。综上所述，这些结果表明，反复刺激κ-阿片受体可显著增加功能性μ-和δ-阿片受体，而反复刺激μ-或δ-阿片受体对小鼠κ-阿片能功能无直接影响。
