Tao P L, Liu W C, Tsuei Y S, Cheng C Y
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, R.O.C.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Feb;355(2):281-7. doi: 10.1007/pl00004944.
U-50,488, a selective kappa-opioid receptor agonist, has been reported to inhibit the development of antinociceptive tolerance to morphine in mice, rats and guinea pigs, but the mechanism involved in this action remains unknown. Since U-50,488 has been reported to suppress the plasma vasopressin level, we investigated the role of vasopressin with U-50,488 in the male Sprague Dawley rat in this study. Animals (230-270 g) were chronically treated with morphine (10 mg/kg, i.p.) twice a day for 6 days in order to induce tolerance to antinociceptive effect measured by tail-flick test. Withdrawal symptoms were precipitated by naloxone (10 mg/kg, i.p.) on day 7. U-50,488 (i.p.) or AVP (i.p. or i.c.v.) or U-50,488 and AVP was (were) coadministered with chronic morphine to investigate their effects on morphine tolerance and dependence. We found that coadministration of 8 mg/kg U-50,488 (i.p.) with morphine almost completely block morphine tolerance and partially block withdrawal symptoms. In contrast, coadministration of AVP (0.3 microgram/kg, i.p., or 0.01 microgram, i.c.v.) with morphine and U-50,488, the effects of U-50,488 to block morphine tolerance and dependence were reversed. In addition, treatment of AVP antagonist (dPTyr(Me)AVP, 0.5 microgram/kg, i.p. or 0.5 microgram, i.c.v.) has the similar effect as U-50,488 to block morphine tolerance. In summary, the effect of U-50,488 to block morphine tolerance and dependence may relate to its inhibitory effect on AVP release.
U - 50,488是一种选择性κ-阿片受体激动剂，据报道它能抑制小鼠、大鼠和豚鼠对吗啡抗伤害感受耐受性的发展，但其作用机制尚不清楚。由于据报道U - 50,488能抑制血浆血管加压素水平，因此在本研究中我们在雄性Sprague Dawley大鼠中研究了血管加压素与U - 50,488的作用。动物（230 - 270克）每天两次腹腔注射吗啡（10毫克/千克），持续6天，以诱导通过甩尾试验测量的抗伤害感受作用的耐受性。在第7天，通过腹腔注射纳洛酮（10毫克/千克）引发戒断症状。将U - 50,488（腹腔注射）或血管加压素（腹腔注射或脑室内注射）或U - 50,488与血管加压素联合使用，与慢性吗啡共同给药，以研究它们对吗啡耐受性和依赖性的影响。我们发现，8毫克/千克U - 50,488（腹腔注射）与吗啡联合给药几乎完全阻断吗啡耐受性，并部分阻断戒断症状。相反，血管加压素（0.3微克/千克，腹腔注射，或0.01微克，脑室内注射）与吗啡和U - 50,488联合给药时，U - 50,488阻断吗啡耐受性和依赖性的作用被逆转。此外，血管加压素拮抗剂（dPTyr(Me)AVP，0.5微克/千克，腹腔注射或0.5微克，脑室内注射）的治疗与U - 50,488阻断吗啡耐受性的效果相似。总之，U - 50,488阻断吗啡耐受性和依赖性的作用可能与其对血管加压素释放的抑制作用有关。
