Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite.
Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite.
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发表时间：
1989-11
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通讯作者：
D. Paul;K. Standifer;C. Inturrisi;G. Pasternak
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作者：
D. Paul;K. Standifer;C. Inturrisi;G. Pasternak
吗啡-6 -葡糖苷是吗啡的主要代谢物，具有有效的镇痛作用。为了更充分地确定这种化合物在吗啡作用中的重要性，我们比较了吗啡及其6 -葡糖苷代谢物在外周和中枢给药后的镇痛作用。给予s.c，吗啡-6 -葡糖苷引起的镇痛效果大约是吗啡的两倍，部分原因是其作用持续时间长，而且还抑制胃肠运动。这两种作用很容易被纳洛酮（s.c）逆转。然而，当静脉注射或鞘内注射时，吗啡-6 -葡糖苷的镇痛作用分别比吗啡强约90倍和650倍。在这些研究中，吗啡作为镇痛药在神经轴的两个水平上都是等效的，而6 -葡糖苷在脊髓水平上的效果比在脊柱上的效果大约高5倍。mu1选择性拮抗剂纳洛唑嗪阻断了全身和体外循环吗啡-6 -葡糖苷酸的镇痛作用，就像阻断吗啡一样，这意味着mu1受体在这些作用中发挥了作用。与吗啡一样，鞘内注射吗啡-6 -葡糖苷酸镇痛对纳洛唑嗪不敏感，提示脊髓内存在mu2机制。总之，这些结果表明吗啡-6 -葡糖苷通过与吗啡相同的受体机制激发其镇痛作用。植入吗啡微丸后，对吗啡高度耐受的小鼠表现出对吗啡-6 -葡糖苷的交叉耐受（s.c）。吗啡-6 -葡糖苷的高效力强烈表明，这种代谢物在吗啡的作用中起重要作用。
Morphine-6 beta-glucuronide is a major metabolite of morphine with potent analgesic actions. To define more fully the importance of this compound in morphine action, we have compared the analgesic actions of morphine and its 6 beta-glucuronide metabolite after both peripheral and central administration. Given s.c., morphine-6 beta-glucuronide elicited analgesia with an effect approximately twice that of morphine due, in part, to its long duration of action and also inhibited gastrointestinal motility. Both actions were easily reversed by naloxone (s.c.). However, when injected either i.c.v. or intrathecally, morphine-6 beta-glucuronide was approximately 90- and 650-fold more potent an analgesic than morphine, respectively. Whereas morphine in these studies was equipotent at both levels of the neuraxis as an analgesic, the 6 beta-glucuronide was approximately 5-fold more effective at the level of the spinal cord than supraspinally. The mu 1-selective antagonist naloxonazine blocked the analgesic effect of systemic and i.c.v. morphine-6 beta-glucuronide much as it blocked morphine, implying a role for mu1 receptors in these actions. Like morphine, morphine-6 beta-glucuronide analgesia after intrathecal injection was not sensitive to naloxonazine, suggesting a mu2 mechanism within the spinal cord. Together, these results imply that morphine-6 beta-glucuronide elicited its analgesic actions through the same receptor mechanisms as morphine. Mice highly tolerant to morphine after implantation of morphine pellets showed cross-tolerance to morphine-6 beta-glucuronide (s.c.). The high potency of morphine-6 beta-glucuronide strongly suggests that this metabolite plays an important role in morphine's actions.