Buprenorphine prevents and reverses the expression of chronic etorphine-induced sensitization of adenylyl cyclase in SK-N-SH human neuroblastoma cells.
Buprenorphine prevents and reverses the expression of chronic etorphine-induced sensitization of adenylyl cyclase in SK-N-SH human neuroblastoma cells.
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发表时间：
1993
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通讯作者：
J. M. Thomas;B. Hoffman
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作者：
J. M. Thomas;B. Hoffman
丁丙诺啡是一种混合激动剂和拮抗剂的阿片类药物，具有减轻药物渴求和成瘾的疗效。由于腺苷酸环化酶系统涉及阿片戒断现象的生化基础，我们比较了丁丙诺啡和全阿片激动剂埃托啡对人神经母细胞瘤细胞SK-N-SH中环AMP （cAMP）合成的急性和慢性影响。两种药物均可急性抑制前列腺素（PG） e1刺激的cAMP积累；用阿片拮抗剂纳曲酮或百日咳毒素预处理可预防两种药物引起的抑制作用。在停用抑制药物后观察到，用艾托啡慢性治疗的细胞诱导pge1刺激的cAMP合成增加。丁丙诺啡慢性治疗似乎有相反的效果，导致PGE1刺激减弱；此外，丁丙诺啡可以阻止乙托啡诱导的cAMP合成增强，无论是在细胞与乙托啡长时间孵育之前还是之后。丁丙诺啡的减弱作用在5分钟内发生，可以通过事先应用纳曲酮来阻止，但不能通过随后的拮抗剂治疗来逆转。这些发现表明丁丙诺啡与阿片受体不可逆结合（伪），导致cAMP合成持续抑制，掩盖了乙托啡诱导的腺苷酸环化酶活性增强。实验证实了这一假设，尽管对细胞进行了大量清洗以去除未结合的丁丙诺啡，但用丁丙诺啡处理细胞显著减少了可用的阿片受体结合位点。丁丙诺啡的这些药效学作用可能与其治疗药物滥用和成瘾的疗效有关。
Buprenorphine is an opiate drug with a mixed agonist-antagonist profile and has therapeutic efficacy in attenuating drug craving and addiction. Because the adenylyl cyclase system has been implicated in the biochemical basis of opiate withdrawal phenomena, we have compared the acute and chronic effects of buprenorphine with the full opiate agonist etorphine on cyclic AMP (cAMP) synthesis in the human neuroblastoma cell SK-N-SH. Both drugs acutely inhibited prostaglandin (PG)E1-stimulated cAMP accumulation; the inhibition caused by either drug was prevented by pretreatment with the opiate antagonist naltrexone or with pertussis toxin. Chronic treatment of the cells with etorphine induced an increase in PGE1-stimulated cAMP synthesis which was observed after withdrawal of the inhibitory drug. Chronic treatment with buprenorphine appeared to have the opposite effect, resulting in an attenuated PGE1 stimulation; additionally, buprenorphine prevented the etorphine-induced enhancement in cAMP synthesis, whether administered before or after prolonged incubation of the cells with etorphine. The attenuating effect of buprenorphine occurred within 5 min and was prevented by a prior application of naltrexone, but could not be reversed by a subsequent treatment with antagonist. These findings suggest that buprenorphine was binding (pseudo)irreversibly to the opiate receptor, resulting in a persistent inhibition of cAMP synthesis which masks the etorphine-induced enhancement of adenylyl cyclase activity. This hypothesis was confirmed by experiments demonstrating that treatment of the cells with buprenorphine significantly reduced available opiate receptor binding sites despite extensive washing of the cells to remove unbound buprenorphine. These pharmacodynamic actions of buprenorphine may be relevant to its therapeutic efficacy in treating drug abuse and addiction.