Mayfield K P, D'Alecy L G
Department of Physiology, University of Michigan Medical School, Ann Arbor.
J Pharmacol Exp Ther. 1994 Jan;268(1):74-7.
Previously an acute adaptation to hypoxia was induced by intermittent, severe hypoxia and this conditioned increase in survival time during subsequent hypoxia was blocked by naloxone. The current study further defined the opioid nature and the receptor type(s) involved in hypoxic adaptation by the use of (+)-naloxone (inactive isomer) and selective opioid antagonists. (+)-Naloxone failed to change significantly the survival times of hypoxic or sham conditioned mice during subsequent hypoxia. The selective opioid antagonists, 7-benzylidenenaltrexone, naltrindole, beta-funaltrexamine and norbinaltorphimine were administered subcutaneously before hypoxic or sham conditioning. The delta-1 and delta-2 selective antagonists, 7-benzylidenenaltrexone and naltrindole respectively, blocked the hypoxic conditioning-induced increase in survival time. The lowest effective 7-benzylidenenaltrexone dose was 3000-fold lower than the lowest effective naltrindole dose indicating that the acute adaptation to hypoxia was predominantly sensitive to delta-1 blockade. Neither the mu antagonist, beta-funaltrexamine, nor the kappa antagonist, norbinaltorphimine, significantly changed survival time in sham or hypoxic conditioned mice. These results support a delta-1 receptor mediated mechanism of acute adaptation to hypoxia.
此前，间歇性严重缺氧可诱导对缺氧的急性适应，且随后缺氧期间这种条件性生存时间的增加会被纳洛酮阻断。本研究通过使用（+）-纳洛酮（无活性异构体）和选择性阿片类拮抗剂，进一步明确了参与缺氧适应的阿片类性质和受体类型。（+）-纳洛酮未能显著改变缺氧或假条件小鼠在随后缺氧期间的生存时间。在缺氧或假条件处理前，皮下注射选择性阿片类拮抗剂7-亚苄基纳曲酮、纳曲吲哚、β-芬太尼和诺宾那托啡。δ-1和δ-2选择性拮抗剂，即7-亚苄基纳曲酮和纳曲吲哚，分别阻断了缺氧条件诱导的生存时间增加。7-亚苄基纳曲酮的最低有效剂量比纳曲吲哚的最低有效剂量低3000倍，表明对缺氧的急性适应主要对δ-1阻断敏感。μ拮抗剂β-芬太尼和κ拮抗剂诺宾那托啡均未显著改变假条件或缺氧条件小鼠的生存时间。这些结果支持了δ-1受体介导的急性缺氧适应机制。
