Paul D, Bodnar R J, Gistrak M A, Pasternak G W
Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Eur J Pharmacol. 1989 Sep 22;168(3):307-14. doi: 10.1016/0014-2999(89)90792-9.
To examine the relative roles of mu 1- and mu 2-receptors in spinal and supraspinal analgesia, we assessed the effects of naloxonazine, naloxone, beta-funaltrexamine (beta-FNA), and ICI-154,129 on tail-flick analgesia produced by intrathecal or intracerebroventricular injections of the highly mu-selective agonist, [D-Ala2,Me-Phe4,Gly(ol)5]enkephalin (DAGO; mu 1 and mu 2), [D-Ser2,Leu5]enkephalin-Thr6 (DSLET; mu 1 and delta), and the selective delta-receptor agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) in mice. Both DAGO and DSLET supraspinal analgesia were mediated through mu 1-receptors. Naloxonazine shifted the supraspinal DAGO dose-response curve 4-fold to the right without changing the curve for spinal DAGO. Likewise, naloxonazine pretreatment shifted supraspinal DSLET analgesia 10-fold, whereas spinal DSLET analgesia was not affected. DPDPE analgesia was not antagonized spinally or supraspinally by naloxonazine pretreatment. These findings suggest that DAGO produces analgesia spinally and supraspinally through different sets of mu-receptors. Moreover, at least two distinct receptor subtypes mediated spinal analgesia. First, naloxone inhibited spinal DAGO analgesia more potently than DPDPE analgesia. Second, the irreversible mu-antagonist, beta-FNA, blocks spinal DAGO analgesia. Since spinal DAGO was insensitive to naloxonazine, ruling out a mu 1 mechanism, these results indicate a role for mu 2-receptors. Spinal DAGO analgesia also developed tolerance to morphine far more slowly than supraspinal DAGO analgesia even though mu-receptors mediate both, as indicated by their sensitivity towards beta-FNA. Finally, the delta-antagonist ICI-154,129 is a more potent inhibitor of spinal DPDPE analgesia than spinal DAGO analgesia. Thus, delta-receptors mediate spinal DPDPE analgesia.
为了研究μ1和μ2受体在脊髓和脊髓上镇痛中的相对作用，我们评估了纳洛酮嗪、纳洛酮、β-芬太尼丁（β-FNA）和ICI-154,129对鞘内或脑室内注射高选择性μ激动剂[D-Ala2,Me-Phe4,Gly(ol)5]脑啡肽（DAGO；μ1和μ2）、[D-Ser2,Leu5]脑啡肽-Thr6（DSLET；μ1和δ）以及选择性δ受体激动剂[D-Pen2,D-Pen5]脑啡肽（DPDPE）在小鼠中产生的甩尾镇痛的影响。DAGO和DSLET的脊髓上镇痛均通过μ1受体介导。纳洛酮嗪使脊髓上DAGO剂量-反应曲线向右移动4倍，而不改变脊髓DAGO的曲线。同样，纳洛酮嗪预处理使脊髓上DSLET镇痛作用移动10倍，而脊髓DSLET镇痛不受影响。纳洛酮嗪预处理在脊髓和脊髓上均未拮抗DPDPE镇痛。这些发现表明DAGO通过不同组的μ受体在脊髓和脊髓上产生镇痛作用。此外，至少两种不同的受体亚型介导脊髓镇痛。首先，纳洛酮比DPDPE镇痛更有效地抑制脊髓DAGO镇痛。其次，不可逆的μ拮抗剂β-FNA阻断脊髓DAGO镇痛。由于脊髓DAGO对纳洛酮嗪不敏感，排除了μ1机制，这些结果表明μ2受体起作用。脊髓DAGO镇痛对吗啡产生耐受性的速度也比脊髓上DAGO镇痛慢得多，尽管μ受体介导两者，这从它们对β-FNA的敏感性可以看出。最后，δ拮抗剂ICI-154,129对脊髓DPDPE镇痛的抑制作用比脊髓DAGO镇痛更强。因此，δ受体介导脊髓DPDPE镇痛。
