Heyman J S, Koslo R J, Mosberg H I, Tallarida R J, Porreca F
Life Sci. 1986 Nov 10;39(19):1795-803. doi: 10.1016/0024-3205(86)90099-8.
The apparent affinity of naloxone at cerebral and spinal sites was estimated using selective mu [D-Ala2, Gly-o15]-enkephalin (DAGO) and delta [D-Pen2, D-Pen5]enkephalin] (DPDPE) opioid agonists in the mouse warm water tail-withdrawal test in vivo; the mu agonist morphine was employed as a reference compound. The approach was to determine the naloxone pA2 using a time-dependent method with both agonist and antagonist given intracerebroventricularly (i.c.v.) or intrathecally (i.th.); naloxone was always given 5 min before the agonist. Complete time-response curves were determined for each agonist at each site in the absence, and in the presence, of a single, fixed i.c.v. or i.th. dose of naloxone. From these i.c.v. or i.th. pairs of time-response curves, pairs of dose-response lines were constructed at various times; these lines showed decreasing displacement with time, indicative of the disappearance of naloxone. The graph of log (dose ratio-1) vs. time was linear with negative slope, in agreement with the time-dependent form of the equation for competitive antagonism. From this plot, the apparent pA2 and naloxone half-life was calculated at each site and against each agonist. The affinity of naloxone was not significantly different when compared between agonists after i.c.v. administration. A small difference was seen between the affinity of i.th. naloxone against DPDPE and DAGO; the i.th. naloxone pA2 against morphine, however, was not different than that for DPDPE and DAGO. The naloxone half-life varied between 6.6 and 16.9 min, values close to those previously reported for this compound. These results suggest that the agonists studied may produce their i.c.v. analgesic effects at the same receptor type or that alternatively, the naloxone pA2 may be fortuitously similar for mu and delta receptors in vivo. Additionally, while the affinity of naloxone appears different for the receptors activated by i.th. DAGO and DPDPE, further work may be necessary before firm conclusions regarding the nature of the spinal analgesic receptor(s) can be drawn.
在小鼠温水甩尾试验中，通过使用选择性μ型[D - Ala2, Gly - o15] - 脑啡肽（DAGO）和δ型[D - Pen2, D - Pen5]脑啡肽（DPDPE）阿片类激动剂，在体内估计纳洛酮在脑和脊髓部位的表观亲和力；μ型激动剂吗啡用作参考化合物。方法是采用时间依赖性方法，将激动剂和拮抗剂脑室内（i.c.v.）或鞘内（i.th.）给药，来测定纳洛酮的pA2；纳洛酮总是在激动剂给药前5分钟给予。在不存在和存在单一固定的i.c.v.或i.th.剂量纳洛酮的情况下，分别测定每个激动剂在每个部位的完整时间 - 反应曲线。从这些i.c.v.或i.th.时间 - 反应曲线对中，在不同时间构建剂量 - 反应线对；这些线显示随着时间推移位移减小，表明纳洛酮消失。log（剂量比 - 1）对时间的图呈负斜率线性，这与竞争性拮抗作用方程的时间依赖性形式一致。从该图中，计算每个部位针对每个激动剂的表观pA2和纳洛酮半衰期。i.c.v.给药后，各激动剂之间比较时，纳洛酮的亲和力无显著差异。鞘内纳洛酮对DPDPE和DAGO的亲和力存在微小差异；然而，鞘内纳洛酮对吗啡的pA2与对DPDPE和DAGO的无差异。纳洛酮半衰期在6.6至16.9分钟之间变化，这些值与该化合物先前报道的值接近。这些结果表明，所研究的激动剂可能在同一受体类型上产生其i.c.v.镇痛作用，或者，纳洛酮在体内对μ型和δ型受体的pA2可能偶然相似。此外，虽然纳洛酮对鞘内DAGO和DPDPE激活的受体的亲和力似乎不同，但在就脊髓镇痛受体的性质得出确凿结论之前，可能还需要进一步研究。
