Mjanger E, Yaksh T L
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee.
J Pharmacol Exp Ther. 1991 Aug;258(2):544-50.
Using rats with chronic i.t. catheters, dose-response curves were carried out using the hot plate (HP) test for a number of receptor-preferring opioids. The ordering of activity (i.t. ED50; nmol) on the HP was: (D-Ala2, N-Me-Phe4, Gly5-ol) enkephalin (DAMGO 0.5); sufentanil (0.4); and morphine (6.6). To assess the effects of pretreatment with the irreversible mu ligand beta-funaltrexamine (beta-FNA), rats received saline, 0.2, 2.0 or 20.0 nmol of beta-FNA. After 24 hr, base-line response latencies were not different from control animals. Dose-response curves for morphine, sufentanil and DAMGO were then obtained. Pretreatment with beta-FNA resulted in a concentration-dependent rightward shift in the agonist dose-response curves with the dose-ratio values of the respective doses of beta-FNA being for morphine: 3.5, 15.7, and 37.3; sufentanil: 1.2, 1.9, and 5.3; and DAMGO: 1.9, 4.0 and 7.3. The slopes of the agonist dose-response curves also displayed mild reductions in slope, the magnitude of which was dependent upon beta-FNA pretreatment concentrations. Testing at 6 days after beta-FNA treatment revealed a significant recovery of effect. beta-FNA (20 nmol, i.t.) had no effect on a just maximally effective dose of ST-91 (90 nmol, i.t.), an alpha-2 adrenergic agonist. beta-FNA (20 nmol, i.t.), but not 2.0 nmol resulted in a modest but significant reduction in the effect of the delta agonist DPLPE (120 nmol). These data are interpreted as supportive of the hypothesis that the mu-preferring ligands differ in the number of spinal receptors that must be occupied to produce a given antinociceptive effect (i.e., they differ in intrinsic efficacy).
使用带有慢性鞘内导管的大鼠，通过热板（HP）试验对多种受体偏好性阿片类药物进行剂量-反应曲线研究。在热板上的活性排序（鞘内注射半数有效剂量；纳摩尔）为：（D-丙氨酸²，N-甲基苯丙氨酸⁴，甘氨酸⁵-醇）脑啡肽（DAMGO 0.5）；舒芬太尼（0.4）；吗啡（6.6）。为评估用不可逆的μ配体β-芬太尼酰苯胺（β-FNA）预处理的效果，大鼠接受生理盐水、0.2、2.0或20.0纳摩尔的β-FNA。24小时后，基线反应潜伏期与对照动物无差异。然后获得吗啡、舒芬太尼和DAMGO的剂量-反应曲线。用β-FNA预处理导致激动剂剂量-反应曲线浓度依赖性右移，β-FNA各剂量的剂量比值分别为：吗啡：3.5、15.7和37.3；舒芬太尼：1.2、1.9和5.3；DAMGO：1.9、4.0和7.3。激动剂剂量-反应曲线的斜率也显示出斜率轻度降低，其幅度取决于β-FNA预处理浓度。在β-FNA治疗6天后进行测试显示效果有显著恢复。β-FNA（20纳摩尔，鞘内注射）对α-2肾上腺素能激动剂ST-91（90纳摩尔，鞘内注射）的刚好最大有效剂量无影响。β-FNA（20纳摩尔，鞘内注射）而非2.0纳摩尔导致δ激动剂DPLPE（120纳摩尔）的效果适度但显著降低。这些数据被解释为支持以下假设：受体偏好性μ配体在产生给定镇痛效果所需占据的脊髓受体数量上存在差异（即它们内在效能不同）。
