Butelman Eduardo R, Ball Jonathan W, Kreek Mary-Jeanne
The Rockefeller University (Box 171), 1230 York Avenue, New York, NY 10021, USA.
Psychopharmacology (Berl). 2002 Oct;164(1):115-20. doi: 10.1007/s00213-002-1195-y. Epub 2002 Aug 8.
The discriminative effects of kappa-agonists may be mediated centrally, whereas their effects in a neuroendocrine biomarker assay (prolactin release) may be mediated by kappa-receptors in hypothalamic areas outside the blood-brain barrier. Prolactin may thus be a useful biomarker, due to its potential to provide quantitative pharmacodynamic data for kappa-opioid ligands in vivo. The potency of centrally penetrating kappa-agonists could be similar in these two assays, due to their ability to occupy kappa-receptor pools inside and outside the blood-brain barrier, following SC administration.
To compare the potency of centrally penetrating kappa-agonists in producing U69,593-like discriminative stimulus effects (U69,593 is considered a selective kappa-agonist), and in producing prolactin release in rhesus monkeys.
Cumulative dose-effect curves of kappa-agonists (R84760, bremazocine, spiradoline and U50,488) were investigated in a food-reinforced U69,593 discrimination ( n=3), and compared to those for the micro -opioids fentanyl and nalbuphine and the delta-agonist SNC80. Selected kappa-opioids (R84760 and spiradoline) were compared to fentanyl, nalbuphine and SNC80 in the neuroendocrine biomarker assay, in intact female rhesus monkeys ( n=4).
All the selective kappa-agonists caused dose-dependent generalization (i.e. at least 90% drug-appropriate responding) in the U69,593 discriminating subjects, and caused robust, dose-dependent prolactin release in female rhesus monkeys. By contrast, fentanyl, nalbuphine and SNC80 did not cause generalization in these subjects. Fentanyl and nalbuphine also caused prolactin release; quantitative antagonism (apparent pK(B)) experiments following nalmefene (0.01, 0.1 mg/kg) differentiated the effects of a selective kappa-agonist (spiradoline) from those of a selective micro -agonist (fentanyl). A positive correlation ( r=0.99) was noted between the mean log ED(50) of kappa-agonists in the discrimination and neuroendocrine assays, from these and previous determinations.
The potency of centrally penetrating kappa-agonists in causing their neuroendocrine effects is similar to their potency in causing discriminative effects. Furthermore, apparent pK(B) experiments with nalmefene differentiated the receptor mediation (i.e. kappa or micro ) of these compounds in the neuroendocrine biomarker assay.
κ-激动剂的辨别效应可能由中枢介导，而它们在神经内分泌生物标志物检测（催乳素释放）中的效应可能由血脑屏障外下丘脑区域的κ-受体介导。因此，催乳素可能是一种有用的生物标志物，因为它有潜力在体内为κ-阿片样物质配体提供定量药效学数据。经皮下给药后，能穿透中枢的κ-激动剂在这两种检测中的效力可能相似，因为它们能够占据血脑屏障内外的κ-受体库。
比较能穿透中枢的κ-激动剂在产生U69,593样辨别刺激效应（U69,593被认为是一种选择性κ-激动剂）以及在恒河猴中引起催乳素释放方面的效力。
在食物强化的U69,593辨别实验中（n = 3）研究了κ-激动剂（R84760、布马佐辛、螺哌丁苯和U50,488）的累积剂量-效应曲线，并与μ-阿片样物质芬太尼和纳布啡以及δ-激动剂SNC80的曲线进行比较。在完整雌性恒河猴（n = 4）的神经内分泌生物标志物检测中，将选定的κ-阿片样物质（R84760和螺哌丁苯）与芬太尼、纳布啡和SNC80进行比较。
所有选择性κ-激动剂在U69,593辨别实验对象中均引起剂量依赖性的泛化（即至少90%的药物适应性反应），并在雌性恒河猴中引起强烈的、剂量依赖性的催乳素释放。相比之下，芬太尼、纳布啡和SNC80在这些实验对象中未引起泛化。芬太尼和纳布啡也引起了催乳素释放；纳美芬（0.01、0.1 mg/kg）给药后的定量拮抗（表观pK(B)）实验区分了选择性κ-激动剂（螺哌丁苯）和选择性μ-激动剂（芬太尼）的效应。根据这些及之前的测定结果，在辨别实验和神经内分泌检测中，κ-激动剂的平均log ED(50)之间存在正相关（r = 0.99）。
能穿透中枢的κ-激动剂引起神经内分泌效应的效力与其引起辨别效应的效力相似。此外，纳美芬的表观pK(B)实验在神经内分泌生物标志物检测中区分了这些化合物受体介导（即κ或μ）的情况。
