Kappa-opioid receptor agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine receptor systems involved in drug reinforcement. kappa-Opioid receptor agonists also modulate dopamine receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a "biomarker" for the ability of kappa-opioid receptor agonists (e.g., (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593)) to modulate a dopamine receptor system in vivo in primates. The effectiveness of dopamine D(2)-like receptor agonists (quinpirole and (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT); 0.0032-0.1 mg/kg) in preventing U69,593-induced prolactin release was studied in intact female rhesus monkeys. Quinpirole and 7-OH-DPAT inhibited U69,593-induced prolactin release (ID(50) values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D(1)-receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazapine (SKF 82958; 1 mg/kg) did not inhibit U69,593-induced prolactin release under the same conditions. In contrast, the largest doses of quinpirole or 7-OH-DPAT presently studied (0.1 mg/kg), did not decrease sedation caused by U69,593 (0.01, 0.032 mg/kg), a prominent effect of centrally penetrating kappa-opioid receptor agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), consistent with kappa-opioid receptor mediation of this effect. These studies suggest that prolactin release is a valid biomarker for the ability of kappa-opioid receptor agonists to modulate dopamine D(2)-like receptor function, and may also be used to quantify dopamine D(2)-like receptor agonist potency in primates.

译文

Kappa-阿片受体激动剂可能具有调节精神兴奋剂滥用的药物治疗潜能,因为它们具有调节参与药物增强的多巴胺受体系统的能力。 κ阿片受体激动剂还调节下丘脑结核漏斗下腺系统中的多巴胺受体功能,该系统对垂体前叶激素催乳素具有抑制作用。催乳素水平因此可能是κ阿片受体激动剂(例如()-(5 alpha,7 alpha,8 beta)-N-甲基-N- [7-(1-吡咯烷基)- 1-oxaspiro [4.5] dec-8-基]-苯乙酰胺(U69,593))在灵长类动物体内调节多巴胺受体系统。多巴胺D(2)样受体激动剂(喹吡罗和(-)-7-羟基-二丙基氨基四氢萘(7-OH-DPAT); 0.0032-0.1 mg / kg)预防U69,593诱导的催乳素释放的有效性为在完整的雌性恒河猴中进行了研究。喹吡罗和7-OH-DPAT抑制U69,593诱导的催乳素释放(ID(50)值分别为0.013和0.0072 mg / kg)。然而,多巴胺D(1)-受体激动剂(/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazapine(在相同条件下,SKF 82958; 1 mg / kg)不会抑制U69,593诱导的催乳素释放。相反,目前研究的最大剂量喹吡罗或7-OH-DPAT(0.1 mg / kg)并未降低U69,593(0.01,0.032 mg / kg)引起的镇静作用,这是中央渗透性阿片类药物的显着作用受体激动剂。纳曲酮(0.32 mg / kg)阻止了U69,593(0.032 mg / kg)的镇静作用,与这种作用的κ阿片受体介导的作用一致。这些研究表明,催乳素释放是κ-阿片受体激动剂调节多巴胺D(2)-样受体功能的能力的有效生物标志物,也可用于量化灵长类动物中多巴胺D(2)-样受体激动剂的效力。 。

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