Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th Street, Richmond, VA 23220, USA.
J Pharmacol Exp Ther. 2012 Mar;340(3):501-9. doi: 10.1124/jpet.111.186783. Epub 2011 Nov 29.
κ opioid receptor agonists that do not readily cross the blood-brain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted κ agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral κ receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central κ receptors. The present study used assays of pain-related stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted κ agonists [the tetrapeptide D-Phe-D-Phe-D-Ile-D-Arg-NH(2) (ffir) and the nonpeptidic compound ((R,S)-N-[2-(N-methyl-3,4-dichlorophenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride (ICI204448)], 2) a centrally penetrating κ agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal anti-inflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted κ agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted κ agonists had little effect, and salvinorin A exacerbated acid-induced depression of ICSS. These results suggest that peripherally restricted κ agonists may be safer than centrally penetrating κ agonists but less efficacious than NSAIDS or μ opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with κ agonists capable of greater peripheral selectivity are warranted.
κ 阿片受体激动剂不易穿透血脑屏障，在全身给药后会受到外周限制，向中枢神经系统分布不良。外周受限的 κ 激动剂有望成为候选的镇痛药，因为它们可能通过外周 κ 受体产生更强的抗伤害作用，而不是通过中枢 κ 受体产生不良的镇静和致幻作用。本研究使用大鼠疼痛相关刺激和行为抑制的测定来比较以下几种药物的作用：1）两种外周受限的 κ 激动剂[四肽 D-Phe-D-Phe-D-Ile-D-Arg-NH（2）（ffir）和非肽化合物（（R，S）-N-[2-（N-甲基-3,4-二氯苯乙酰氨基）-2-（3-羧基苯基）-乙基]吡咯烷盐酸盐（ICI204448）]，2）一种穿透中枢的 κ 激动剂（salvinorin A），和 3）几种参考药物，包括非甾体抗炎药（NSAID；酮洛芬）。腹腔注射稀乳酸作为有害刺激物，刺激伸展反应，并抑制内侧前脑束电刺激维持的颅内自我刺激（ICSS）。酮洛芬、外周受限的 κ 激动剂和 salvinorin A 均可阻断酸刺激引起的伸展反应。然而，只有酮洛芬能阻断酸诱导的 ICSS 抑制。外周受限的 κ 激动剂作用较小，而 salvinorin A 加剧了酸诱导的 ICSS 抑制。这些结果表明，外周受限的 κ 激动剂可能比穿透中枢的 κ 激动剂更安全，但与 NSAIDs 或 μ 阿片受体激动剂相比，阻断与疼痛相关的行为抑制的效果较差；然而，ffir 和 ICI204448 的外周选择性有限，需要进行更具外周选择性的 κ 激动剂的进一步研究。
