Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, USA.
Psychopharmacology (Berl). 2010 Jun;210(2):149-59. doi: 10.1007/s00213-009-1770-6. Epub 2010 Jan 26.
Selective, centrally acting kappa opioid agonists produce antinociception in a wide range of preclinical assays, but these compounds perform poorly as analgesics in humans. This discrepancy may be related to the behavioral depressant effects of kappa agonists. Kappa antagonists do not typically produce antinociception, but they produce antidepressant-like effects in some preclinical assays.
The objective of this study was to test the hypothesis that the kappa agonist U69,593 and the kappa antagonist norbinaltorphimine would produce pronociceptive and antinociceptive effects, respectively, in an assay of pain-depressed behavior.
Effects of U69,593 (0.056-0.56 mg/kg), norbinaltorphimine (10-32 mg/kg), and morphine (3.2 mg/kg) were evaluated on the stimulation of a stretching response and the depression of intracranial self-stimulation (ICSS) of the medial forebrain bundle produced in rats by a common noxious stimulus (intraperitoneal administration of dilute lactic acid).
U69,593 produced a dose-dependent blockade of acid-stimulated stretching but only exacerbated acid-induced depression of ICSS. Thus, U69,593 produced antinociception in the assay of pain-stimulated behavior but pronociceptive effects in the assay of pain-depressed behavior. Norbinaltorphimine did not alter acid-stimulated stretching or acid-induced depression of ICSS. The mu opioid agonist morphine blocked both acid-stimulated stretching and acid-induced depression of ICSS.
These results support the hypothesis that prodepressant effects of kappa agonists may limit their clinical utility as analgesics. These results do not support the use of kappa antagonists to treat depressant effects of pain. These findings illustrate the potential value of using complementary assays of pain-stimulated and pain-depressed behaviors for preclinical evaluation of candidate analgesics.
选择性、中枢作用的κ阿片受体激动剂在广泛的临床前试验中产生镇痛作用，但这些化合物在人类中作为镇痛药的效果很差。这种差异可能与κ激动剂的行为抑制作用有关。κ拮抗剂通常不会产生镇痛作用，但在一些临床前试验中会产生抗抑郁样作用。
本研究的目的是检验假设，即 κ 激动剂 U69,593 和 κ 拮抗剂诺比那肽将分别在疼痛抑制行为的试验中产生促痛和镇痛作用。
在大鼠中，评估 U69,593（0.056-0.56mg/kg）、诺比那肽（10-32mg/kg）和吗啡（3.2mg/kg）对刺激伸展反应和抑制内侧前脑束的颅内自我刺激（ICSS）的影响，由一种常见的有害刺激（腹腔内给予稀释的乳酸）引起。
U69,593 产生了剂量依赖性的酸刺激伸展反应的阻断作用，但仅加剧了酸诱导的 ICSS 抑制。因此，U69,593 在疼痛刺激行为的试验中产生了镇痛作用，但在疼痛抑制行为的试验中产生了促痛作用。诺比那肽不改变酸刺激伸展或酸诱导的 ICSS 抑制。μ阿片受体激动剂吗啡阻断了酸刺激伸展和酸诱导的 ICSS 抑制。
这些结果支持了这样的假设，即 κ 激动剂的促抑郁作用可能限制了它们作为镇痛药的临床应用。这些结果不支持使用 κ 拮抗剂来治疗疼痛的抑郁作用。这些发现说明了使用疼痛刺激和疼痛抑制行为的互补试验来对候选镇痛药进行临床前评估的潜在价值。
