Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Psychopharmacology (Berl). 2010 Oct;212(2):215-25. doi: 10.1007/s00213-010-1946-0. Epub 2010 Aug 4.
Psychological dependence is one of the worst side effects of morphine. It limits the clinical availability of morphine and non-patient morphine users suffer from addiction. An analgesic, which is more potent than morphine but without the liability of psychological dependence, has long been sought in the clinic. We have recently developed a new μ-opioid receptor agonist, N(α)-amidino-Tyr-D-Arg-Phe-β-Ala (amidino-TAPA), as a potent analgesic with an antinociceptive profile that is distinct from morphine, including the release of endogenous κ-opioid peptides. The activation of κ-opioid receptors has been suggested to suppress the development of psychological dependence by μ-opioid receptor agonists. In the present study, the psychological dependence liability and the related locomotor-enhancing effect of amidino-TAPA were evaluated.
Amidino-TAPA injected subcutaneously produced an extremely potent and longer lasting antinociception than morphine in ddY mice, prodynorphin-knockout mice, and wild-type C57BL/6J mice. Unlike subcutaneously injected morphine, which had potent locomotor-enhancing and rewarding effects at antinociceptive doses in ddY mice, amidino-TAPA injected subcutaneously did not induce significant locomotor-enhancing and rewarding effects at antinociceptive or even higher doses in ddY mice. In wild-type C57BL/6J mice, amidino-TAPA showed the same pharmacological profile (potent antinociception, lack of locomotor-enhancing and rewarding effects) as in ddY mice. However, amidino-TAPA produced potent locomotor-enhancing and rewarding effects at antinociceptive doses in prodynorphin-knockout mice.
The present results suggest that amidino-TAPA is a potent analgesic without the liability of psychological dependence because it releases endogenous κ-opioid peptides.
心理依赖是吗啡最严重的副作用之一。它限制了吗啡的临床应用，而非患者使用吗啡也会成瘾。临床上一直寻求一种比吗啡作用更强但没有心理依赖风险的镇痛药。我们最近开发了一种新型μ-阿片受体激动剂 N(α)-酰胺基-Tyr-D-Arg-Phe-β-Ala（酰胺基-TAPA），作为一种强效镇痛药，其镇痛作用与吗啡不同，包括内源性κ-阿片肽的释放。κ-阿片受体的激活被认为可以抑制μ-阿片受体激动剂引起的心理依赖的发展。在本研究中，评估了酰胺基-TAPA 的心理依赖倾向和相关的运动增强效应。
酰胺基-TAPA 皮下注射在 ddY 小鼠、前原啡肽敲除小鼠和野生型 C57BL/6J 小鼠中产生了比吗啡更强效且持续时间更长的镇痛作用。与皮下注射吗啡在镇痛剂量下具有强烈的运动增强和奖赏作用不同，酰胺基-TAPA 皮下注射在 ddY 小鼠中即使在镇痛或更高剂量下也不会引起明显的运动增强和奖赏作用。在野生型 C57BL/6J 小鼠中，酰胺基-TAPA 表现出与 ddY 小鼠相同的药理学特征（强效镇痛、缺乏运动增强和奖赏作用）。然而，酰胺基-TAPA 在镇痛剂量下在前原啡肽敲除小鼠中产生了强烈的运动增强和奖赏作用。
本研究结果表明，酰胺基-TAPA 是一种强效的无心理依赖倾向的镇痛药，因为它释放内源性 κ-阿片肽。
