Long J B, Petras J M, Holaday J W
Department of Medical Neurosciences, Walter Reed Army Institute of Research, Washington, D.C.
J Pharmacol Exp Ther. 1988 Mar;244(3):1169-77.
The delta opioid receptor antagonist ICI 174864 produces postural abnormalities and barrel rolling after i.c.v. injection and hindlimb and tail flaccidity after spinal subarachnoid injection in rats. These effects appear to result from nonopioid characteristics of ICI 174864 because they are neither shared nor blocked by other opioid antagonists (naloxone, ICI 154129 and WIN 44,441-3) and are produced by two compounds (ICI 174644 and ICI 178173) that are structurally related to ICI 174864 but lack its delta antagonist properties. Barrel rolling and hindlimb paralysis are also produced by dynorphin A-related peptides; however, rats failed to demonstrate tolerance or cross-tolerance to the hindlimb paralytic actions of ICI 174864 or dynorphin A (1-13) after 7 days of continuous spinal intrathecal infusion of either of these compounds. Whereas hindlimb responses to low doses of ICI 174864 (1.6-6.2 nmol intrathecally) were usually transient, higher doses (6.2-25 nmol intrathecally) produced persistent hindlimb motor dysfunction, altered nociception, priapism, hindlimb edema, bladder infarction and atony and urinary incontinence. Neuronal and axonal changes in the lumbosacral spinal cords of rats with persistent and transient neurologic deficits provided direct evidence of the neuropathologic actions of ICI 174864 (3.1 and 6.2 nmol) and ICI 174644 (25 nmol). These results indicate that 1) use of ICI 174864 as a selective delta opioid receptor antagonist is potentially compromised by its nonopioid neuropathologic actions and 2) ICI 174864 and dynorphin A-related peptides are unique among opioid agonists and antagonists in sharing barrel rolling and hindlimb paralytic effects. A similar mechanism of action may underlie the shared nonopioid actions of these peptides.
δ阿片受体拮抗剂ICI 174864经脑室内注射后会导致大鼠出现姿势异常和翻滚行为，经脊髓蛛网膜下腔注射后会导致大鼠后肢和尾巴松弛。这些效应似乎是由ICI 174864的非阿片样特性引起的，因为它们既不被其他阿片受体拮抗剂（纳洛酮、ICI 154129和WIN 44,441-3）所共有，也不被其阻断，并且由两种与ICI 174864结构相关但缺乏其δ拮抗剂特性的化合物（ICI 174644和ICI 178173）所产生。强啡肽A相关肽也会导致翻滚行为和后肢麻痹；然而，在连续7天经脊髓鞘内注射这两种化合物中的任何一种后，大鼠对ICI 174864或强啡肽A（1-13）的后肢麻痹作用未能表现出耐受性或交叉耐受性。虽然低剂量的ICI 174864（鞘内注射1.6 - 6.2 nmol）引起的后肢反应通常是短暂的，但较高剂量（鞘内注射6.2 - 25 nmol）会导致持续的后肢运动功能障碍、伤害感受改变、阴茎异常勃起、后肢水肿、膀胱梗死和无张力以及尿失禁。患有持续性和短暂性神经功能缺损的大鼠腰骶脊髓中的神经元和轴突变化为ICI 174864（3.1和6.2 nmol）和ICI 174644（25 nmol）的神经病理作用提供了直接证据。这些结果表明：1）ICI 174864作为选择性δ阿片受体拮抗剂的应用可能因其非阿片样神经病理作用而受到影响；2）ICI 174864和强啡肽A相关肽在阿片类激动剂和拮抗剂中在共有翻滚行为和后肢麻痹作用方面是独特的。这些肽类共有的非阿片样作用可能有类似的作用机制。
