Long J B, Martinez-Arizala A, Echevarria E E, Tidwell R E, Holaday J W
Department of Medical Neurosciences, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Eur J Pharmacol. 1988 Aug 9;153(1):45-54. doi: 10.1016/0014-2999(88)90586-9.
Dynorphin A-(1-17) acts through non-opioid mechanisms to produce dose-related neurological deficits following injection into the lumbar spinal subarachnoid space in rats. Hindlimb motor function was examined following subarachnoid injection of dynorphin A fragments and other opioid peptides derived from prodynorphin to establish: (1) which portion(s) of the dynorphin A molecule cause hindlimb motor dysfunction, and (2) whether these paralytic actions are shared by other opioids (dynorphin B, alpha-neo-endorphin, and beta-neo-endorphin) derived from the same promolecule. To minimize the influence of enzymatic inactivation on relative bioactivities, peptides were coinjected with a combination of peptidase inhibitors previously shown to enhance the actions of dynorphin A fragments in vitro. Dynorphin A-(1-17) and -(2-17) produced dose-related neurological deficits with equal potencies and durations. Although without effect when injected alone, dynorphin A-(1-8), -(1-7) and -(3-8) caused transient motor dysfunction when co-injected with peptidase inhibitors. In contrast, dynorphin A-(1-6), -(1-5) and -(6-17) did not disrupt hindlimb motor function with or without peptidase inhibition. Dynorphin B, alpha-neo-endorphin and beta-neo-endorphin also caused hindlimb dysfunction which was potentiated by peptidase inhibition. These deficits appeared to result from non-opioid actions of these three peptides, since they were not blocked by the opioid antagonist naloxone. Thus, the paralytic effects of dynorphin A: (1) result from non-opioid actions involving the 3-7 or 3-8 positions of the molecule, and (2) are shared by other prodynorphin-derived opioid peptides.
强啡肽A-(1-17)通过非阿片类机制发挥作用，在大鼠腰段脊髓蛛网膜下腔注射后产生剂量相关的神经功能缺损。蛛网膜下腔注射强啡肽A片段及其他源自前强啡肽的阿片肽后，对后肢运动功能进行检测，以确定：(1)强啡肽A分子的哪部分导致后肢运动功能障碍，以及(2)这些麻痹作用是否为源自同一前体分子的其他阿片类物质（强啡肽B、α-新内啡肽和β-新内啡肽）所共有。为尽量减少酶失活对相对生物活性的影响，将肽与先前已证实在体外可增强强啡肽A片段作用的肽酶抑制剂组合共同注射。强啡肽A-(1-17)和-(2-17)产生剂量相关的神经功能缺损，效价和持续时间相同。强啡肽A-(1-8)、-(1-7)和-(3-8)单独注射时无作用，但与肽酶抑制剂共同注射时会引起短暂的运动功能障碍。相比之下，强啡肽A-(1-6)、-(1-5)和-(6-17)无论有无肽酶抑制，均不会破坏后肢运动功能。强啡肽B、α-新内啡肽和β-新内啡肽也会导致后肢功能障碍，肽酶抑制可增强这种作用。这些缺损似乎是由这三种肽的非阿片类作用引起的，因为它们不受阿片类拮抗剂纳洛酮的阻断。因此，强啡肽A的麻痹作用：(1)是由涉及分子3-7或3-8位的非阿片类作用引起的，(2)为其他源自前强啡肽的阿片肽所共有。
