Shen K F, Crain S M
Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461 USA.
Brain Res. 1992 Nov 27;597(1):74-83. doi: 10.1016/0006-8993(92)91507-b.
We previously showed that mouse sensory dorsal root ganglion (DRG) neurons chronically exposed to 1 microM D-ala2-D-leu5-enkephalin (DADLE) or morphine for > 2-3 days in culture become tolerant to the usual opioid inhibitory receptor-mediated effects, i.e. shortening of the duration of the calcium-dependent component of the action potential (APD), and supersensitive to opioid excitatory APD-prolonging effects elicited by low opioid concentrations. Whereas nanomolar concentrations of dynorphin(1-13) or morphine are generally required to prolong the APD of naive DRG neurons (by activating excitatory opioid receptors), femtomolar levels become effective after chronic opioid treatment. Whereas 1-30 nM naloxone or diprenorphine prevent both excitatory and inhibitory opioid effects but do not alter the APD of native DRG neurons, both opioid antagonists unexpectedly prolong the APD of most of the chronic opioid-treated cells. In the present study, chronic exposure of DRG neurons to 1 microM DADLE together with cholera toxin-B subunit (which selectively blocks GM1 ganglioside-regulated opioid excitatory, but not inhibitory, receptor functions) prevented the development of opioid excitatory supersensitivity and markedly attenuated tolerance to opioid inhibitory effects. Conversely, sustained exposure of DRG neurons to 1 nM DADLE, which selectively activates excitatory opioid receptor functions, resulted in characteristic opioid excitatory supersensitivity but no tolerance. These results suggest that 'dependence'-like properties can be induced in chronic opioid-treated sensory neurons in the absence of tolerance. On the other hand, development of some components of tolerance in these cells may require sustained activation of both excitatory, as well as inhibitory, opioid receptor functions.
我们之前发现，在培养过程中，小鼠感觉性背根神经节（DRG）神经元若长期（> 2 - 3天）暴露于1微摩尔的D - 丙氨酸2 - D - 亮氨酸5 - 脑啡肽（DADLE）或吗啡中，会对通常由阿片类抑制性受体介导的效应产生耐受性，即动作电位（APD）中钙依赖性成分的持续时间缩短，并且对低浓度阿片类药物引发的阿片类兴奋性APD延长效应变得超敏感。对于未处理的DRG神经元，通常需要纳摩尔浓度的强啡肽（1 - 13）或吗啡才能延长其APD（通过激活兴奋性阿片类受体），而在慢性阿片类药物处理后，飞摩尔水平的药物就会变得有效。虽然1 - 30纳摩尔的纳洛酮或二丙诺啡可同时阻断阿片类药物的兴奋性和抑制性效应，但不会改变天然DRG神经元的APD，但这两种阿片类拮抗剂却意外地延长了大多数慢性阿片类药物处理细胞的APD。在本研究中，DRG神经元长期暴露于1微摩尔的DADLE并同时接触霍乱毒素B亚基（其选择性阻断GM1神经节苷脂调节的阿片类兴奋性而非抑制性受体功能），可防止阿片类兴奋性超敏反应的发生，并显著减弱对阿片类抑制性效应的耐受性。相反，DRG神经元持续暴露于1纳摩尔的DADLE（其选择性激活兴奋性阿片类受体功能）会导致典型的阿片类兴奋性超敏反应，但不会产生耐受性。这些结果表明，在不存在耐受性的情况下，慢性阿片类药物处理的感觉神经元中可诱导出类似“依赖性”的特性。另一方面，这些细胞中某些耐受性成分的发展可能需要兴奋性和抑制性阿片类受体功能的持续激活。
