Juni Aaron, Klein Gad, Kest Benjamin
Doctoral Program in Neuropsychology, Queens College, City University of New York, Flushing, NY 11367, USA.
Brain Res. 2006 Jan 27;1070(1):35-44. doi: 10.1016/j.brainres.2005.11.054. Epub 2006 Jan 10.
Hyperalgesia following chronic morphine treatment is thought to be a response to opioid receptor activation and analgesia and contribute to the development of analgesic tolerance. Here, the relationship between these variables was studied in mice tested for nociceptive sensitivity on the tail-withdrawal test during chronic infusion of various morphine doses. Hyperalgesic onset was preceded by dose-dependent analgesia except for the lowest morphine dose, which caused hyperalgesia 6 h after the start of infusion. Morphine ED50 values obtained at various infusion intervals demonstrated both analgesic tolerance in the absence of hyperalgesia and hyperalgesia in the absence of tolerance. Continuous opioid receptor antagonism using naltrexone pellets abolished analgesia during continuous morphine administration, transiently potentiated hyperalgesia, and revealed differences in hyperalgesic onset between morphine infusion doses. Acute injection of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 attenuated hyperalgesia in naltrexone-treated mice, demonstrating a role for this receptor in morphine hyperalgesia unrelated to its effects upon morphine analgesia. In mice where hyperalgesia subsided after continuous infusion of the highest morphine dose (i.e., hyperalgesic adaptation), hyperalgesia was restored after infusing the lower but not higher morphine dose. In addition, acute injection of morphine-3beta-glucoronide (M3G) caused hyperalgesia that was cross-adaptive with the lower morphine dose only. The data demonstrate that morphine hyperalgesia is independent of prior or concurrent opioid receptor activity or analgesia and is unrelated to analgesic tolerance. Furthermore, the lack of hyperalgesic cross-adaptation between high and low morphine doses, and their differential cross-adaptation with M3G hyperalgesia, also suggests distinct morphine dose-dependent hyperalgesic systems.
长期使用吗啡后出现的痛觉过敏被认为是对阿片受体激活和镇痛的一种反应，并促成镇痛耐受性的形成。在此，我们研究了在慢性输注不同剂量吗啡期间，通过甩尾试验检测伤害性感受敏感性的小鼠中这些变量之间的关系。除了最低剂量的吗啡外，痛觉过敏的出现之前都有剂量依赖性的镇痛作用，最低剂量的吗啡在输注开始6小时后引起痛觉过敏。在不同输注间隔获得的吗啡半数有效剂量（ED50）值表明，在没有痛觉过敏的情况下存在镇痛耐受性，在没有耐受性的情况下存在痛觉过敏。使用纳曲酮缓释片持续拮抗阿片受体可消除持续给予吗啡期间的镇痛作用，短暂增强痛觉过敏，并揭示了吗啡输注剂量之间痛觉过敏发作的差异。急性注射N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801可减轻纳曲酮处理小鼠的痛觉过敏，表明该受体在与吗啡镇痛作用无关的吗啡痛觉过敏中起作用。在连续输注最高剂量吗啡后痛觉过敏消退的小鼠中（即痛觉过敏适应），输注较低但不是较高剂量的吗啡后痛觉过敏得以恢复。此外，急性注射吗啡-3β-葡萄糖醛酸苷（M3G）仅引起与较低剂量吗啡交叉适应的痛觉过敏。数据表明，吗啡痛觉过敏独立于先前或同时存在的阿片受体活性或镇痛作用，且与镇痛耐受性无关。此外，高低剂量吗啡之间缺乏痛觉过敏交叉适应，以及它们与M3G痛觉过敏的差异交叉适应，也表明存在不同的吗啡剂量依赖性痛觉过敏系统。
