Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, C/ Julián Clavería 6, 33006, Oviedo, Asturias, Spain.
Naunyn Schmiedebergs Arch Pharmacol. 2010 Jan;381(1):59-71. doi: 10.1007/s00210-009-0471-3. Epub 2009 Nov 26.
The analgesic efficacy of opiates can be enhanced in inflammatory states due to peripheral and spinal alterations. We describe here that the analgesic effect induced by intrathecal (i.t.) morphine assessed by measuring thermal withdrawal latencies is enhanced in carrageenan-inflamed mice. The spinal micro-opioid receptor (MOR) population is not up-regulated as demonstrated by Western blot assays. In contrast, behavioural experiments show the involvement of changes in transduction mechanisms activated by spinal opioid receptors. The i.t. administration of the nitric oxide (NO) synthase inhibitor L-NMMA (3-30 microg) antagonised with a similar potency and efficacy morphine-induced analgesia in inflamed and non-inflamed mice, discarding that an increase in NO release could be responsible of the enhancement of morphine-induced analgesia. The analgesic effects evoked by the i.t. administration of the direct G(i/o) protein activator mastoparan (0.03-10 microg), but not those induced by the N-type calcium channel blocker omega-conotoxin GVIA (3-30 ng), were potentiated in inflamed mice, suggesting that postsynaptic and not presynaptic mechanisms could be involved. Furthermore, the inhibitory effects on morphine-induced analgesia produced by the G(i/o) protein inhibitor pertussis toxin (0.1-17 ng) or the G-coupled inwardly rectifying potassium (GIRK) channels inhibitor tertiapin-Q (0.75-750 ng) were greatly enhanced in inflamed mice. These results suggest that differences in the transduction mechanism activated by MOR at postsynaptic level, probably related with GIRK channels activity, could participate in the potentiation of morphine-induced spinal analgesia in acutely inflamed mice.
阿片类药物的镇痛效果在炎症状态下由于外周和脊髓的改变而增强。我们在这里描述了通过测量热退缩潜伏期评估鞘内（i.t.）吗啡引起的镇痛作用在角叉菜胶炎症小鼠中增强。脊髓微阿片受体（MOR）群体没有上调，如Western blot 测定所示。相比之下，行为实验表明涉及激活脊髓阿片受体的转导机制的变化。NO 合酶抑制剂 L-NMMA（3-30μg）的鞘内给药以相似的效力和功效拮抗吗啡在炎症和非炎症小鼠中的镇痛作用，排除 NO 释放的增加可能是吗啡诱导的镇痛增强的原因。直接 G(i/o)蛋白激活剂蜂毒肽（0.03-10μg）的鞘内给药引起的镇痛作用在炎症小鼠中增强，但 N 型钙通道阻断剂ω-芋螺毒素 GVIA（3-30ng）诱导的镇痛作用没有增强，表明可能涉及突触后而不是突触前机制。此外，G(i/o)蛋白抑制剂百日咳毒素（0.1-17ng）或 G 偶联内向整流钾（GIRK）通道抑制剂 tertiapin-Q（0.75-750ng）对吗啡诱导的镇痛作用的抑制作用在炎症小鼠中大大增强。这些结果表明，MOR 在突触后水平激活的转导机制的差异，可能与 GIRK 通道活性有关，可能参与急性炎症小鼠中吗啡诱导的脊髓镇痛作用的增强。
