Liang D, Li X, Clark J D
Department of Anesthesiology, Stanford University and Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, 94304, Palo Alto, CA, USA.
Neuroscience. 2004;123(3):769-75. doi: 10.1016/j.neuroscience.2003.10.007.
The chronic administration of morphine and related opioid drugs results in tolerance and dependence which limits the clinical utility of these agents. Neuronal plasticity is probably responsible in large part for tolerance and dependence. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a crucial role in the neuroplastic events underlying memory formation and other phenomena. However, the role of this kinase in morphine tolerance remains unclear. To clarify this issue we explored mRNA and protein expression of CaMKIIalpha in spinal cord tissue from control and morphine treated mice using real-time polymerase chain reaction, Western blot analysis and confocal microscopy. Our chronic exposure paradigm involved the subcutaneous implantation of morphine pellets for 6 days prior to tissue analysis. The results indicate that the levels of CaMKIIalpha mRNA and protein were robustly increased in spinal cord tissue from morphine-treated mice. Confocal microscopy demonstrated that the increase in CaMKIIalpha expression was primarily localized to superficial laminae of the dorsal horn. In addition, the abundance of phosphorylated CaMKIIalpha was increased in spinal cord tissue from morphine-treated mice. We conclude that enhanced CaMKIIalpha expression and activity in spinal cord tissue may contribute to the development of morphine tolerance in mice. The involvement of this enzyme in opioid tolerance suggests other parallels may exist between the neuroplastic events related to memory formation and those related to opioid tolerance or pain.
长期使用吗啡及相关阿片类药物会导致耐受性和依赖性，这限制了这些药物的临床应用。神经元可塑性可能在很大程度上导致了耐受性和依赖性。钙/钙调蛋白依赖性蛋白激酶II（CaMKII）在记忆形成及其他现象所涉及的神经可塑性事件中起关键作用。然而，该激酶在吗啡耐受性中的作用仍不清楚。为阐明这一问题，我们使用实时聚合酶链反应、蛋白质免疫印迹分析和共聚焦显微镜，研究了对照小鼠和吗啡处理小鼠脊髓组织中CaMKIIα的mRNA和蛋白质表达。我们的长期暴露实验模式包括在组织分析前6天皮下植入吗啡缓释片。结果表明，吗啡处理小鼠脊髓组织中CaMKIIα的mRNA和蛋白质水平显著升高。共聚焦显微镜显示，CaMKIIα表达的增加主要定位于背角浅层。此外，吗啡处理小鼠脊髓组织中磷酸化CaMKIIα的丰度增加。我们得出结论，脊髓组织中CaMKIIα表达和活性的增强可能有助于小鼠吗啡耐受性的形成。该酶参与阿片类药物耐受性表明，与记忆形成相关的神经可塑性事件和与阿片类药物耐受性或疼痛相关的神经可塑性事件之间可能存在其他相似之处。
