Trujillo Keith A
Department of Psychology, California State University San Marcos, San Marcos, CA 92096-0001, USA.
Neurotox Res. 2002 Jun;4(4):373-91. doi: 10.1080/10298420290023954.
Long-term administration of opiates leads to changes in the effects of these drugs, including tolerance, sensitization and physical dependence. There is, as yet, incomplete understanding of the neural mechanisms that underlie these phenomena. Tolerance, sensitization and physical dependence can be considered adaptive processes similar to other experience-dependent changes in the brain, such as learning and neural development. There is considerable evidence demonstrating that N-methyl-D-aspartate (NMDA) receptors and downstream signaling cascades may have an important role in different forms of experience-dependent changes in the brain and behavior. This review will explore evidence indicating that NMDA receptors and downstream messengers may be involved in opiate tolerance, sensitization and physical dependence. This evidence has been used to develop a cellular model of NMDA receptor/opiate interactions. According to this model, mu opioid receptor stimulation leads to a protein kinase C-mediated activation of NMDA receptors. Activation of NMDA receptors leads to influx of calcium and activation of calcium-dependent processes. These calcium-dependent processes have the ability to produce critical changes in opioid-responsive neurons, including inhibition of opioid receptor/second messenger coupling. This model is similar to cellular models of learning and neural development in which NMDA receptors have a central role. Together, the evidence suggests that the mechanisms that underlie changes in the brain and behavior produced by long-term opiate use may be similar to other central nervous system adaptations. The experimental findings and the resulting model may have implications for the treatment of pain and addiction.
长期服用阿片类药物会导致这些药物的作用发生变化，包括耐受性、敏化和身体依赖性。目前，对于这些现象背后的神经机制仍未完全了解。耐受性、敏化和身体依赖性可被视为与大脑中其他依赖经验的变化（如学习和神经发育）类似的适应性过程。有大量证据表明，N-甲基-D-天冬氨酸（NMDA）受体和下游信号级联反应可能在大脑和行为的不同形式的依赖经验的变化中起重要作用。本综述将探讨表明NMDA受体和下游信使可能参与阿片类药物耐受性、敏化和身体依赖性的证据。这些证据已被用于建立NMDA受体/阿片类药物相互作用的细胞模型。根据该模型，μ阿片受体刺激导致蛋白激酶C介导的NMDA受体激活。NMDA受体的激活导致钙内流和钙依赖性过程的激活。这些钙依赖性过程能够在阿片反应性神经元中产生关键变化，包括抑制阿片受体/第二信使偶联。该模型类似于NMDA受体起核心作用的学习和神经发育细胞模型。总之，证据表明长期使用阿片类药物导致大脑和行为变化的机制可能与其他中枢神经系统适应性变化相似。实验结果和由此产生的模型可能对疼痛治疗和成瘾治疗有启示意义。
