Eitan Shoshana, Bryant Camron D, Saliminejad Nazli, Yang Yu C, Vojdani Elroy, Keith Duane, Polakiewicz Roberto, Evans Christopher J
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Neuropsychiatric Institute, Los Angeles, California 90024, USA.
J Neurosci. 2003 Sep 10;23(23):8360-9. doi: 10.1523/JNEUROSCI.23-23-08360.2003.
Opioid-receptor activation in cell lines results in phosphorylation of p42/44 mitogen-activated protein kinase (MAPK), which contributes to agonist-induced desensitization of adenylate cyclase signaling. In this study, morphine-induced MAPK modulation was examined in the mouse brain using antibodies against phosphorylated MAPK. Thirty minutes after systemic morphine, MAPK modulation was observed in brain areas associated with analgesia and reward. Activation of MAPK was increased in the anterior cingulate (Acc), somato-sensory and association cortices, and locus ceruleus (LC). In contrast, MAPK activation was decreased in the nucleus accumbens and central amygdala (CeA). Double-label confocal microscopy revealed that morphine-induced MAPK modulation occurred predominantly in cells not expressing mu-opioid receptors, with the exception of the LC. Furthermore, the NMDA receptor antagonist 3,3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonate blocked morphine-induced MAPK modulation in several cortical areas including the Acc. We then examined morphine-induced MAPK modulation during expression of either analgesic tolerance or locomotor sensitization, which were differentiated by two repeated morphine regimens. Analgesic tolerance was accompanied by tolerance to morphine-induced MAPK modulation in all of the brain areas examined except the CeA. Locomotor sensitization resulted in sensitization to morphine-induced MAPK activation in the posterior basolateral amygdala. Additionally, a pronounced instatement of morphine-induced MAPK activation was observed in CA3 hippocampal processes. This instatement was observed during expression of tolerance; however, it was not significant during sensitization. In summary, these results provide distinct, region-specific mechanisms for morphine-induced MAPK modulation in the mouse brain and give insight into the brain circuitry involved in acute and adaptive opioid behaviors.
在细胞系中，阿片受体激活会导致p42/44丝裂原活化蛋白激酶（MAPK）磷酸化，这有助于激动剂诱导的腺苷酸环化酶信号脱敏。在本研究中，使用针对磷酸化MAPK的抗体在小鼠脑中检测了吗啡诱导的MAPK调节。全身注射吗啡30分钟后，在与镇痛和奖赏相关的脑区观察到MAPK调节。前扣带回（Acc）、体感和联合皮层以及蓝斑（LC）中的MAPK激活增加。相比之下，伏隔核和中央杏仁核（CeA）中的MAPK激活减少。双标共聚焦显微镜显示，除LC外，吗啡诱导的MAPK调节主要发生在不表达μ-阿片受体的细胞中。此外，NMDA受体拮抗剂3,3-（2-羧基哌嗪-4-基）-丙基-1-膦酸酯阻断了包括Acc在内的几个皮层区域中吗啡诱导的MAPK调节。然后，我们在镇痛耐受或运动敏化表达过程中检测了吗啡诱导的MAPK调节，这两种情况通过两种重复的吗啡给药方案进行区分。除CeA外，在所有检测的脑区中，镇痛耐受伴随着对吗啡诱导的MAPK调节的耐受。运动敏化导致后基底外侧杏仁核中对吗啡诱导的MAPK激活的敏化。此外，在CA3海马突中观察到吗啡诱导的MAPK激活明显恢复。这种恢复在耐受表达期间观察到；然而，在敏化期间并不显著。总之，这些结果为小鼠脑中吗啡诱导的MAPK调节提供了独特的、区域特异性的机制，并深入了解了参与急性和适应性阿片类行为的脑回路。
