Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Neuropsychopharmacology. 2010 Mar;35(4):955-66. doi: 10.1038/npp.2009.199. Epub 2009 Dec 2.
Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a delta-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of delta-opioid receptor (deltaOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a deltaOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and deltaOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior.
阿片成瘾是一种慢性、复发性行为障碍，滥用的阿片类药物与其所处环境之间形成的习得性关联是通过巴甫洛夫（经典）条件作用过程产生的。然而，调节与阿片类药物相关线索反应或由于反复给予非依赖于情境的阿片类药物而导致的敏化发展的机制的信号转导机制/途径尚不清楚。在这项研究中，我们在急性和重复给予吗啡后，检查了参与成瘾行为的大脑区域中各种经典信号分子的磷酸化水平。采用无偏置位置条件作用协议来检查与（1）吗啡奖赏效应的表达和（2）对这种效应的敏化发展相关的磷酸化变化。鉴于数据表明，阻断δ-阿片受体（δOR）可防止对吗啡奖赏效应的敏化发展，我们还检查了δ-受体拮抗剂对吗啡诱导的条件行为和经典信号分子磷酸化的影响。我们发现，在与记忆巩固相关的大脑区域（如海马体和皮层）中，对吗啡诱导的条件行为敏化反应的表达会特异性诱导 CREB 磷酸化。在 AMPA 谷氨酸受体的 GluR1 亚基的情况下，也观察到类似的效应，尽管程度较小。磷酸化 CREB 和 pGluR1 的水平增加被预先用 δOR 拮抗剂处理显著阻断。这些结果表明，磷酸化 CREB、AMPA 和 δOR 活性在介导对吗啡依赖条件行为的敏化反应的表达中起关键作用。
