Listos Joanna, Baranowska-Bosiacka Irena, Wąsik Agnieszka, Talarek Sylwia, Tarnowski Maciej, Listos Piotr, Łupina Małgorzata, Antkiewicz-Michaluk Lucyna, Gutowska Izabela, Tkacz Marta, Pilutin Anna, Orzelska-Górka Jolanta, Chlubek Dariusz, Fidecka Sylwia
Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodźki 4a St., 20-093, Lublin, Poland.
Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72 Av., 70-111, Szczecin, Poland.
Psychopharmacology (Berl). 2016 Jun;233(12):2383-97. doi: 10.1007/s00213-016-4289-7. Epub 2016 Apr 18.
Experimental data informs that not only do the dose and time duration of dependent drugs affect the severity of withdrawal episodes. Previous withdrawal experiences may intensify this process, which is referred as sensitization to withdrawal signs. Adenosine and dopamine (DA) receptors may be involved in this sensitization.
Rats were continuously and sporadically treated with increasing doses of morphine for 8 days. In rats, sporadically treated with morphine, morphine administration was modified by adding three morphine-free periods. Adenosine agonists were given during each of the morphine-free periods (six injections in total). On the 9th day, morphine was injected. One hour later, naloxone was administered to induce morphine withdrawal signs. Then, the animals were placed into cylinders and the number of jumpings was recorded. Next, the rats were decapitated and brain and brain structures (striatum, hippocampus, and prefrontal cortex) were dissected for neurochemical, molecular, and immunohistochemical experiments within DAergic pathways.
We demonstrated that previous experiences of opioid withdrawal intensified subsequent withdrawal signs. Adenosine ligands attenuated the sensitization to withdrawal signs. In a neurochemical study, the release of DA and its metabolites was impaired in all structures. Significant alterations were also observed in mRNA and protein expression of DA receptors.
Results demonstrate that intermittent treatment with morphine induces alterations in the DAergic system which may be responsible for sensitization to morphine withdrawal signs. Although adenosine ligands attenuate this type of sensitization, they are not able to fully restore the physiological brain status.
实验数据表明，不仅依赖药物的剂量和持续时间会影响戒断发作的严重程度。先前的戒断经历可能会加剧这一过程，这被称为对戒断症状的敏感化。腺苷和多巴胺（DA）受体可能参与了这种敏感化过程。
对大鼠连续8天间歇性给予递增剂量的吗啡。对于间歇性给予吗啡的大鼠，通过增加三个无吗啡期来调整吗啡给药方式。在每个无吗啡期给予腺苷激动剂（共注射6次）。在第9天，注射吗啡。1小时后，给予纳洛酮以诱发吗啡戒断症状。然后，将动物放入圆筒中，记录跳跃次数。接下来，将大鼠断头，解剖大脑及脑结构（纹状体、海马体和前额叶皮质），用于多巴胺能通路内的神经化学、分子和免疫组织化学实验。
我们证明，先前的阿片类药物戒断经历会加剧随后的戒断症状。腺苷配体减弱了对戒断症状的敏感化。在一项神经化学研究中，所有结构中多巴胺及其代谢产物的释放均受损。多巴胺受体的mRNA和蛋白表达也观察到显著变化。
结果表明，间歇性给予吗啡会诱导多巴胺能系统发生改变，这可能是对吗啡戒断症状敏感化的原因。尽管腺苷配体减弱了这种类型的敏感化，但它们无法完全恢复大脑的生理状态。
