CONICET - Universidad de Buenos Aires, Instituto de Investigaciones Farmacológicas (ININFA), Buenos Aires, Argentina.
Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.
Pharmacol Biochem Behav. 2019 May;180:11-21. doi: 10.1016/j.pbb.2019.02.015. Epub 2019 Mar 6.
Previous studies in our laboratory showed an interaction between the GABAergic and opioid systems involved in the analgesic effect of baclofen (BAC). Furthermore, it is known that sex differences exist regarding various pharmacological responses of morphine (MOR) and they are related to an increased sensitivity to MOR effects in males. The aims of the present study were to evaluate the possible involvement of the GABA receptors in the antinociceptive responses induced by MOR (1, 3 and 9 mg/kg, s.c.) administration using both pharmacological (BAC 2 mg/kg, i.p.; and 2-OH-saclofen, SAC 0.3 mg/kg, intra cisterna magna) and genetic approaches (GABA knockout mice; GABA KO) in mice of both sexes. In addition, we explored the alterations in c-Fos expression of different brain areas involved in the antinociceptive effect of MOR using both approaches. The pharmacological approach showed a higher dose-dependent antinociceptive effect of MOR in male mice compared to female mice. BAC and SAC pretreatment potentiated and attenuated the antinociceptive effect of MOR, respectively, in both sexes. The genetic approach revealed a dose-dependent antinociceptive effect of MOR in the wild type mice, but not in the GABA KO mice and no sex differences were observed. Additionally, BAC and SAC pretreatment and the lack of GABA subunit of the GABA receptor prevented the changes observed in c-Fos expression in the cingulate cortex and nucleus accumbens of male mice. Our results suggest that the GABA receptors are involved in the MOR antinociceptive effect of both male and female mice.
先前在我们实验室的研究表明，γ-氨基丁酸能系统和阿片系统之间存在相互作用，涉及巴氯芬（BAC）的镇痛作用。此外，已知吗啡（MOR）的各种药理学反应存在性别差异，并且与男性对 MOR 效应的敏感性增加有关。本研究的目的是评估 MOR（1、3 和 9mg/kg，sc）给药引起的镇痛反应中 GABA 受体的可能参与，使用药理学方法（BAC 2mg/kg，ip；和 2-OH- saclofen，SAC 0.3mg/kg，鞘内给药）和遗传方法（GABA 敲除小鼠；GABA KO）在雌雄小鼠中进行评估。此外，我们使用这两种方法探索了 MOR 镇痛作用涉及的不同脑区中 c-Fos 表达的变化。药理学方法显示，与雌性小鼠相比，雄性小鼠的 MOR 具有更高的剂量依赖性镇痛作用。BAC 和 SAC 预处理分别增强和减弱了 MOR 的镇痛作用，在两性中均如此。遗传方法显示，野生型小鼠存在剂量依赖性的 MOR 镇痛作用，但在 GABA KO 小鼠中不存在，并且没有观察到性别差异。此外，BAC 和 SAC 预处理以及 GABA 受体亚单位的缺乏阻止了雄性小鼠扣带皮层和伏隔核中 c-Fos 表达的变化。我们的结果表明，GABA 受体参与了雌雄小鼠的 MOR 镇痛作用。
