Grupo de Psicobiologia/Depto de Psicologia/CECH-UFSCar, Rod. Washington Luís, Km 235, 13565-905 São Carlos, SP, Brazil.
Brain Res. 2009 Oct 19;1294:29-37. doi: 10.1016/j.brainres.2009.07.055. Epub 2009 Jul 25.
Intra-amygdala infusion of midazolam, a benzodiazepine receptor agonist, produces anxiolytic-like effects in mice when first exposed to the elevated plus-maze (EPM) and blocks antinociception induced in mice confined in the open arm of the EPM. However, benzodiazepines fail to alter anxiety in maze-experienced rodents, a phenomenon defined as "one-trial tolerance" (OTT). The main purpose of the present study was to investigate whether intra-amygdala midazolam attenuates the open arm-induced antinociception (OAA) in maze-experienced mice. Nociception was assessed by the writhing test (intra-peritoneal injection of 0.6% acetic acid). In Experiment 1, nociception was recorded in maze-experienced mice without prior drug treatment. Experiment 2 investigated the effects of systemic midazolam (0.5, 1.0 and 2.0 mg/kg, s.c.), injected before EPM trial 2, on OAA in maze-experienced mice. In Experiment 3, the effects on OAA of intra-amygdala midazolam (30 nmol/0.1 microl), injected before trial 1 (maze-naive) or before trial 2 (maze-experienced), were observed. The effects on OAA of intra-amygdala midazolam injected before trial 1 and trial 2 were also investigated (Experiment 4). The results showed that OAA remained unchanged in maze-experienced mice and was insensitive to systemic midazolam. However, intra-amygdala midazolam attenuated OAA in maze-naive mice, but not in maze-experienced mice. Even when given before both trial 1 and trial 2, intra-amygdala midazolam failed to alter OAA in maze-experienced mice. Taken together, these results confirm that the GABA(A)/benzodiazepine receptor complex located within the amygdala plays a role in OAA in maze-naive mice. The lack of effects following systemic or intra-amygdala midazolam on OAA in maze-experienced mice suggests that the OTT is also observed in the modulation of nociception and that the GABA(A)/benzodiazepine receptor located within this limbic forebrain structure participates in this process.
内侧杏仁核内给予苯二氮䓬受体激动剂咪达唑仑，可使首次暴露于高架十字迷宫（EPM）的小鼠产生抗焦虑样作用，并阻断限制在 EPM 开放臂中的小鼠的抗伤害感受。然而，苯二氮䓬类药物不能改变迷宫经验丰富的啮齿动物的焦虑，这种现象被定义为“单次试验耐受”（OTT）。本研究的主要目的是研究内侧杏仁核内咪达唑仑是否减弱了迷宫经验丰富的小鼠中开放臂诱导的抗伤害感受（OAA）。通过扭体试验（腹腔内注射 0.6%醋酸）评估伤害感受。在实验 1 中，在没有预先给予药物治疗的情况下，在迷宫经验丰富的小鼠中记录伤害感受。实验 2 研究了在 EPM 试验 2 前给予系统咪达唑仑（0.5、1.0 和 2.0 mg/kg，sc）对迷宫经验丰富的小鼠 OAA 的影响。在实验 3 中，观察了内侧杏仁核内咪达唑仑（30 nmol/0.1 μl）在试验 1（迷宫-naive）或试验 2（迷宫经验丰富）前注射对 OAA 的影响。还研究了内侧杏仁核内咪达唑仑在试验 1 和试验 2 前注射对 OAA 的影响（实验 4）。结果表明，OAA 在迷宫经验丰富的小鼠中保持不变，并且对系统咪达唑仑不敏感。然而，内侧杏仁核内咪达唑仑减弱了迷宫-naive 小鼠的 OAA，但对迷宫经验丰富的小鼠没有影响。即使在试验 1 和试验 2 前都给予咪达唑仑，也不能改变迷宫经验丰富的小鼠的 OAA。总之，这些结果证实，位于杏仁核内的 GABA(A)/苯二氮䓬受体复合物在迷宫-naive 小鼠的 OAA 中起作用。系统或内侧杏仁核内咪达唑仑对迷宫经验丰富的小鼠 OAA 无影响表明，在痛觉调制中也观察到 OTT，并且位于该边缘前脑结构内的 GABA(A)/苯二氮䓬受体参与了这一过程。
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