D-cycloloserine reduces neuropathic pain behavior through limbic NMDA-mediated circuitry
D-cycloloserine reduces neuropathic pain behavior through limbic NMDA-mediated circuitry
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DOI：
10.1016/j.pain.2007.03.003
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发表时间：
2007-11-01
期刊：
影响因子：
7.4
通讯作者：
Apkarian, A. Vania
中科院分区：
文献类型：
--
作者：
Millecamps, Magali;Centeno, Maria V.;Apkarian, A. Vania
人脑成像研究表明，慢性神经性疼痛具有强烈的情绪成分，由内侧前额叶皮层（mPFC）活动介导；在啮齿类动物中，mPFC参与行为的情感和认知方面，包括巴甫洛夫恐惧条件反射的消失。总之，这些发现表明，大脑皮层可能会调节疼痛的记忆痕迹。AS d -环丝氨酸（DCS）是一种NMDA受体的部分激动剂，可以增强学习能力，促进获得性恐惧的消退，在本研究中，我们测试了其对神经性疼痛行为的疗效。在神经损伤大鼠（SNI）中，重复每日口服DCS以剂量依赖性方式降低损伤肢体的机械敏感性；这种效果在停止DCS治疗后持续数周。此外，再次暴露于DCS进一步增强了抗感受性行为。反复口服DCS也可减少癌症化疗药物引起的神经性疼痛行为。将DCS直接注射到SNI大鼠的mPFC（尤其是前边缘皮质）或杏仁核（但不注射到丘脑、脑岛或枕叶皮质）可急性诱导抗感觉。NMDA和甘氨酸模拟mpfc内DCS输注的抗伤感受作用，HA 966阻断其作用。SNI大鼠mPFC中NR2B表达下调；然而，重复口服DCS后，这种效果被逆转。最后，向mPFC注入DCS可逆转SNI大鼠损伤足跖机械刺激诱导的位置回避行为。这些发现表明，边缘nmda介导的回路参与了神经性疼痛行为的长期减少。(C) 2007国际疼痛研究协会。Elsevier B.V.版权所有。
Human brain imaging studies suggest that chronic neuropathic pain has a strong emotional component that is mediated by medial prefrontal cortex (mPFC) activity; in rodents, the mPFC is involved in emotional and cognitive aspects of behavior, including the extinction of Pavlovian fear conditioning. Together, these findings suggest that the cortex may modulate the memory trace of pain. AS D-Cycloserine (DCS), a partial agonist of the NMDA receptor, can enhance learning and potentiate the extinction of acquired fear, in the present study we tested its efficacy in neuropathic pain behavior. In rats with spared nerve injury (SNI), repeated daily oral administration of DCS reduced mechanical sensitivity of the injured limb in a dose-dependent manner; this effect continued for weeks after the cessation of DCS treatment. In addition, re-exposure to DCS further enhanced antinociceptive behavior. Repeated oral DCS administration also reduced cancer chemotherapy drug-induced neuropathic pain behavior. Infusions of DCS directly into the mPFC (especially within prelimbic cortex) or the amygdala (but not into thalamus, insula, or occipital cortex) acutely induced antinociception in SNI rats. The antinociceptive effect of intra-mPFC DCS infusions was mimicked by NMDA and glycine, and blocked by HA 966. In the mPFC of SNI rats, NR2B expression was down-regulated; however, this effect was reversed with repeated oral DCS. Lastly, infusions of DCS into mPFC reversed place avoidance behavior induced by mechanical stimulation of the injured paw in SNI rats. These findings indicate that limbic NMDA-mediated circuitry is involved in long-term reduction in neuropathic pain behavior. (C) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.