Department of Anesthesiology, Molecular Neurobiology Program, The Helen and Martin Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, Departments of Otolaryngology and Physiology and Neuroscience, and Department of Biochemistry, New York University School of Medicine, New York, New York 10016.
J Neurosci. 2013 Nov 27;33(48):19034-44. doi: 10.1523/JNEUROSCI.2454-13.2013.
Depression is a salient emotional feature of chronic pain. Depression alters the pain threshold and impairs functional recovery. To date, however, there has been limited understanding of synaptic or circuit mechanisms that regulate depression in the pain state. Here, we demonstrate that depression-like behaviors are induced in a rat model of chronic neuropathic pain. Using this model, we show that chronic pain selectively increases the level of GluA1 subunits of AMPA-type glutamate receptors at the synapses of the nucleus accumbens (NAc), a key component of the brain reward system. We find, in addition, that this increase in GluA1 levels leads to the formation of calcium-permeable AMPA receptors (CPARs). Surprisingly, pharmacologic blockade of these CPARs in the NAc increases depression-like behaviors associated with pain. Consistent with these findings, an AMPA receptor potentiator delivered into the NAc decreases pain-induced depression. These results show that transmission through CPARs in the NAc represents a novel molecular mechanism modulating the depressive symptoms of pain, and thus CPARs may be a promising therapeutic target for the treatment of pain-induced depression. More generally, these findings highlight the role of central glutamate signaling in pain states and define the brain reward system as an important region for the regulation of depressive symptoms of pain.
抑郁是慢性疼痛的一个显著情绪特征。抑郁会改变疼痛阈值并损害功能恢复。然而，迄今为止，对于调节疼痛状态下抑郁的突触或回路机制的理解有限。在这里，我们证明了慢性神经病理性疼痛模型中会诱导出类似抑郁的行为。使用这种模型，我们表明慢性疼痛会选择性地增加伏隔核（NAc）突触中 AMPA 型谷氨酸受体 GluA1 亚基的水平，伏隔核是大脑奖励系统的关键组成部分。此外，我们发现这种 GluA1 水平的增加会导致形成钙通透性 AMPA 受体（CPAR）。令人惊讶的是，在 NAc 中阻断这些 CPARs 的药理学阻断会增加与疼痛相关的类似抑郁的行为。这些发现与这些发现一致，在 NAc 中递送电刺激 AMPA 受体增强剂会降低疼痛引起的抑郁。这些结果表明，NAc 中的 CPAR 传递代表了调节疼痛抑郁症状的新分子机制，因此 CPAR 可能是治疗疼痛引起的抑郁的有前途的治疗靶点。更普遍地说，这些发现强调了中枢谷氨酸信号在疼痛状态中的作用，并将大脑奖励系统定义为调节疼痛抑郁症状的重要区域。
