Calcium-Permeable AMPA Receptors in the Nucleus Accumbens Regulate Depression-Like Behaviors in the Chronic Neuropathic Pain State
Calcium-Permeable AMPA Receptors in the Nucleus Accumbens Regulate Depression-Like Behaviors in the Chronic Neuropathic Pain State
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DOI：
10.1523/jneurosci.2454-13.2013
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发表时间：
2013-11-27
影响因子：
5.3
通讯作者：
Wang, Jing
中科院分区：
文献类型：
--
作者：
Goffer, Yossef;Xu, Duo;Wang, Jing
抑郁是慢性疼痛的一个显著情绪特征。抑郁症改变疼痛阈值，损害功能恢复。然而，迄今为止，对疼痛状态下调节抑郁的突触或回路机制的理解有限。在这里，我们证明了抑郁样行为在慢性神经性疼痛大鼠模型中被诱导。通过这个模型，我们发现慢性疼痛选择性地增加了伏隔核（NAc）突触中ampa型谷氨酸受体GluA1亚基的水平，这是大脑奖励系统的关键组成部分。此外，我们发现，GluA1水平的增加导致钙渗透AMPA受体（CPARs）的形成。令人惊讶的是，对NAc中这些cpar的药物阻断会增加与疼痛相关的抑郁样行为。与这些发现一致的是，一种AMPA受体增强剂进入NAc可以减少疼痛引起的抑郁。这些结果表明，在NAc中通过CPARs的传播代表了一种调节疼痛抑郁症状的新的分子机制，因此CPARs可能是治疗疼痛性抑郁症的一个有希望的治疗靶点。更广泛地说，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。
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.