Tonic Suppression of the Mesolimbic Dopaminergic System by Enhanced Corticotropin-Releasing Factor Signaling Within the Bed Nucleus of the Stria Terminalis in Chronic Pain Model Rats
Tonic Suppression of the Mesolimbic Dopaminergic System by Enhanced Corticotropin-Releasing Factor Signaling Within the Bed Nucleus of the Stria Terminalis in Chronic Pain Model Rats
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DOI：
10.1523/jneurosci.3047-18.2019
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发表时间：
2019-10-16
影响因子：
5.3
通讯作者：
Minami, Masabumi
中科院分区：
文献类型：
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作者：
Takahashi, Daiki;Asaoka, Yuta;Minami, Masabumi
尽管中脑边缘多巴胺能系统的功能障碍与慢性疼痛有关，但其潜在机制仍有待阐明。我们假设，在慢性疼痛过程中，从终纹背外侧床核（dIBNST）到腹侧被盖区（VTA）的神经元通路的抑制性输入增加可能会诱导中脑边缘多巴胺能系统的紧张性抑制。为了验证这一假设，雄性Sprague道利大鼠进行脊神经结扎以诱导神经性疼痛，然后在该神经元通路中测量自发IPSC（sIPSC）。包含dlBNST的脑切片的全细胞膜片钳电生理学显示，手术后4周，在VTA投射的dlBNST神经元中，sIPSC的频率显著增加。接下来，检查dIBNST内促肾上腺皮质激素释放因子（CRF）信号传导在增加的sIPSC中的作用。CRF增加假手术对照组中VTA投射dlBNST神经元中sIPSC的频率，但在慢性疼痛大鼠中不增加。相比之下，NBI27914，CRF 1型受体拮抗剂，降低慢性疼痛大鼠中VTA投射dlBNST神经元中sIPSC的频率，但在对照动物中不降低。此外，组织学分析显示CRF mRNA在dlBNST中的表达增加。最后，双侧注射NBI 27914到慢性疼痛大鼠的dlBNST激活中脑边缘多巴胺能神经元，诱导条件性位置偏爱。总之，这些结果表明，中脑边缘多巴胺能系统是紧张性抑制慢性疼痛期间通过增强CRF信号传导内的dlBNST通过增加抑制输入到腹侧被盖区投射dlBNST神经元。
Although dysfunction of the mesolimbic dopaminergic system has been implicated in chronic pain, the underlying mechanisms remain to be elucidated. We hypothesized that increased inhibitory inputs to the neuronal pathway from the dorsolateral bed nucleus of the stria terminalis (dIBNST) to the ventral tegmental area (VTA) during chronic pain may induce tonic suppression of the mesolimbic dopaminergic system. To test this hypothesis, male Sprague Dawley rats were subjected to spinal nerve ligation to induce neuropathic pain and then spontaneous IPSCs (sIPSCs) were measured in this neuronal pathway. Whole-cell patch-clamp electrophysiology of brain slices containing the dlBNST revealed that the frequency of sIPSCs significantly increased in VTA-projecting dlBNST neurons 4 weeks after surgery. Next, the role of corticotropin-releasing factor (CRF) signaling within the dlBNST in the increased sIPSCs was examined. CRF increased the frequency of sIPSCs in VTA-projecting dlBNST neurons in sham-operated controls, but not in chronic pain rats. By contrast, NBI27914, a CRF type 1 receptor antagonist, decreased the frequency of sIPSCs in VTA-projecting dlBNST neurons in the chronic pain rats, but not in the control animals. In addition, histological analyses revealed the increased expression of CRF mRNA in the dlBNST. Finally, bilateral injections of NBI27914 into the dlBNST of chronic pain rats activated mesolimbic dopaminergic neurons and induced conditioned place preference. Together, these results suggest that the mesolimbic dopaminergic system is tonically suppressed during chronic pain by enhanced CRF signaling within the dlBNST via increased inhibitory inputs to VTA-projecting dlBNST neurons.