Conditional knockout of CRMP2 in neurons, but not astrocytes, disrupts spinal nociceptive neurotransmission to control the initiation and maintenance of chronic neuropathic pain.
Conditional knockout of CRMP2 in neurons, but not astrocytes, disrupts spinal nociceptive neurotransmission to control the initiation and maintenance of chronic neuropathic pain.
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有条件地敲除神经元（而非星形胶质细胞）中的 CRMP2 会破坏脊髓伤害性神经传递，从而控制慢性神经性疼痛的发生和维持。
DOI：
10.1097/j.pain.0000000000002344
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发表时间：
2022-02-01
期刊：
影响因子：
7.4
通讯作者：
Khanna R
中科院分区：
文献类型：
--
作者：
Boinon L;Yu J;Madura CL;Chefdeville A;Feinstein DL;Moutal A;Khanna R
主要针对初级传入伤害感觉神经元的机制研究揭示了坍缩反应介质蛋白2 （CRMP2）的上调，CRMP2是n型电压门控钙（Cav2）的双重运输调节因子。2)以及Nav1。7个电压门控钠通道-作为神经性疼痛的潜在决定因素。CRMP2是否参与周围神经损伤后神经性疼痛加工的异常兴奋性突触传递尚不清楚。在这里，我们询问CRMP2在突触传递和慢性疼痛的开始或维持中的作用。在大鼠中，短干扰rna介导的脊髓中CRMP2的敲低降低了急性脊髓切片中浅表背角神经元自发兴奋性突触后电流的频率和幅度，但没有自发抑制性突触后电流。对微兴奋性突触后电流和抑制性突触后电流无影响。在一种互补的靶向方法中，使用钙/钙调素依赖性蛋白激酶II α启动子从小鼠神经元中有条件地敲除CRMP2来驱动Cre重组酶的表达，可以降低自发兴奋性突触后电流的频率和幅度，但不会降低微型兴奋性SCss。使用胶质纤维酸性蛋白启动子有条件地敲除小鼠星形胶质细胞中的CRMP2对突触传递没有影响。在雄性和雌性小鼠中，有条件地敲除神经元中CRMP2可逆转由备用神经损伤引起的机械性异常痛。此外，在这些小鼠中，还可以防止备用神经损伤引起的异常性疼痛的发生。我们的数据强烈表明，CRMP2是驱动疼痛信号的谷氨酸能神经传递的关键调节因子，并有助于生理性疼痛向病理性疼痛的转变。
Mechanistic studies principally focusing on primary afferent nociceptive neurons uncovered the upregulation of collapsin response mediator protein 2 (CRMP2)—a dual trafficking regulator of N-type voltage-gated calcium (Cav2. 2) as well as Nav1. 7 voltage-gated sodium channels—as a potential determinant of neuropathic pain. Whether CRMP2 contributes to aberrant excitatory synaptic transmission underlying neuropathic pain processing after peripheral nerve injury is unknown. Here, we interrogated CRMP2’s role in synaptic transmission and in the initiation or maintenance of chronic pain. In rats, short-interfering RNA-mediated knockdown of CRMP2 in the spinal cord reduced the frequency and amplitude of spontaneous excitatory postsynaptic currents, but not spontaneous inhibitory postsynaptic currents, recorded from superficial dorsal horn neurons in acute spinal cord slices. No effect was observed on miniature excitatory postsynaptic currents and inhibitory postsynaptic currents. In a complementary targeted approach, conditional knockout of CRMP2 from mouse neurons using a calcium/calmodulin-dependent protein kinase II alpha promoter to drive Cre recombinase expression reduced the frequency and amplitude of spontaneous excitatory postsynaptic currents, but not miniature excitatory SCss. Conditional knockout of CRMP2 from mouse astrocytes using a glial fibrillary acidic protein promoter had no effect on synaptic transmission. Conditional knockout of CRMP2 in neurons reversed established mechanical allodynia induced by a spared nerve injury in both male and female mice. In addition, the development of spared nerve injury–induced allodynia was also prevented in these mice. Our data strongly suggest that CRMP2 is a key regulator of glutamatergic neurotransmission driving pain signaling and that it contributes to the transition of physiological pain into pathological pain.
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影响因子：
64.8
作者：
GOSHIMA, Y;NAKAMURA, F;STRITTMATTER, SM
通讯作者：
STRITTMATTER, SM
影响因子：
25
作者：
Chan KY;Jang MJ;Yoo BB;Greenbaum A;Ravi N;Wu WL;Sánchez-Guardado L;Lois C;Mazmanian SK;Deverman BE;Gradinaru V
通讯作者：
Gradinaru V
影响因子：
21.3
作者：
Fukata, Y;Itoh, TJ;Kaibuchi, K
通讯作者：
Kaibuchi, K
影响因子：
9.8
作者：
D'Mello, R.;Dickenson, A. H.
通讯作者：
Dickenson, A. H.
DOI：
10.1080/19336950.2021.1885836
发表时间：
2021-12
期刊：
Channels (Austin, Tex.)
影响因子：
--
作者：
Kopach O;Voitenko N
通讯作者：
Voitenko N