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Spinal long-term potentiation (LTP) at C-fiber synapses is hypothesized to underlie chronic pain. However, a causal link between spinal LTP and chronic pain is still lacking. Here, we report that high-frequency stimulation (HFS; 100 Hz, 10 V) of the mouse sciatic nerve reliably induces spinal LTP without causing nerve injury. LTP-inducible stimulation triggers chronic pain lasting for more than 35 days and increases the number of calcitonin gene-related peptide (CGRP) terminals in the spinal dorsal horn. The behavioral and morphological changes can be prevented by blocking NMDA receptors, ablating spinal microglia, or conditionally deleting microglial brain-derived neurotrophic factor (BDNF). HFS-induced spinal LTP, microglial activation, and upregulation of BDNF are inhibited by antibodies against colony-stimulating factor 1 (CSF-1). Together, our results show that microglial CSF1 and BDNF signaling are indispensable for spinal LTP and chronic pain. The microglia-dependent transition of synaptic potentiation to structural alterations in pain pathways may underlie pain chronicity.
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Zhou, Li-Jun; Peng, Jiyun; Xu, Ya-Nan; Zhang, Jun; Wei, Xiao; Mai, Chun-Lin; Liu, Yong; Murugan, Madhuvika; Eyo, Ukpong B.; Umpierre, Anthony D.; Xin, Wen-Jun; Chen, Tao; Li, Mingtao; Wang, Hui; Richardson, Jason; Tan, Zhi; Liu, Xian-Guo; and Wu, Long-Jun, "Microglia Are Indispensable for Synaptic Plasticity in the Spinal Dorsal Horn and Chronic Pain" (2019). Environmental Health Sciences. 56.
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