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Summary: 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. : Zhou et al. characterize chronic pain behaviors triggered by LTP-inducible HFS without nerve injury. They identify that HFS-induced LTP is accompanied by an increase in CGRP terminals in the spinal dorsal horn. Activation of neuronal CSF1-microglial BDNF signaling is indispensable for the synaptic and structural plasticity underlying HFS-induced chronic pain. Keywords: long-term potentiation, chronic pain, calcitonin gene-related peptide, microglia, high-frequency stimulation, colony-stimulating factor 1, brain-derived neurotrophic factor