Spinal long-term potentiation(LTP)at C-fiber synapses induced by injury or electrical high frequency stimulation(HFS)of peripheral nerve is believed to underlie chronic pain.However,the evidence demonstrating the causal link between spinal LTP and chronic pain is still lacking.Here we reported that LTP-inducible HFS that did not cause physical nerve injury triggered pain hypersensitivity lasting for at least 3 weeks in mice and rats.HFS activated spinal microglia via colony stimulating factor 1(CSF1)signaling and induced CGRP afferent sprouting in the dorsal horn.Genetic ablation of resident microglia prevented the HFS-induced long lasting synaptic potentiation,CGRP afferent sprouting and chronic pain.Using transgenic mice with specific deletion of microglial BDNF,we further delineated that microglial BDNF promotes HFS-and CSF1-induced sprouting of CGRP primary afferents.Together,the results dissect an intriguing neuronal CSF1 to microglial BDNF signaling cascade in chronic pain generated directly by LTPinducible electrical stimulation.Therefore,our study demonstrates a causal link between spinal LTP and chronic pain,and provides novel insights into the microglial mechanism underlying acute to chronic pain transition after intensive noxious stimulation of the peripheral nerve.