Brain-derived neurotrophic factor (BDNF) plays a critical role in the pathogenesis of neuropathic pain, but its regulation of BDNF release is not fully understood. To further understand the regulation of BDNF release, the microglial cell line, C8-D1A (microglia, in short), were cultured as a model. The levels of BDNF were determined by enzyme-linked immunoassay. Apoptotic microglia were assessed by flow cytometry. The protease-activated receptor 2 (PAR2) was activated by tryptase. Exposure to corticotripin releasing hormone (CRH) induced BDNF release from microglia. Apoptosis was evident in microglia after activation by CRH. Tryptase-induced PAR2 activation reduced the frequency of apoptosis of microglia, but enhanced the BDNF levels in the culture medium, which was partially blocked by PAR2 antagonists. We conclude that PAR2 agonists can promote the BDNF release from microglia; the PAR2 antagonists may be a potential therapeutic target to attenuate the BDNF-related neuropathic pain.