μ-Opioid receptor regulates microRNA-190 (miR-190) in an agonist-dependent manner; fentanyl, but not morphine, decreases the miR-190 level in rat primary hippocampal neuron cultures and in mouse hippocampi. In this study, the correlation between the cellular content of miR-190 and the mRNA level of its host gene, talin2, suggested that fentanyl decreases the miR-190 level by inhibiting the transcription of talin2. Fentanyl-induced β-arrestin2-mediated ERK phosphorylation led to the phosphorylation of Yin Yang1 (YY1). Inaddition, YY1 phosphorylation impaired the association of YY1 with the -208 to -200 region on the Talin2 promoter, and this association was essential for YY1 to stimulate the transcription of talin2. Thus, fentanyl decreased the transcription of talin2 and subsequently the cellular level of miR-190 by inducing YY1 phosphorylation. In contrast, because morphine induces ERK phosphorylation via the protein kinase C pathway, morphine did not induce YY1 phosphorylation and had no effect on the transcription of talin2 and the cellular content of miR-190. This study therefore delineates a signaling pathway that mediates the effects of fentanyl on miR-190 expression.