CDK5 inhibits the clathrin-dependent internalization of TRPV1 by phosphorylating the clathrin adaptor protein AP2μ2

, which reduced the interaction between TRPV1 and AP2μ2, leading to decreased TRPV1 internalization. Intrathecal delivery of a cell-penetrating fusion peptide corresponding to the Cdk5 phosphorylation site in AP2μ2, which competed with AP2μ2 for phosphorylation by Cdk5, increased the abundance of TRPV1 on the surface of dorsal root ganglion neurons and reduced complete Freund's adjuvant (CFA)-induced inflammatory thermal hyperalgesia in rats. In addition to describing a mechanism of TRPV1 constitutive internalization and its inhibition by CDK5, these findings demonstrate that CDK5 promotes inflammatory thermal hyperalgesia by reducing TRPV1 internalization, providing previously unidentified insights into the search for drug targets to treat pain.