Despite the important roles of protein kinase Ce (PKC epsilon) and transient receptor potential vanilloind 1 (TRPV1) in inflammatory hypersensitivity, how PKC epsilon is involved in the regulation of thermal hyperalgesia is not fully understood. We report here that PKC epsilon is SUMOylated at a C-terminal lysine residue (K534), which enhances the sensitivity of the TRPV1 channel. We demonstrate that PKC epsilon phosphorylation promotes its SUMOylation, which in turn regulates the phosphorylation level of TRPV1 serine 800 residue via controlling the binding of PKC epsilon and TRPV1 and increased PKC epsilon kinase activity. More importantly, the reduced ability of PKC epsilon knock-down mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 4/5 dorsal root ganglia neurons of wild-type PKC epsilon, but not the SUMOylation-deficient PKC epsilon mutant. Therefore, the SUMOylation of PKC epsilon potentiates inflammatory thermal hyperalgesia through stabilizing the interaction with TRPV1 to enhance its function by phosphorylation.