Streptozotocin (STZ) is a diabetogenic agent extensively used to induce diabetes and to study complications including diabetic peripheral neuropathy (DPN). While studying the influence of transient receptor potential vanilloid 1 (TRPV1) on DPN in the STZ-induced diabetic mouse model, we found that a proportion of STZ-treated mice was nondiabetic but still exhibited hyperalgesia. To understand the mechanism underlying this phenomenon, dorsal root ganglion (DRG) neurons and stably TRPV1 expressing human embryonic kidney (HEK) 293T cells were used to study the expression and function of TRPV1. Incubation of DRG neurons with STZ resulted in a significant increase in the amplitude of capsaicin-induced TRPV1-mediated current and Ca(2+) influx compared with vehicle-treated sister cultures. It was also found that STZ treatment induced higher levels of reactive oxygen species, which was abolished with concomitant treatment with catalase. Treatment of cells with H(2)O(2) mimicked the effects of STZ. Western blot analysis revealed an increase in TRPV1 protein content and phospho p38 (p-p38) mitogen-activated protein kinase (MAPK) levels in DRG of STZ-injected diabetic and nondiabetic hyperalgesic mice compared with control mice. Furthermore, in stably TRPV1-expressing HEK 293T cells, STZ treatment induced an increase in TRPV1 protein content and p-p38 MAPK levels, which was abolished with concomitant treatment with catalase or p38 MAPK inhibitor. These results reveal that STZ has a direct action on neurons and modulates the expression and function of TRPV1, a nociceptive ion channel that is responsible for inflammatory thermal pain.