Pain in diabetes is a common debilitating condition for which pathophysiology remains poorly understood. To evaluate the underlying mechanisms, we used intravenous injection of streptozotocin to produce rapid (24-hour) onset of diabetes (blood glucose > 300 mg/dL and urine glucose > 2,000 mg/dL with polyuria). In this model, mechanical and thermal hyperalgesia and tactile allodynia are detectable by 48 hours after streptozotocin administration in the absence of ketonuria or physical debility. Treatment with insulin attenuated hyperglycemia and prevented the development of mechanical and thermal hyperalgesia. Direct application of streptozotocin to peripheral nerve did not produce hyperalgesia. We conclude that streptozotocin can induce pain independent of a general debility or direct toxic effect of streptozotocin on peripheral nerve and that elevated blood glucose may contribute to the enhanced nociception.