A significant percentage of patients with type 2 diabetes mellitus develop peripheral polyneuropathy and experience severe and unremitting chronic neuropathic pain. This condition is among the most difficult to manage and often resists effective treatment altogether. This pain can be debilitating, frequently leads to physical impairments and functional limitations and can significantly impact on the quality of life. The pathophysiology of the diabetic neuropathy and its painful variant remain poorly understood. The Zucker diabetic fatty (ZDF) rat is an animal model of Type 2 diabetes, characterized by the spontaneous onset of diabetes at approximately 70 days of age. This model shows insulin resistance with hyperglycaemia and hyperinsulinea and as such closely mimics human Type 2 diabetes. Increasing our knowledge of the CNS mechanisms involved in painful Type 2 diabetic neuropathy should facilitate the development of treatments that are more effective and specific than those currently available. Accordingly, we tested ZDF and Zucker lean non-diabetic control rats for the presence of neuropathic pain by measuring behavioral responses to innocuous mechanical and noxious thermal stimuli. Diabetic rats showed increased sensitivity to stimuli by 10 weeks of age compared to the lean control rats. This hyper-responsiveness lasted for up to 14 weeks of age, at which time we evaluated the changes in brain activation associated with diabetes-induced neuropathic pain. We found differences in the basal (unstimulated) activation patterns in diabetic rats with neuropathic pain compared to age matched non-diabetic control animals in several supraspinal regions. For example, compared to control rats, ZDF rats showed significant increases in activation in somatosensory and limbic structures. Our results suggest that, as a consequence of and in parallel to the development of a diabetic neuropathy, maladaptive alterations occur in the functional activation of multiple CNS structures involved in pain perception and/or pain modulation.