Mechanisms and Treatment of Type II Painful Diabetic Neuropathy

Diabetes affects almost 9% of the United States population and approximately one-third of these patients experience painful diabetic neuropathy (PDN), but commercial analgesic drugs are not very effective for PDN. Preclinical studies of PDN suggest that methylglyoxal (MG), a cellular metabolite of glucose that is markedly increased in the blood of hyperglycemic patients, contributes to PDN and therefore may be targeted for the development of new analgesics. However, these studies used streptozotocin, a cytotoxin that ablates pancreatic b-cells. Streptozotocin produces a rapid onset of hyperglycemia that does not reflect the natural history of type 2 diabetes. So instead, we study PDN in the Zucker Diabetic Fatty (ZDF) rat and Leprdb/db (db/db) mouse hereditary models of type 2 diabetes. In ZDF we observed behavioral signs of motivational/affective pain (using a novel mechanical conflict-avoidance assay), and in both ZDF and db/db we found elevated plasma MG. To begin to determine MG function, we established a mouse model of MG-induced pain that includes multiple behavioral signs of spontaneous, evoked, and affective pain (using a conditioned place aversion assay), as well molecular signs of spinal neuron activation using pERK expression. We will test the central hypothesis that elevated MG in type 2 diabetes causes PDN and that this metabolic hyperalgesia can be alleviated by drugs targeting MG (Aim 1) and TRPA1 (Aim 2), thus advancing a new pharmacotherapeutic strategy for PDN as illustrated in Figure 1. AIM 1 will test the hypothesis that MG drives neuropathic pain (PDN) in type 2 diabetes. We predict that normalization of MG levels with MG scavengers or catabolism enhancers will reduce pain behavior and stimulus-evoked spinal neuron activation in the db/db and ZDF models of type 2 diabetes. AIM 2 will test the hypothesis that TRPA1 mediates PDN in type 2 diabetes. Our preliminary data indicate that genetic deletion or pharmacological inhibition of TRPA1 blocks MG-induced pain. Indeed, TRPA1 is a leading target for the development of new analgesics for chronic pain, but has not been tested in models of type 2 PDN. To fill this gap, we will treat diabetic db/db mice, ZDF rats, and their controls with TRPA1 antagonists. We predict that this will reduce MG-induced affective pain (Aim 2A) and motivational/affective pain and noxious stimulus-evoked spinal neuron activation in db/db and ZDF (Aim 2B).