Emerging role of microglial kinin B1 receptor in diabetic pain neuropathy

Nowadays diabetes mellitus has reached epidemic level and is considered as the primary cause of foot amputation and pain neuropathy. The classical theories explaining the development of diabetic pain neuropathy include the imbalance of neuronal biochemical pathways (Polyol pathway, Na+/K+ ATPase pump, AGE, ROS) and microangiopathy which promote nerve fibers depolarization, sensitization, ectopic discharges, demyelization and ultimately neuronal death. However, the current pharmacotherapy targeting those pathways brings variable, not always satisfactory and temporal relief in patients experiencing diabetic pain neuropathy. Interestingly, recent research in animal models yielded compelling evidence that glial cells, mainly microglia, play a critical role in the mediation of diabetic pain facilitation mechanisms. Preventing microglia activation could therefore be considered as a potential therapeutic target. The lack of specific agents inhibiting microglia activity remains, however, a major obstacle for further treatment in diabetic patients. An alternative and new strategy would be the targeting of key mediators involved in microglia activation, migration and the subsequent release of pro-inflammatory substances contributing to neuronal hyperexitability. The present review summarizes recent evidence that the kinin B1 receptor (B1R) may represent such a target of potential value for new medicines in the treatment of chronic pain. A few selective B1R antagonists have been fully characterized in animal models although small molecules orally active are urgently needed for targeting human B1R on CNS microglia. Thus far, the pharmacological blockade of kinin B1R in various animal paradigms or its genetic deletion in B1R knock-out mice failed to cause unwanted side effects, making this approach feasible. This is consistent with the highly inducible feature of this atypical G-protein coupled receptor whose expression can be seen as the alarming signature of immune and inflammatory diseases, notably diabetes mellitus.