Hyperalgesia in non-obese diabetic (NOD) mice: a role for the inducible bradykinin B1 receptor.

Most studies performed to investigate the role of the inducible bradykinin B(1) receptor in the pathology and complications of type 1 diabetes have been carried out using the model of streptozotocin (STZ)-induced diabetes. The model of spontaneous autoimmune diabetes in non-obese diabetic (NOD) mice involves a long-term inflammatory process that closely resembles the human type 1 diabetes. In the present study, we aimed at establishing the correlation between the progress of diabetic hyperalgesia and the incidence of diabetes, as a function of age, in NOD mice. We also evaluated the implication of the bradykinin B(1) receptor, a receptor up-regulated during the inflammatory progress of diabetes, in the development of diabetic hyperalgesia in NOD mice. Female NOD mice were followed up from the 4th to the 32nd week of age for the incidence of diabetes. Only NOD mice with plasma glucose concentration >20 mmol/l were considered diabetic. The nociception was assessed using the hot plate and the tail immersion pain tests and the effect of acute and chronic administration of the selective bradykinin B(1) receptor agonist, desArg(9)bradykinin and its selective antagonists, R-715 (Ac-Lys-[D-beta Nal(7), Ile(8)]desArg(9)bradykinin) and R-954 (Ac-Orn-[Oic(2), alpha-MePhe(5), D-beta Nal(7), Ile(8)]desArg(9)bradykinin), on the development of diabetic hyperalgesia was studied. Diabetic NOD mice developed a significant time-dependent hyperalgesia, as measured in both tests, starting from the 8th week of age with the maximum effect observed over 16 to 20 weeks, whereas the incidence of diabetes in the tested NOD mice was only 40.16% at the age of 16 weeks and reached a maximum of 73.23% at the age 24 weeks. Both acute and chronic administration of desArg(9)bradykinin (400 microg/kg) markedly increased the hyperalgesic activity in diabetic NOD mice in the hot plate and tail immersion nociceptive tests. The selective bradykinin B(1) receptor antagonist R-715 (400 microg/kg) and its more potent and long acting analogue R-954 (200 microg/kg), administered in acute or chronic manner, significantly attenuated diabetic hyperalgesia in NOD mice in both thermal pain tests and restored nociceptive responses to values observed in control non-diabetic siblings. Our results bring the first evidence that the development of hyperalgesia in NOD mice, a model of spontaneous type 1 diabetes, precedes the occurrence of hyperglycemia and is mediated by the bradykinin B(1) receptor. It is suggested that bradykinin B(1) receptor antagonism could become a novel therapeutic approach to the treatment of diabetic neuropathic complications.