Role of bradykinin B(1) receptors in diabetes-induced hyperalgesia in streptozotocin-treated mice.

Insulin-dependent diabetes mellitus (type-1 diabetes) is an inflammatory autoimmune disease associated with vascular permeability changes leading to many complications including nephropathy, retinopathy, hypertension, hyperalgesia and neuropathy. The bradykinin B(1) receptor was recently found to be upregulated during the development of the diabetes and to be involved in its complications. Kinins are known to be important mediators of a variety of biological effects including cardiovascular homeostasis, inflammation and nociception. In the present study, we studied the effect of the selective B(1) receptor agonist, des-Arg(9)-bradykinin, and its specific antagonists, Ac-Lys-[D-beta Nal(7), Ile(8)]des-Arg(9)-bradykinin (R-715) and Ac-Orn-[Oic(2), alphaMe Phe(5), D-beta Nal(7), Ile(8)]des-Arg(9)-bradykinin (R-954), on diabetic hyperalgesia. Diabetes was induced in male CD-1 mice by injecting a single high dose of streptozotocin (200 mg kg(-1), i.p.) and the nociception was assessed using the hot plate and the tail flick tests, 1 week following the injection of streptozotocin. Our results showed that induction of diabetes by streptozotocin provoked a marked hyperalgesia in diabetic mice expressed as about 11% decrease in hot plate reaction time and 26% decrease in tail flick reaction time. Following acute administration of R-715 (200-800 microg kg(-1), i.p.) and R-954 (50-600 microg kg(-1), i.p.), this hyperalgesic activity was blocked and the hot plate and tail flick latencies of diabetic mice returned to normal values observed in control healthy mice. In addition, the acute administration of des-Arg(9)-bradykinin (200-600 microg kg(-1), i.p.) significantly potentiated diabetes-induced hyperalgesia, an effect that was totally reversed by R-715 (1.6-2.4 mg kg(-1), i.p.) and R-954 (0.8-1.6 mg kg(-1), i.p.). These results provide a major evidence for the implication of the bradykinin B(1) receptors in the development of hyperalgesia associated with diabetes and suggest a novel approach to the treatment of this diabetic complication using the bradykinin B(1) receptor antagonists.