Beneficial effect of chronic treatment with the selective bradykinin B 1 receptor antagonists, R-715 and R-954, in attenuating streptozotocin-diabetic thermal hyperalgesia in mice

Abstract

Kinins are important mediators of cardiovascular homeostasis, inflammation and nociception. Bradykinin (BK) B 1 receptors (BKB 1-R) are over-expressed in pathological conditions including diabetes, and were reported to play a role in hyperglycemia, renal abnormalities, and altered vascular permeability associated with type 1 diabetes. Recent studies from our laboratory demonstrated that BKB 1-R are implicated in streptozotocin (STZ)-diabetes-mediated hyperalgesia, since acute administration of the selective BKB 1-R antagonists significantly and dose-dependently inhibited such hyperalgesic activity. In the present study, we examined the effect of chronic treatment of STZ-diabetic mice with the selective BKB 1-R agonist desArg 9bradykinin (DBK) and two specific antagonists R-715 and R-954, on diabetic hyperalgesia. Diabetes was induced in male CD-1 mice by injecting a single high dose of STZ (200 mg/kg, i.p.) and nociception was assessed using the hot plate, plantar stimulation, tail immersion and tail flick tests. Drugs were injected i.p. twice daily for 7 days, starting 4 days after STZ. We showed that chronically administered R-715 (400 μg/kg) and R-954 (200 μg/kg), significantly attenuated the hyperalgesic effect developed in STZ-diabetic mice as measured by the four thermal nociceptive tests. Further, chronic treatment with DBK (400 μg/kg) produced a marked potentiation of the hyperalgesic activity, an effect that was reversed by both R-715 and R-954. The results from this chronic study confirm a pivotal role of the BKB 1-R in the development of STZ-diabetic hyperalgesia and suggest a novel approach to the treatment of this short-term diabetic complication using BKB 1-R antagonists.