Kinins are important mediators of cardiovascular homeostasis,
inflammation and nociception.
Bradykinin (BK) B(1) receptors (BKB1-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 BKB1-R are implicated in
streptozotocin (STZ)-diabetes-mediated
hyperalgesia, since acute administration of the selective BKB1-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 BKB1-R agonist desArg9bradykinin (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 (200mg/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 micrograms/kg) and R-954 (200 micrograms/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 micrograms/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 BKB1-R in the development of STZ-diabetic
hyperalgesia and suggest a novel approach to the treatment of this short-term
diabetic complication using BKB1-R antagonists.