title: Kinin B1 receptor antagonists inhibit diabetes-induced hyperalgesia in mice.
abstract: Insulin-dependent diabetes mellitus (type 1 diabetes) is an inflammatory autoimmune disease associated with vascular permeability changes leading to many complications including nephropathy, retinopathy, neuropathy, hypertension and hyperalgesia. The bradykinin B(1) receptors (BKB(1)-R) were recently found to be upregulated alongside the development of type 1 diabetes and to be involved in its complications. Kinins are important mediators of a variety of biological effects including cardiovascular homeostasis, inflammation and nociception. In the present study, we studied the effect of a selective BKB(1)-R agonist desArg(9)-BK (DBK) and two selective receptor antagonists, the R-715 (Ac-Lys-[D-beta Nal(7), Ile(8)] desArg(9)-BK) and the R-954 (Ac-Orn-[Oic(2), alphaMe Phe(5), D-beta Nal(7), Ile(8)] desArg(9)-BK) on diabetic hyperalgesia. Type 1 diabetes was induced in male CD-1 mice via a single injection of streptozotocin (STZ, 200mg/kg, i.p.), one week before the test. Nociception, a measure of hyperalgesia, was assessed using the plantar stimulation (Hargreaves) and the tail-immersion tests. The induction of type 1 diabetes provoked a significant hyperalgesic activity in diabetic mice, causing an 11% decrease in plantar stimulation reaction time and 13% decrease in tail-immersion reaction time, compared to normal mice. Following acute administration of R-715 (100-600 microg/kg, i.p.), or R-954 (50-400 microg/kg, i.p.), the STZ-induced hyperalgesic activity was blocked in a dose-dependent manner and the hot plate and tail-immersion latencies of diabetic mice returned to normal values observed in control healthy mice. In addition, the acute administration of DBK (400 microg/kg, i.p.) significantly potentiated diabetes-induced hyperalgesia, an effect that was totally reversed by R-715 (1.6-2.4 mg/kg, i.p.) and R-954 (0.8-1.2mg/kg, i.p.). These results provide further evidence for the implication of the BKB(1)-R in type 1 diabetic hyperalgesia and suggest a novel approach in the treatment of this complication using the BKB(1)-R antagonists.
authors.affiliation: Institute of Pharmacology of Sherbrooke, School of Medicine, University of Sherbrooke, Sherbrooke, PQ, Canada J1H 5N4.
authors.forename: Bichoy H
authors.initials: BH
authors.lastname: Gabra
authors.forename: Pierre
authors.initials: P
authors.lastname: Sirois
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology*; D007101:Immersion; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D011930:Reaction Time / Q000187:drug effects; D043783:Receptor, Bradykinin B1
chemical_list: D001786:Blood Glucose; D065168:Bradykinin Receptor Antagonists; C120984:R 715; D043783:Receptor, Bradykinin B1; C024626:bradykinin, des-Arg(9)-; D001920:Bradykinin