The role of kinin B[indice inférieur 1] receptor in diabetic hyperalgesia
Gabra, Bichoy H
Autoimmune insulin-dependent type 1 diabetes involves an overproduction of cytokines, including interleukin-1[bêta] (IL-1[bêta]) and tumour necrosis factor-[alpha] (TNF-[alpha]), which leads to T-cell-mediated pancreatic [bêta]-cell destruction. It is associated with a series of complications including nephropathy, retinopathy and painful diabetic neuropathy (PDN). Several neurovascular systems are activated in type 1 diabetes including the inducible bradykinin (BK)B[indice inférieur 1] receptor (BKB[indice inférieur 1]-R) subtype which is generally absent or of little impact in healthy states, but highly induced or over-expressed under pathological conditions among which type 1 diabetes, where the over-production of cytokines, the hyperglycemia and the oxidative stress are critical factors for its up-regulation. The present project aimed at studying the development of hyperalgesia in rodent models of type 1 diabetes and characterising the role of the inducible BKB[indice inférieur 1]-R in this diabetic complication, through the use of selective BKB[indice inférieur 1]-R agonists and antagonists. Nociception was evaluated with two types of thermal pain tests; spinal (tail immersion and tail flick tests) and supra-spinal (hot plate and plantar stimulation) tests. Chemically streptozotocin (STZ)-induced diabetic mice and rats showed a marked hyperalgesia that was stable over 4 weeks following the STZ injection. Non-obese diabetic (NOD) and BioBreeding/Worcester (BB/Wor) rats, models of autoimmune spontaneous type 1 diabetes, similarly developed significant hyperalgesia over time (4-32 and 4-24 weeks of age, respectively). Hyperalgesia observed in NOD mice and BB/Wor rats did not correlate with hyperglycemia, but rather preceded the increase in the animal plasma glucose concentration. This finding supports the hypothesis that type 1 diabetic complications start early during the progression of the disease, even before the diagnosis of the state of hyperglycemia. The selective BKB[indice inférieur 1]-R agonist, desArg[indice supérieur 9]BK (DBK), which did not affect nociception in control non-diabetic animals, potentiated hyperalgesia in STZ-diabetic and NOD mice. In addition, the acute and chronic administration of the selective BKB[indice inférieur 1]-R antagonists R-715 and R-954 significantly attenuated diabetic hyperalgesia in all tested animals models. Our results also showed that stimulation of the inducible BKB[indice inférieur 1]-R activates several neurotransmitter systems responsible for the mediation of diabetic hyperalgesia including the substance P (SP), nitric oxide (NO) and calcitonin gene-related peptide (CGRP). Nevertheless, the hyperalgesia observed in wild type diabetic mice was totally absent in the BKB[indice inférieur 1]-R-knockout (KO) diabetic mice in which DBK had no effect on nociceptive responses."--Résumé abrégé par UMI.