The kinin system mediates hyperalgesia through the inducible bradykinin B1 receptor subtype: evidence in various experimental animal models of type 1 and type 2 diabetic neuropathy

Abstract

Both insulin-dependent (type 1) and insulin-independent (type 2) diabetes are complex disorders characterized by symptomatic glucose intolerance due to either defective insulin secretion, insulin action or both. Unchecked hyperglycemia leads to a series of complications among which is painful diabetic neuropathy, for which the kinin system has been implicated. Here, we review and compare the profile of several experimental models of type 1 and 2 diabetes (chemically induced versus gene-prone) and the incidence of diabetic neuropathy upon aging. We discuss the efficacy of selective antagonists of the inducible bradykinin B1 receptor (BKB1-R) subtype against hyperalgesia assessed by various nociceptive tests. In either gene-prone models of type 1 and 2 diabetes, the incidence of hyperalgesia mostly precedes the development of hyperglycemia. The administration of insulin, achieving euglycemia, does not reverse hyperalgesia. Treatment with a selective BKB1-R antagonist does not affect basal nociception in most normal control rats, whereas it induces a significant time- and dose-dependent attenuation of hyperalgesia, or even restores nociceptive responses, in experimental diabetic neuropathy models. Diabetic hyperalgesia is absent in streptozotocin-induced type 1 diabetic BKB1-R knockout mice. Thus, selective antagonism of the inducible BKB1-R subtype may constitute a novel and potential therapeutic approach for the treatment of painful diabetic neuropathy.

Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice

“…Thus far, the effect of KKS on the neuropathy induced by long-lasting diabetes has been focused on the suppressive effect of B1R on diabetic hyperalgesia (47). However, another important aspect of diabetic neuropathy is the hypoalgesia caused by polyneuropathy in peripheral nerves, which can lead to lower limb amputations that have a major impact on the quality of life and disability of diabetic patients (48).…”

Continuous -Opioid Receptor Activation Reduces Neuronal Voltage-Gated Sodium Channel (NaV1.7) Levels through Activation of Protein Kinase C in Painful Diabetic Neuropathy

“…The pathogenesis of pain in the setting of diabetes is complex. Previous studies have implicated involvement alterations in the peripheral kinin system (Gabra et al, 2006) and in peripheral vanilloid receptors (Hong and Wiley, 2005), in addition to described spinal and supraspinal mechanisms (Calcutt, 2002;Ramos et al, 2007) in the development of pain. The first study of sodium channels in peripheral nerve in PDN identified increases in RNA and protein of several voltage-gated sodium channel ␣ subunit isoforms, although in that study the investigators did not observe an increase in Na V 1.7 RNA or protein (Craner et al, 2002).…”

Effect of Bradykinin Receptor Antagonists on Vincristine- and Streptozotocin-Induced Hyperalgesia in a Rat Model of Chemotherapy-Induced and Diabetic Neuropathy

“…Pesquero et al [24] first described hypoalgesia in B 1 receptor-deficient mice. Gabra et al [25][26][27] suggest that the kinin system mediates hyperalgesia through the inducible BK B 1 receptor subtype in animal models of diabetic neuropathy. Diabetic hyperalgesia was absent after STZ administration in the model of type 1 diabetes in B 1 receptor knockout mice [25,28] .…”