Direct Role of Streptozotocin in Inducing Thermal Hyperalgesia by Enhanced Expression of Transient Receptor Potential Vanilloid 1 in Sensory Neurons

Abstract

Streptozotocin (STZ) is a diabetogenic agent extensively used to induce diabetes and to study complications including diabetic peripheral neuropathy (DPN). While studying the influence of transient receptor potential vanilloid 1 (TRPV1) on DPN in the STZ-induced diabetic mouse model, we found that a proportion of STZ-treated mice was nondiabetic but still exhibited hyperalgesia. To understand the mechanism underlying this phenomenon, dorsal root ganglion (DRG) neurons and stably TRPV1 expressing human embryonic kidney (HEK) 293T cells were used to study the expression and function of TRPV1. Incubation of DRG neurons with STZ resulted in a significant increase in the amplitude of capsaicin-induced TRPV1-mediated current and Ca 2ϩ influx compared with vehicle-treated sister cultures. It was also found that STZ treatment induced higher levels of reactive oxygen species, which was abolished with concomitant treatment with catalase. Treatment of cells with H 2 O 2 mimicked the effects of STZ. Western blot analysis revealed an increase in TRPV1 protein content and phospho p38 (p-p38) mitogen-activated protein kinase (MAPK) levels in DRG of STZ-injected diabetic and nondiabetic hyperalgesic mice compared with control mice. Furthermore, in stably TRPV1-expressing HEK 293T cells, STZ treatment induced an increase in TRPV1 protein content and p-p38 MAPK levels, which was abolished with concomitant treatment with catalase or p38 MAPK inhibitor. These results reveal that STZ has a direct action on neurons and modulates the expression and function of TRPV1, a nociceptive ion channel that is responsible for inflammatory thermal pain.

Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice

“…However, it has been shown that STZ can directly stimulate DRG neurons and induce thermal hyperalgesia without affecting blood glucose levels (Pabbidi et al, 2008). Concurrent with the increase in blood glucose levels, a significant decrease in the withdrawal threshold was observed 1 day after treatment with 200 mg/kg STZ (Fig.…”

NAD+Activates KNaChannels in Dorsal Root Ganglion Neurons

“…In many instances, neuropathic pain occurs as a direct result of hyperexcitable DRG neurons. Indeed, streptozotocin, an NAD ϩ -depleting agent and pancreatic ␤-cell toxin, used to induce experimental diabetes in animal models, is directly toxic to sensory neurons resulting in measurable thermal hyperalgesia before hyperglycemia ensues (Pabbidi et al, 2008). These would suggest that a direct coupling might exist between resting NAD ϩ levels and the intrinsic firing properties of DRG neurons.…”

Visceral Hypersensitivity and Altered Colonic Motility in Type 2 Diabetic Rat

“…In this regard, an approach to assess the potential correlation between the 2 pathophysiological outcomes of diabetes (peripheral neuropathy and visceral hypersensitivity) deserves researchers' attention in future studies. STZ, in a bell-shaped concentration-dependent manner, can directly act on sensory neurons to upregulate transient receptor potential vanilloid type 1 and consequently induce thermal hypersensitivity, 23 based on which one could speculate that the visceral hypersensitivity in the 48% of our diabetic rat model might result from STZ-induced sensitization of sensory neurons, not necessarily from STZ-induced diabetes and associated neuropathy. This speculation needs assumptions that the concentration of STZ in sensory ganglia is in the effective dose range (20-200 M) after a single neonatal injection of 90 mg/kg STZ, and the STZ-induced sensitization of sensory neurons could persist for 8 weeks.…”