Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons

Abstract

Individuals with end-stage diabetic peripheral neuropathy present with decreased pain sensation. Transient receptor potential vanilloid type 1 (TRPV1) is implicated in pain signaling and resides on sensory dorsal root ganglion (DRG) neurons. We investigated the expression and functional activity of TRPV1 in DRG neurons of the Ins2+/Akita mouse at 9 months of diabetes using immunohistochemistry, live single cell calcium imaging, and whole-cell patch-clamp electrophysiology. 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence assay was used to determine the level of Reactive Oxygen Species (ROS) in DRGs. Although TRPV1 expressing neuron percentage was increased in Ins2+/Akita DRGs at 9 months of diabetes compared to control, capsaicin-induced Ca2+ influx was smaller in isolated Ins2+/Akita DRG neurons, indicating impaired TRPV1 function. Consistently, capsaicin-induced Ca2+ influx was decreased in control DRG neurons cultured in the presence of 25 mM glucose for seven days versus those cultured with 5.5 mM glucose. The high glucose environment increased cytoplasmic ROS accumulation in cultured DRG neurons. Patch-clamp recordings revealed that capsaicin-activated currents decayed faster in isolated Ins2+/Akita DRG neurons as compared to those in control neurons. We propose that in poorly controlled diabetes, the accelerated rate of capsaicin-sensitive TRPV1 current decay in DRG neurons decreases overall TRPV1 activity and contributes to peripheral neuropathy.

Peripheral neuropathy in the pre-diabetic state of the type 2 diabetes mouse model (TSOD mice) involves TRPV1 expression in dorsal root ganglions

“…In LPA-induced mouse models ( Ohsawa et al, 2013 ) and STZ-induced diabetic mouse models ( Hong et al, 2008 ), TRPV1 was also expressed in large cells of the DRG. The DRG in Akita mice, an animal model of type 1 DM ( Chen et al, 2019 ), also showed increased TRPV1-positive cells. This is consistent with our results.…”

Effects and mechanism of the etanercept on pancreatic encephalopathy

“…Detection of reactive oxygen species (ROS) level. cellular roS level was measured fluorometrically using the ROS sensitive dye 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) as described by chen et al (33). Briefly, H19-7/IGF-IR cells treated as indicated were collected, centrifuged at 500 x g for 5 min at room temperature, resuspended in PBS with dcFH-da (10 µM), and incubated at room temperature for 30 min in darkness.…”

The Pharmacokinetics of Butylscopolamine in Camel Plasma after Intravenous Administration

“…118 In the long-term diabetic microenvironment, earlier studies demonstrated that TRPV1 desensitization in DRGs decreased TRPV1 activity and contributed to peripheral diabetic neuropathy. 146 Furthermore, the injection of capsaicin attenuated hyperglycaemia in Zucker diabetic fatty animals which is a model of human type 2 diabetes mellitus. 145 In this sense, TRPV1 knockout mice exhibited impairment in glucose metabolism manifested by a decrease in glucose-induced insulin secretion.…”