The role of Na_v1.7 and methylglyoxal-mediated activation of TRPA1 in itch and hypoalgesia in a murine model of type 1 diabetes

Abstract

Methylglyoxal (MGO), an endogenous reactive carbonyl compound, plays a key role in the pathogenesis of diabetic neuropathy. The aim of this study is to investigate the role of MGO in diabetic itch and hypoalgesia, two common symptoms associated with diabetic neuropathy. Methods : Scratching behavior, mechanical itch (alloknesis), and thermal hypoalgesia were quantified after intradermal (i.d.) injection of MGO in naïve mice or in diabetic mice induced by intraperitoneal (i.p.) injection of streptozotocin (STZ). Behavioral testing, patch-clamp recording, transgenic mice, and gene expression analysis were used to investigate the mechanisms underlying diabetic itch and hypoalgesia in mice. Results : I.d. injection of MGO evoked dose-dependent scratching in normal mice. Addition of MGO directly activated transient receptor potential ankyrin 1 (TRPA1) to induce inward currents and calcium influx in dorsal root ganglia (DRG) neurons or in TRPA1-expressing HEK293 cells. Mechanical itch, but not spontaneous itch was developed in STZ-induced diabetic mice. Genetic ablation of Trpa1 ( Trpa1 -/- ), pharmacological blockade of TRPA1 and Na v 1.7, antioxidants, and mitogen-activated protein kinase kinase enzyme (MEK) inhibitor U0126 abrogated itch induced by MGO or in STZ-induced diabetic mice. Thermal hypoalgesia was induced by intrathecal (i.t.) injection of MGO or in STZ-induced diabetic mice, which was abolished by MGO scavengers, intrathecal injection of TRPA1 blockers, and in Trpa1 -/- mice. Conclusion : This study revealed that Na v 1.7 and MGO-mediated activation of TRPA1 play key roles in itch and hypoalgesia in a murine model of type 1 diabetes. Thereby, we provide a novel potential therapeutic strategy for the treatment of itch and hypoalgesia induced by diabetic neuropathy.

Circular RNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in type 1 diabetes mellitus

“…This model resembles the key features of T1DM patients with a loss of β-cell function and the development of hyperglycemia 46 - 48 . At present, the STZ-induced mouse model is one of the most widely used animal models of human autoimmune diabetes in T1DM studies 46 , 49 - 51 . In our study, we focused the effect of circPPM1F on development of STZ-induced diabetes mellitus.…”

3’-O-Methylorobol Inhibits the Voltage-Gated Sodium Channel Nav1.7 with Anti-Itch Efficacy in A Histamine-Dependent Itch Mouse Model

“…Itch-related ion channels are the key regulators in itch progression [20]. Recent evidence has indicated that the TTX-S VGSC subtype Nav1.7 in primary sensory neurons plays a significant role in mediating itching [15,17,18]. The discovery of novel gating modifiers of Nav1.7 should hold significant potential for effective treatment of itching.…”

“…Conversely, a monoclonal antibody that suppresses Nav1.7 activity by interacting with the voltage sensor effectively inhibits the histamine-dependent itch in mice [17]. Recently, it was reported that the pharmacological blockade of Nav1.7 reduced itching induced by methylglyoxal or in streptozotocin-induced diabetic mice, indicating that Nav1.7 played a key role in itching in a mouse model of type 1 diabetes [18]. All of these significant findings suggest that Nav1.7 is a novel and promising target for itch management.…”

New insights into the mechanisms behind mechanical itch

“…However, the Ca v 3.2 inhibitor failed to inhibit touch-evoked scratching in a mouse model of type Ι diabetes. [59] Further research should be undertaken to investigate whether hydrogen sulphide, Cav3.2, Aδ-LTMRs and C-LTMRs contribute to mechanical itch sensitization under chronic itch conditions.…”