KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats.

Abstract

Background Diabetic neuropathic pain is poorly controlled by analgesics, and the precise molecular mechanisms underlying hyperalgesia remain unclear. The KCNQ2/3/5 channels expressed in dorsal root ganglion neurons are important in pain transmission. The expression and activity of KCNQ2/3/5 channels in dorsal root ganglion neurons in rats with diabetic neuropathic pain were investigated in this study. Methods The mRNA levels of KCNQ2/3/5 channels were analyzed by real-time polymerase chain reaction. The protein levels of KCNQ2/3/5 channels were evaluated by Western blot assay. KCNQ2/3/5 channel expression in situ in dorsal root ganglion neurons was detected by double fluorescent labeling technique. M current (IM) density and neuronal excitability were determined by whole-cell voltage and current clamp recordings. Mechanical allodynia and thermal hyperalgesia were assessed by von Frey filaments and plantar analgesia tester, respectively. Results The mRNA and protein levels of KCNQ2/3/5 channels significantly decreased, followed by the reduction of IM density and elevation of neuronal excitability of dorsal root ganglion neurons from diabetic rats. Activation of KCNQ channels with retigabine reduced the hyperexcitability and inhibition of KCNQ channels with XE991 enhanced the hyperexcitability. Administration of retigabine alleviated both mechanical allodynia and thermal hyperalgesia, while XE991 augmented both mechanical allodynia and thermal hyperalgesia in diabetic neuropathic pain in rats. Conclusion The findings elucidate the mechanisms by which downregulation of the expression and reduction of the activity of KCNQ2/3/5 channels in diabetic rat dorsal root ganglion neurons contribute to neuronal hyperexcitability, which results in hyperalgesia. These data provide intriguing evidence that activation of KCNQ2/3/5 channels might be the potential new targets for alleviating diabetic neuropathic pain symptoms.

• Authors: Ting Yu, Lei Li, Huaxiang Liu, Hao Li, Zhen Liu, Zhenzhong Li
• Journal: Molecular pain (Mol Pain) 2018 Jan-Dec Vol. 14 Pg. 1744806918793229 ISSN: 1744-8069 [Electronic] United States
• PMID: 30027794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone
• Anthracenes
• Carbamates
• KCNQ Potassium Channels
• Membrane Transport Modulators
• Nerve Tissue Proteins
• Phenylenediamines
• Potassium Channel Blockers
• RNA, Messenger
• TRPV Cation Channels
• Trpv1 protein, rat
• ezogabine
• Streptozocin

Topics

• Animals
• Anthracenes (pharmacology)
• Carbamates (pharmacology, therapeutic use)
• Cells, Cultured
• Diabetic Neuropathies (chemically induced, drug therapy, pathology)
• Disease Models, Animal
• Ganglia, Spinal (pathology)
• Gene Expression Regulation (drug effects)
• KCNQ Potassium Channels (genetics, metabolism)
• Membrane Transport Modulators (pharmacology, therapeutic use)
• Nerve Tissue Proteins (metabolism)
• Neurons (drug effects, metabolism)
• Pain Threshold (drug effects, physiology)
• Patch-Clamp Techniques
• Phenylenediamines (pharmacology, therapeutic use)
• Potassium Channel Blockers (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Streptozocin (toxicity)
• TRPV Cation Channels (metabolism)