HCN channel antagonist ZD7288 ameliorates neuropathic pain and associated depression.

Abstract

Chronic neuropathic pain has demonstrated that coexisting psychiatric disorders are associated with disability and poorer treatment outcomes. Hyperpolarization-activated cyclic nucleotide-gated (HCN, Ih) channels play a major role in pain via hyperexcitability and facilitation of ectopic firing in neurons. Neuronal hyperexcitability contributes to pain maintenance and anxiety/depression. GABA-mediated inhibitory postsynaptic neurotransmission in the brain is impaired in the pathophysiology of chronic neuropathic pain with comorbidity mood disorders. Currently, interaction of HCN channels and GABAergic synaptic transmission inhibition in neuropathic pain and the associated comorbidity anxiety/depression mechanism remains relatively unknown. To address this, the HCN channel inhibitor, ZD7288, was administrated to Wistar Kyoto (WKY) rats after spared nerve injury (SNI). Our findings show that intracerebroventricular injection of ZD7288 concurrently attenuates co-existing nociceptive and depression-like behaviors, and increases glutamicacid decarboxylase (GAD67/65) expression and GABA levels in the hippocampus and thalamus with High-performance liquid chromatography technique. It suggests that inhibition of HCN channels is likely to decrease the hyperexcitability of neurons in rat SNI and improve the level of GABA. Further, HCN channel may offer a new strategy to alleviate both neuropathic pain and comorbidity for depression.

• Authors: Lujia Yang, Xiaoyan Liu, Kai Yao, Yan Sun, Fan Jiang, Haitao Yan, Peng Mao, Shuangyi Fan, Xiaoli Wei, Ying Liu, Weixiu Yuan, Shuzhuo Zhang
• Journal: Brain research (Brain Res) Vol. 1717 Pg. 204-213 (08 15 2019) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 30940440 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• Cyclic Nucleotide-Gated Cation Channels
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
• Pyrimidines
• ICI D2788
• Glutamate Decarboxylase

Topics

• Animals
• Brain (metabolism)
• Cyclic Nucleotide-Gated Cation Channels (metabolism)
• Depression (drug therapy, metabolism, physiopathology)
• Depressive Disorder (metabolism, physiopathology)
• GABAergic Neurons (drug effects, metabolism)
• Glutamate Decarboxylase (metabolism)
• Hippocampus (metabolism)
• Hyperalgesia (drug therapy, metabolism)
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels (antagonists & inhibitors, metabolism)
• Male
• Neuralgia (metabolism, physiopathology)
• Neurons (metabolism)
• Pyrimidines (pharmacology)
• Rats
• Rats, Inbred WKY
• Thalamus (metabolism)