HCN2 contributes to oxaliplatin-induced neuropathic pain through activation of the CaMKII/CREB cascade in spinal neurons.

Abstract

Emerging evidence showed that hyperpolarization-activated cation channels (HCN) participate in the development of inflammatory and neuropathic pain. However, the role of HCN2 in oxaliplatin-induced neuropathic pain remains unknown. Here, we found that HCN2 expression was upregulated in a rat model of oxaliplatin-induced neuropathic pain. Intrathecal injection of ZD7288, an HCN specific inhibitor, decreased the HCN2 level, as well as weakened the neuropathic pain behaviors compared to naive rats. Besides, mechanistic studies revealed that the expression of the spinal N-methyl-D-aspartate receptor subunit 2B was increased after oxaliplatin administration and was reduced by ZD7288 administration. The nociceptive behaviors were reversed by NR2B antagonist Ro 25-6981 in HCN2-overexpression rats. Furthermore, the underlying cellular mechanism demonstrated that ZD7288 administration restrained the enhanced activation of the neuronal calcium-calmodulin-dependent kinase II (CaMKII)/cyclic adenosine monophosphate response element-binding protein cascade after oxaliplatin administration. Moreover, pretreatment of CaMKII inhibitor KN-93 suppressed the nociceptive behaviors, as well as NR2B upregulation induced by overexpression of HCN2. In a word, HCN2 is conducive to oxaliplatin-induced neuropathic pain by activating the neuronal CaMKII/CREB cascade.

• Authors: Xiaoyu Liu, Lidong Zhang, Li Jin, Yuanhui Tan, Weiyan Li, Jun Tang
• Journal: Molecular pain (Mol Pain) 2018 Jan-Dec Vol. 14 Pg. 1744806918778490 ISSN: 1744-8069 [Electronic] United States
• PMID: 29806529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP Response Element-Binding Protein
• Hcn2 protein, rat
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
• NR2B NMDA receptor
• Organoplatinum Compounds
• Potassium Channels
• Receptors, N-Methyl-D-Aspartate
• Oxaliplatin
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Animals
• Behavior, Animal
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Disease Models, Animal
• Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels (metabolism)
• Male
• Neuralgia (chemically induced, metabolism, pathology)
• Neurons (metabolism, pathology)
• Organoplatinum Compounds (adverse effects)
• Oxaliplatin
• Potassium Channels (metabolism)
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Signal Transduction
• Spinal Cord (pathology)
• Up-Regulation