HCN2 contributes to oxaliplatin-induced neuropathic pain through activation of the CaMKII/CREB cascade in spinal neurons.
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.
['Liu|Xiaoyu|X|', 'Zhang|Lidong|L|', 'Jin|Li|L|', 'Tan|Yuanhui|Y|', 'Li|Weiyan|W|', 'Tang|Jun|J|']
D000818:Animals D001522:Behavior, Animal D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 D017362:Cyclic AMP Response Element-Binding Protein D004195:Disease Models, Animal D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels D008297:Male D009437:Neuralgia D009474:Neurons D009944:Organoplatinum Compounds D000077150:Oxaliplatin D015221:Potassium Channels D017207:Rats, Sprague-Dawley D016194:Receptors, N-Methyl-D-Aspartate D015398:Signal Transduction D013116:Spinal Cord D015854:Up-Regulation
HCN2 neuropathic pain CaMKII/CREB oxaliplatin NR2B