Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury.

Abstract

Accumulating evidence shows that inhibition of glycogen synthase kinase-3beta (GSK-3β) ameliorates cognitive impairments caused by a diverse array of diseases. Our previous work showed that spared nerve injury (SNI) that induces neuropathic pain causes short-term memory deficits. Here, we reported that GSK-3β activity was enhanced in hippocampus and reduced in spinal dorsal horn following SNI, and the changes persisted for at least 45 days. Repetitive applications of selective GSK-3β inhibitors (SB216763, 5 mg/kg, intraperitoneally, three times or AR-A014418, 400 ng/kg, intrathecally, seven times) prevented short-term memory deficits but did not affect neuropathic pain induced by SNI. Surprisingly, we found that the repetitive SB216763 or AR-A014418 induced a persistent pain hypersensitivity in sham animals. Mechanistically, both β-catenin and brain-derived neurotrophic factor (BDNF) were upregulated in spinal dorsal horn but downregulated in hippocampus following SNI. Injections of SB216763 prevented the BDNF downregulation in hippocampus but enhanced its upregulation in spinal dorsal horn in SNI rats. In sham rats, SB216763 upregulated both β-catenin and BDNF in spinal dorsal horn but affect neither of them in hippocampus. Finally, intravenous injection of interleukin-1beta that induces pain hypersensitivity and memory deficits mimicked the SNI-induced the differential regulation of GSK-3β/β-catenin/BDNF in spinal dorsal horn and in hippocampus. Accordingly, the prolonged opposite changes of GSK-3β activity in hippocampus and in spinal dorsal horn induced by SNI may contribute to memory deficits and neuropathic pain by differential regulation of BDNF in the two regions. GSK-3β inhibitors that treat cognitive disorders may result in a long-lasting pain hypersensitivity.

• Authors: Chun-Lin Mai, Xiao Wei, Wen-Shan Gui, Ya-Nan Xu, Jun Zhang, Zhen-Jia Lin, Zhi Tan, Ying-Tong Meng, Yong-Yong Li, Li-Jun Zhou, Xian-Guo Liu
• Journal: Molecular pain (Mol Pain) 2019 Jan-Dec Vol. 15 Pg. 1744806919826789 ISSN: 1744-8069 [Electronic] United States
• PMID: 30632435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Brain-Derived Neurotrophic Factor
• Enzyme Inhibitors
• Indoles
• Interleukin-1beta
• Maleimides
• Nerve Tissue Proteins
• SB 216763
• Thiazoles
• beta Catenin
• N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
• Urea
• Glycogen Synthase Kinase 3 beta

Topics

• Animals
• Brain-Derived Neurotrophic Factor (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Gene Expression Regulation (drug effects)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Hippocampus (metabolism)
• Hyperalgesia (etiology, pathology)
• Indoles (therapeutic use)
• Interleukin-1beta (pharmacology)
• Male
• Maleimides (therapeutic use)
• Memory Disorders (etiology, pathology, prevention & control)
• Nerve Tissue Proteins (metabolism)
• Pain Measurement
• Peripheral Nerve Injuries (complications)
• Rats
• Rats, Sprague-Dawley
• Spinal Cord Dorsal Horn (metabolism)
• Thiazoles (therapeutic use)
• Time Factors
• Urea (analogs & derivatives, therapeutic use)
• beta Catenin (metabolism)