Epigenetic upregulation of Cdk5 in the dorsal horn contributes to neuropathic pain in rats.

Abstract

Numerous reports have shown that cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase, critically contributes to the induction and maintenance of chronic pain induced by peripheral inflammation and nerve injury. Recent evidence has also suggested the critical role of an epigenetic mechanism in the setting of chronic pain. The present study aims to elucidate the cyclic AMP response element-binding protein (CREB)-mediated upregulation of Cdk5 and its functional significance in rats with neuropathic pain induced by chronic constriction injury (CCI) in the sciatic nerve. Significantly increased expression of Cdk5 was observed in the dorsal horn of rats with CCI, and intrathecal delivery of Cdk5 inhibitor roscovitine significantly attenuated the mechanical allodynia in these rats. Phosphorylation of CREB and its occupancy in the Cdk5 promoter region was also increased in the dorsal horn, which led to increased histone H4 acetylation in the Cdk5 promoter region and the upregulated transcription of Cdk5. Inhibition of CREB activity attenuated the upregulation of Cdk5 and alleviated the mechanical allodynia in rats with CCI. These results demonstrated a CREB-mediated epigenetic upregulation of Cdk5 in the dorsal horn, which critically contributed to the maintenance of painful behavior in the rats with neuropathic pain.

• Authors: Kai Li, Guo-Qing Zhao, Long-Yun Li, Guang-Zhi Wu, Shu-sen Cui
• Journal: Neuroreport (Neuroreport) Vol. 25 Issue 14 Pg. 1116-21 (Oct 01 2014) ISSN: 1473-558X [Electronic] England
• PMID: 25055140 (Publication Type: Journal Article)

Chemical References

• Cyclic AMP Response Element-Binding Protein
• Protein Kinase Inhibitors
• Purines
• Roscovitine
• Cyclin-Dependent Kinase 5
• Cdk5 protein, rat

Topics

• Acetylation
• Animals
• Chronic Disease
• Constriction, Pathologic
• Cyclic AMP Response Element-Binding Protein (antagonists & inhibitors, metabolism)
• Cyclin-Dependent Kinase 5 (antagonists & inhibitors, metabolism)
• Disease Models, Animal
• Epigenesis, Genetic
• Hyperalgesia (drug therapy, genetics, metabolism)
• Male
• Neuralgia (drug therapy, genetics, metabolism)
• Phosphorylation
• Promoter Regions, Genetic
• Protein Kinase Inhibitors (pharmacology)
• Purines (pharmacology)
• Rats, Sprague-Dawley
• Roscovitine
• Sciatic Nerve (injuries)
• Spinal Cord Dorsal Horn (drug effects, metabolism)
• Touch
• Up-Regulation