Casein kinase II regulates N-methyl-D-aspartate receptor activity in spinal cords and pain hypersensitivity induced by nerve injury.

Abstract

Increased N-methyl-d-aspartate receptor (NMDAR) activity and phosphorylation in the spinal cord are critically involved in the synaptic plasticity and central sensitization associated with neuropathic pain. However, the mechanisms underlying increased NMDAR activity in neuropathic pain conditions remain poorly understood. Here we show that peripheral nerve injury induces a large GluN2A-mediated increase in NMDAR activity in spinal lamina II, but not lamina I, neurons. However, NMDAR currents in spinal dorsal horn neurons are not significantly altered in rat models of diabetic neuropathic pain and resiniferatoxin-induced painful neuropathy (postherpedic neuralgia). Inhibition of protein tyrosine kinases or protein kinase C has little effect on NMDAR currents potentiated by nerve injury. Strikingly, casein kinase II (CK2) inhibitors normalize increased NMDAR currents of dorsal horn neurons in nerve-injured rats. In addition, inhibition of calcineurin, but not protein phosphatase 1/2A, augments NMDAR currents only in control rats. CK2 inhibition blocks the increase in spinal NMDAR activity by the calcineurin inhibitor in control rats. Furthermore, nerve injury significantly increases CK2α and CK2β protein levels in the spinal cord. In addition, inhibition of CK2 or CK2β knockdown at the spinal level substantially reverses pain hypersensitivity induced by nerve injury. Our study indicates that neuropathic pain conditions with different etiologies do not share the same mechanisms, and increased spinal NMDAR activity is distinctly associated with traumatic nerve injury. CK2 plays a prominent role in the potentiation of NMDAR activity in the spinal dorsal horn and may represent a new target for treatments of chronic pain caused by nerve injury.

• Authors: Shao-Rui Chen, Hong-Yi Zhou, Hee Sun Byun, Hong Chen, Hui-Lin Pan
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 350 Issue 2 Pg. 301-12 (Aug 2014) ISSN: 1521-0103 [Electronic] United States
• PMID: 24898266 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Receptors, N-Methyl-D-Aspartate
• Protein-Tyrosine Kinases
• Casein Kinase II
• Protein Kinase C
• Calcineurin

Topics

• Animals
• Calcineurin (physiology)
• Casein Kinase II (analysis, physiology)
• Diabetic Neuropathies (etiology)
• Hyperalgesia (etiology)
• Male
• Neuralgia (etiology)
• Peripheral Nerve Injuries (complications)
• Protein Kinase C (physiology)
• Protein-Tyrosine Kinases (physiology)
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (physiology)
• Spinal Cord (physiology)