title: 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.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Zhou
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Byun
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas huilinpan@mdanderson.org.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology; D047390:Casein Kinase II / Q000032:analysis / Q000502:physiology*; D003929:Diabetic Neuropathies / Q000209:etiology; D006930:Hyperalgesia / Q000209:etiology; D008297:Male; D009437:Neuralgia / Q000209:etiology*; D059348:Peripheral Nerve Injuries / Q000150:complications*; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D011505:Protein-Tyrosine Kinases; D047390:Casein Kinase II; D011493:Protein Kinase C; D019703:Calcineurin