title: Casein kinase II inhibition reverses pain hypersensitivity and potentiated spinal N-methyl-D-aspartate receptor activity caused by calcineurin inhibitor.
abstract: Clinically used calcineurin inhibitors, including tacrolimus (FK506) and cyclosporine A, can induce calcineurin inhibitor-induced pain syndrome (CIPS), which is characterized as severe pain and pain hypersensitivity. Increased synaptic N-methyl-D-aspartate receptor (NMDAR) activity in the spinal dorsal horn plays a critical role in the development of CIPS. Casein kinase II (CK2), a serine/threonine protein kinase, can regulate synaptic NMDAR activity in the brain. In this study, we determined whether spinal CK2 is involved in increased NMDAR activity and pain hypersensitivity caused by systemic administration of FK506 in rats. FK506 treatment caused a large increase in the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) evoked by primary afferent stimulation and in the frequency of miniature EPSCs of spinal dorsal horn neurons. CK2 inhibition with either 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB) or 4,5,6,7-tetrabromobenzotriazole (TBB) completely normalized the amplitude of evoked NMDAR-EPSCs of dorsal horn neurons in FK506-treated rats. In addition, DRB or TBB significantly attenuated the amplitude of NMDAR currents elicited by puff application of N-methyl-D-aspartate to dorsal horn neurons in FK506-treated rats. Furthermore, treatment with DRB or TBB significantly reduced the frequency of miniature EPSCs of spinal dorsal horn neurons increased by FK506 treatment. In addition, intrathecal injection of DRB or TBB dose-dependently reversed tactile allodynia and mechanical hyperalgesia in FK506-treated rats. Collectively, our findings indicate that CK2 inhibition abrogates pain hypersensitivity and increased pre- and postsynaptic NMDAR activity in the spinal cord caused by calcineurin inhibitors. CK2 inhibitors may represent a new therapeutic option for the treatment of CIPS.
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine (Y.-M.H., S.-R.C., H.C., H.-L.P.), The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Anesthesiology (Y.-M.H.), Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, Peoples Republic of China.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Hu
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000818:Animals; D065095:Calcineurin Inhibitors; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology / Q000627:therapeutic use; D019706:Excitatory Postsynaptic Potentials; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D055369:Miniature Postsynaptic Potentials; D016202:N-Methylaspartate / Q000502:physiology*; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000378:metabolism / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism* / Q000503:physiopathology; D016559:Tacrolimus / Q000009:adverse effects*; D014110:Touch; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C405354:4,5,6,7-tetrabromobenzotriazole; D065095:Calcineurin Inhibitors; D014230:Triazoles; D004004:Dichlororibofuranosylbenzimidazole; D016202:N-Methylaspartate; D047390:Casein Kinase II; D016559:Tacrolimus