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 NMDARmediated 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-b-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 dosedependently 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.

Protein kinase C gamma-mediated phosphorylation of GluA1 in the postsynaptic density of spinal dorsal horn neurons accompanies neuropathic pain, and dephosphorylation by calcineurin is associated with prolonged analgesia

“…Together with the recent demonstration that calcineurin also critically influenced the phosphorylation of NMDA receptors [2,5] our data indicate that the phosphatase may play a pivotal role in the regulation of the overall activity of ionotropic gluatamate receptors at synapses in the spinal dorsal horn.…”

Casein Kinase II RegulatesN-Methyl-d-Aspartate Receptor Activity in Spinal Cords and Pain Hypersensitivity Induced by Nerve Injury

“…Indeed, systemic administration of FK-506 can cause long-lasting pain hypersensitivity through potentiating NMDAR activity in the spinal dorsal horn . Thus, inhibition of CK2 and NMDAR function may reduce calcineurin inhibitor-induced pain syndrome Hu et al, 2014).…”

“…If CK2 controls NMDAR activity through phosphorylation, then inhibition of endogenous CK2 should prevent the calcineurin inhibitor FK-506 from potentiating the NMDAR activity in the spinal cord Hu et al, 2014). Indeed, concurrent treatment with FK-506 with DRB or TBB abolished the FK-506-induced potentiation of NMDAR-EPSCs in dorsal horn neurons of control rats (Fig.…”

CK2 in Organ Development, Physiology, and Homeostasis

“…The phosphorylation by CK2 of NMDA receptor and other proteins contributes to synaptic plasticity [ 37 ]. Because CK2 is involved in NMDA receptor regulation, and this receptor is required for pain hypersensitivity caused by immunosuppressants such as cyclosporine A, CK2 inhibition may help in reducing immunosuppressant-induced pain hypersensitivity [ 38 ].…”