Calcineurin-inhibitor induced pain syndrome after organ transplantation

Collini, Andrea; Bartolomeis, Carmine De; Barni, Roberto; Ruggieri, Giuliana; Bernini, Marco; Carmellini, Mario

doi:10.1038/sj.ki.5001833

Cited by 50 publications

(55 citation statements)

References 17 publications

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“…In addition, calcineurin inhibitors, such as cyclosporin A and FK-506 (tacrolimus), are the most commonly used immunosuppressive drugs to prevent the rejection of transplanted organs and tissues. However, these drugs can cause unexplained persistent pain and pain hypersensitivity, often referred to as calcineurin inhibitor-induced pain syndrome (Grotz et al, 2001;Collini et al, 2006). Indeed, systemic administration of FK-506 can cause long-lasting pain hypersensitivity through potentiating NMDAR activity in the spinal dorsal horn .…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Zhou

Byun

et al. 2014

J Pharmacol Exp Ther

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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 CK2a and CK2b protein levels in the spinal cord. In addition, inhibition of CK2 or CK2b 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.

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Section: Discussionmentioning

confidence: 99%

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

Chen

Zhou

Byun

et al. 2014

J Pharmacol Exp Ther

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“…Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine A, are commonly used immunosuppressants and have greatly improved the long-term survival of patients after organ and tissue transplantation. However, these drugs can result in unexplained severe pain and pain hypersensitivity, clinically known as calcineurin inhibitor-induced pain syndrome (CIPS) (Grotz et al, 2001;Collini et al, 2006;Noda et al, 2008;Kakihana et al, 2012). CIPS predominantly affects the lower limbs, and the pain is particularly excruciating during standing and walking (Grotz et al, 2001;Fujii et al, 2006;Noda et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Casein Kinase II Inhibition Reverses Pain Hypersensitivity and Potentiated Spinal N-Methyl-d-aspartate Receptor Activity Caused by Calcineurin Inhibitor

Chen

et al. 2014

J Pharmacol Exp Ther

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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.

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“…5,9,10 Those reports suggest that the effects of calcineurin inhibition on vascular tone play an important role in the development of CIPS. 8 However, only one patient received diltiazem in our study, and thus, we could not assess the efficacy of calcium channel blockers for CIPS in the setting of allo-HSCT. This study confirmed that discontinuation, dose reduction, or switching to another CI is effective for management of CIPS.…”

Section: Discussionmentioning

confidence: 96%

Clinical characteristics of calcineurin inhibitor-induced pain syndrome (CIPS) after allogeneic hematopoietic stem cell transplantation

Doki

Kakihana

Ashizawa

et al. 2017

Journal of Hematopoietic Cell Transplantation

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Calcineurin inhibitor CI -induced pain syndrome CIPS was first described in an organ transplant recipient in 1991, 1 and has been subsequently reported among patients undergoing allogeneic hematopoietic stem cell transplantation allo-HSCT . [2][3][4] The characteristic clinical features of CIPS include severe pain localized in the bilateral lower limbs, elevated CI trough levels at the onset, lack of response to common analgesics, bone marrow edema as seen with magnetic resonance imaging, and increased uptake as seen with bone scintigraphy. Calcineurin inhibitor(CI) -induced pain syndrome(CIPS)is a rare complication after allogeneic hematopoietic stem cell transplantation(allo-HSCT) . However, because of its rarity, the optimal management of this complication remains unknown. We analyzed the clinical features and treatment outcomes of the patients who developed CIPS after allo-HSCT. The study included patients who underwent allo-HSCT between January 2003 and December 2014 at the hospitals participating in the KSGCT. Sixteen patients developed CIPS. The most common symptom was leg pain, which was observed in 9 patients, followed by leg pain associated with pruritus in five, and pruritus only in two. The median time from allo-HSCT to CIPS was 16 days. CIPS occurred within 30 days of starting CIs in 14 patients(87.5%) . CI was discontinued in four patients; the dose of CI was reduced in two patients, and seven patients were switched to another CI. The symptoms in all of those 13 patients with intervention resolved within 6 days from the onset of CIPS. The possibility of CIPS must be considered when patients who have undergone allo-HSCT develop intolerable leg pain and／or pruritus. Our findings suggest that withdrawal／dose reduction of the CI or substitution with another CI is an effective treatment for

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Calcineurin-inhibitor induced pain syndrome after organ transplantation

Cited by 50 publications

References 17 publications

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

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

Casein Kinase II Inhibition Reverses Pain Hypersensitivity and Potentiated Spinal N-Methyl-d-aspartate Receptor Activity Caused by Calcineurin Inhibitor

Clinical characteristics of calcineurin inhibitor-induced pain syndrome (CIPS) after allogeneic hematopoietic stem cell transplantation

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