ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2020
Calcineurin Inhibition Causes α2δ-1-Mediated Tonic Activation of Synaptic NMDA Receptors and Pain Hypersensitivity.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 49 citations in OpenAlex.
- Sensory neuron BRAF mediates opioid-induced hyperalgesia and tolerance via presynaptic NMDA receptor hyperactivity.The Journal of clinical investigation · 2026Article
- Phytochemicals with potential NMDAR-inhibitory activities: a review of neuroprotective mechanisms against excitotoxicity.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2026Review
- Cardiac α2δ1 C-terminal contributes to left atrial hypertrophy in chronic ischemic heart failure, in association with changes in membrane GluN1 and p-CAMKII/p-HDAC4 signaling.Cell and tissue research · 2026Article
- HIV-1 gp120 Induces Nociceptive Hypersensitivity via α2δ-1-Bound NMDA Receptors at Primary Afferent→Excitatory Neuron Synapses.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Calcineurin inhibitor-induced pain syndrome: an uncommon side effect of immunosuppressive therapy after allogeneic hematopoietic stem cell transplant. a case report and review of the literature.Annals of hematology · 2026Review
- Molecular Partners of Voltage-Gated Calcium Channel β and αThe Journal of membrane biology · 2026Review
- Tonic GABA and Glycine Inhibition Control Pain Hypersensitivity via Limiting α2δ-1- and mGluR5-Dependent NMDA Receptor Activity at Primary Afferent→Excitatory Neuron Synapses.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- LRRC8A constitutively inhibits pain hypersensitivity in rodent models by restraining NMDA receptor activity at spinal cord synapses.Science translational medicine · 2025Article
- GαScience signaling · 2025Article
- Article
- α2δ-2 regulates synaptic GluK1 kainate receptors in Purkinje cells and motor coordination.Brain : a journal of neurology · 2025Article
- α2δ-1-Linked NMDA and AMPA Receptors in Neuropathic Pain and Gabapentinoid Action.Journal of neurochemistry · 2025Review
- A comprehensive review of the clinical presentation, diagnosis, and treatment of calcineurin inhibitor-induced pain syndrome.European journal of medical research · 2025Review
- Article
- Neuroplasticity in the transition from acute to chronic pain.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Calcineurin and CK2 Reciprocally Regulate Synaptic AMPA Receptor Phenotypes via α2δ-1 in Spinal Excitatory Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- The role of voltage-gated calcium channel α2δ-1 in the occurrence and development in myofascial orofacial pain.BMC oral health · 2024Article
- Quercetin alleviates chronic unpredictable mild stress-induced depression-like behavior by inhibiting NMDAR1 with α2δ-1 in rats.CNS neuroscience & therapeutics · 2024Article
- Constitutive KCC2 Cell- and Synapse-Specifically Regulates NMDA Receptor Activity in the Spinal Cord.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- [Tacrolimus Induces Pain by Upregulating the Synaptic Expression of AMPA Receptors in the Spinal Cord Dorsal Horn].Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2024Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2δ-1-GluN1 complexes in the spinal cord and the level of α2δ-1-bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2δ-1 with gabapentin or disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat peptide completely reversed the effects of FK506. In α2δ-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2δ-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2δ-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2δ-1-bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.