Upregulation of Nuclear Factor of Activated T-Cells by Nerve Injury Contributes to Development of Neuropathic Pain

The Journal of Physiology

et al. 2013

Self Cite

122

Key points• We developed an animal model to study the mechanisms underlying the pain syndrome commonly seen in organ transplant patients receiving calcineurin inhibitors.• Systemic treatment with the calcineurin inhibitor induces long-lasting pain hypersensitivity and increases glutamate receptor activity in the spinal cord.• Blocking glutamate receptor activity at the spinal cord level effectively reduces pain hypersensitivity induced by the calcineurin inhibitor.• This information advances our understanding of the molecular basis of pain caused by calcineurin inhibitors and identifies new strategies for treating such pain syndrome in transplant patients.Abstract Calcineurin inhibitors, such as cyclosporin A and tacrolimus (FK506), have played a pivotal role in the preservation of allograft function. However, these drugs can cause unexplained severe pain in patients, often referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin can regulate NMDA receptor (NMDAR) activity, the causal relationship between spinal synaptic plasticity and CIPS remains unknown. In this study, we showed that systemic administration of FK506 (1.5 mg kg −1 day −1 ) for 7 days in rats led to long-lasting nociceptive and mechanical hypersensitivity. Whole-cell patch-clamp recordings in spinal cord slices revealed that FK506 treatment caused a large increase in the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation. The amplitude of NMDAR currents elicited by puff NMDA application to dorsal horn neurons was also significantly greater in FK506-treated than in vehicle-treated rats. The frequency of spontaneous and miniature EPSCs in most dorsal horn neurons was profoundly increased in FK506-treated rats and was reduced by blocking NMDARs. Furthermore, blocking GluN2A or GluN2B subunits similarly reduced the amplitude of evoked EPSCs and the frequency of miniature EPSCs in dorsal horn neurons of FK506-treated rats. In addition, intrathecal injection of an NMDAR antagonist or systemic administration of memantine effectively reversed nociceptive and mechanical hypersensitivity in FK506-treated rats. Our findings indicate that calcineurin inhibition increases glutamate-mediated nociceptive input by potentiating presynaptic and postsynaptic NMDAR activity in spinal cords. NMDAR antagonists may represent a new therapeutic option for the treatment of CIPS.

Section: Resultsmentioning

confidence: 99%

Calcineurin inhibitor induces pain hypersensitivity by potentiating pre‐ and postsynaptic NMDA receptor activity in spinal cords

The Journal of Physiology

et al. 2013

Self Cite

122

“…IEM-1460 was dissolved in normal saline and administered in a volume of 5 ml, followed by a 10-ml flush with normal saline. Intrathecal injection of normal saline has no effect on the tactile withdrawal threshold in SNL rats (Chen and Pan, 2005;Cai et al, 2013). In SNL rats, intrathecal injection of 5-20 mg of IEM-1460 dose-dependently increased the withdrawal threshold in response to von Frey filaments applied to the left hindpaw (n 5 8 rats in each group; Fig.…”

Section: Ampa Receptor Plasticity In Neuropathic Painmentioning

confidence: 98%

Nerve Injury Increases GluA2-Lacking AMPA Receptor Prevalence in Spinal Cords: Functional Significance and Signaling Mechanisms

The Journal of Pharmacology and Experimental Therapeutics

Zhou

Byun

et al. 2013

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The glutamate a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are critically involved in the excitatory synaptic transmission, and blocking AMPARs at the spinal level reverses neuropathic pain. However, little is known about changes in the composition of synaptic AMPARs in the spinal dorsal horn after peripheral nerve injury. AMPARs lacking the GluA2 subunit are permeable to Ca 21 , and their currents show unique inward rectification. We found that AMPARmediated excitatory postsynaptic currents (AMPAR-EPSCs) of spinal dorsal horn neurons exhibited a linear current-voltage relationship in control rats, whereas AMPAR-EPSCs of dorsal horn neurons displayed inward rectification in rats with spinal nerve injury. In nerve-injured rats, compared with control rats, the GluA2 protein level was significantly less in the plasma membrane but was greater in the cytosolic vesicle fraction in the dorsal spinal cord. However, the GluA1 protein levels in these fractions did not differ significantly between nerve-injured and control rats. Blocking N-methyl-D-aspartate receptors (NMDARs) abolished inward rectification of AMPAR-EPSCs of dorsal horn neurons in nerve-injured rats. Furthermore, inhibition of calpain or calcineurin, but not protein kinase C, completely blocked nerve injury-induced inward rectification of AMPAR-EPSCs of dorsal horn neurons. In addition, blocking GluA2-lacking AMPARs at the spinal cord level reduced nerve injury-induced pain hypersensitivity. Our study suggests that nerve injury increases GluA2 internalization and the prevalence of GluA2-lacking AMPARs in the spinal dorsal horn to maintain chronic neuropathic pain. Increased prevalence of spinal GluA2-lacking AMPARs in neuropathic pain is mediated by NMDARs and subsequent stimulation of calpain and calcineurin signaling.

“…2,31 Rotarod performance test was conducted using a rotarod accelerator treadmill (Med Associates Inc., USA) to determine motor function of rats as previously described. 32 The falling latency was measured from the start of the acceleration until the rat fell off the drum.…”

Section: Behavioral Assessment Of Nociceptionmentioning

confidence: 99%

α2δ-1–Bound N-Methyl-d-aspartate Receptors Mediate Morphine-induced Hyperalgesia and Analgesic Tolerance by Potentiating Glutamatergic Input in Rodents

Deng

et al. 2019

Anesthesiology

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Background: Chronic use of μ-opioid receptor agonists paradoxically causes both hyperalgesia and the loss of analgesic efficacy. Opioid treatment increases presynaptic N-methyl-d-aspartate receptor activity to potentiate nociceptive input to spinal dorsal horn neurons. However, the mechanism responsible for this opioid-induced activation of presynaptic N-methyl-d-aspartate receptors remains unclear. α2δ-1, formerly known as a calcium channel subunit, interacts with N-methyl-d-aspartate receptors and is primarily expressed at presynaptic terminals. This study tested the hypothesis that α2δ-1-bound N-methyl-d-aspartate receptors contribute to presynaptic N-methyl-d-aspartate receptor hyperactivity associated with opioid-induced hyperalgesia and analgesic tolerance.Methods: Rats (5 mg/kg) and wild-type and α2δ-1-knockout mice (10 mg/kg) were treated intraperitoneally with morphine twice/day for 8 consecutive days, and nociceptive thresholds were examined. Presynaptic N-methyl-d-aspartate receptor activity was recorded in spinal cord slices. Coimmunoprecipitation was performed to examine protein-protein interactions.Results: Chronic morphine treatment in rats increased α2δ-1 protein amounts in the dorsal root ganglion and spinal cord. Chronic morphine exposure also increased the physical interaction between α2δ-1 and N-methyl-d-aspartate receptors by 1.5 ± 0.3 fold (means ± SD, P = 0.009, n = 6) and the prevalence of α2δ-1-bound N-methyl-d-aspartate receptors at spinal cord synapses. Inhibiting α2δ-1 with gabapentin or genetic knockout of α2δ-1 abolished the increase in presynaptic N-methyl-d-aspartate receptor activity in the spinal dorsal horn induced by morphine treatment. Furthermore, uncoupling the α2δ-1-Nmethyl-d-aspartate receptor interaction with an α2δ-1 C terminus-interfering peptide fully reversed morphine-induced tonic activation of N-methyl-d-aspartate receptors at the central terminal of primary afferents. Finally, intraperitoneal injection of gabapentin or intrathecal injection of an α2δ-1 C terminus-interfering peptide or α2δ-1 genetic knockout abolished the mechanical and thermal hyperalgesia induced by chronic morphine exposure and largely preserved morphine's analgesic effect during 8 days of morphine treatment.conclusions: α2δ-1-Bound N-methyl-d-aspartate receptors contribute to opioid-induced hyperalgesia and tolerance by augmenting presynaptic N-methyl-d-aspartate receptor expression and activity at the spinal cord level. What We Already Know about This Topic• Presynaptic N-methyl-d-aspartate receptors contribute to opioid tolerance and hyperalgesia as well as neuropathic pain • The α2δ-1 protein subunit enhances presynaptic N-methyl-daspartate receptor activity What This Article Tells Us That Is New• Using mouse and rat models, it was demonstrated that α2δ-1 is essential for the increase in presynaptic N-methyl-d-aspartate receptor activity seen during chronic morphine exposure • Inhibiting α2δ-1 activity using gabapentin or genetically deleting the gene coding for α2δ-1 results in diminished o...