Increased Presynaptic and Postsynaptic α<sub>2</sub>-Adrenoceptor Activity in the Spinal Dorsal Horn in Painful Diabetic Neuropathy

et al. 2017

Neuropharmacology

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Chemotherapeutic drugs, including bortezomib, often cause painful peripheral neuropathy, which is a severe dose-limiting adverse effect experienced by many cancer patients. The glutamate N-methyl-D-aspartate receptors (NMDARs) at the spinal cord level are critically involved in the synaptic plasticity associated with neuropathic pain. In this study, we determined whether treatment with bortezomib, a proteasome inhibitor, affects the NMDAR activity of spinal dorsal horn neurons. Systemic treatment with bortezomib in rats did not significantly affect postsynaptic NMDAR currents elicited by puff application of NMDA directly to dorsal horn neurons. Bortezomib treatment markedly increased the baseline frequency of miniature excitatory postsynaptic currents (EPSCs), which was completely normalized by the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5). AP5 also reduced the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation in bortezomib-treated, but not vehicle-treated, rats. Furthermore, inhibition of protein kinase C (PKC) with chelerythrine fully reversed the increased frequency of miniature EPSCs and the amplitude of evoked EPSCs in bortezomib-treated rats. Intrathecal injection of AP5 and chelerythrine both profoundly attenuated mechanical allodynia and hyperalgesia induced by systemic treatment with bortezomib. In addition, treatment with bortezomib induced striking membrane translocation of PKC-βII, PKC-δ, and PKC-ε in the dorsal root ganglion. Our findings indicate that bortezomib treatment potentiates nociceptive input from primary afferent nerves via PKC-mediated tonic activation of presynaptic NMDARs. Targeting presynaptic NMDARs and PKC at the spinal cord level may be an effective strategy for treating chemotherapy-induced neuropathic pain.

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord

Xie

et al. 2017

Neuropharmacology

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“…To activate the device, we pressed a foot pedal to activate a motor that applied a constantly increasing force on a linear scale. When the animal displayed pain by either withdrawing of the paw or vocalizing, the pedal was immediately released, and the animal's nociceptive threshold on the scale was recorded (9,46).…”

Section: Methodsmentioning

confidence: 99%

Presynaptic N-Methyl-d-aspartate (NMDA) Receptor Activity Is Increased Through Protein Kinase C in Paclitaxel-induced Neuropathic Pain

Xie

Journal of Biological Chemistry

et al. 2016

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Painful peripheral neuropathy is a severe adverse effect of chemotherapeutic drugs such as paclitaxel (Taxol). The glutamate N-methyl-D-aspartate receptors (NMDARs) are critically involved in the synaptic plasticity associated with neuropathic pain. However, paclitaxel treatment does not alter the postsynaptic NMDAR activity of spinal dorsal horn neurons. In this study, we determined whether paclitaxel affects presynaptic NMDAR activity by recording excitatory postsynaptic currents (EPSCs) of dorsal horn neurons in spinal cord slices. In paclitaxel-treated rats, the baseline frequency of miniature EPSCs (mEPSCs) was significantly increased; the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5) completely normalized this frequency. Also, AP5 significantly reduced the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation and reversed the reduction in the paired-pulse ratio of evoked EPSCs in paclitaxel-treated rats. Blocking GluN2A-containing, but not GluN2B-containing, NMDARs largely decreased the frequency of mEPSCs and the amplitude of evoked EPSCs of dorsal horn neurons in paclitaxel-treated rats. Furthermore, inhibition of protein kinase C fully reversed the increased frequency of mEPSCs and the amplitude of evoked EPSCs in paclitaxel-treated rats. Paclitaxel treatment significantly increased the protein level of GluN2A and phosphorylated GluN1 in the dorsal root ganglion. In addition, intrathecal injection of AP5 or systemic administration of memantine profoundly attenuated pain hypersensitivity induced by paclitaxel. Our findings indicate that paclitaxel treatment induces tonic activation of presynaptic NMDARs in the spinal cord through protein kinase C to potentiate nociceptive input from primary afferent nerves. Targeting presynaptic NMDARs at the spinal cord level may be an effective strategy for treating chemotherapy-induced neuropathic pain.The severe neuropathic pain caused by many effective chemotherapeutic agents, including paclitaxel (Taxol), bortezomib, oxaliplatin, and vincristine, is often the reason for discontinuation of what is otherwise life-saving therapy (1). Paclitaxel, which acts by stabilizing the microtubule cytoskeleton against depolymerization, is widely used to treat patients with breast, lung, ovarian, and other types of solid cancers. The peripheral neuropathy induced by paclitaxel treatment is frequently associated with burning pain, tingling, and numbness in the feet and hands (2-4). Such conditions are chronic and respond poorly to standard analgesics such as opioids, anticonvulsants, and antidepressants (1). Paclitaxel treatment can also damage primary afferent nerves and neurons in the dorsal root ganglion (DRG) 3 (5-7). However, the molecular mechanisms responsible for the increased nociceptive input in paclitaxelinduced neuropathic pain are not fully known.The glutamate N-methyl-D-aspartate receptors (NMDARs) are tetramers that contain two essential GluN1 subunits co-assembled with two GluN2 and/or GluN3 subunits, and GluN2 subunits are required for gluta...

“…Lamina II of the spinal cord is the central site of termination of the majority of unmyelinated C-fibers carrying nociceptive information (20 -22). Excitatory postsynaptic currents (EPSCs) were recorded using whole-cell voltage clamp techniques (14,23). The impedance of the glass electrode was 4 -7 M⍀ when the pipette was filled with the internal solution containing (in mM) 135 potassium gluconate, 5 KCl, 2.0 MgCl 2 , 0.5 CaCl 2 , 5.0 HEPES, 5.0 EGTA, 5.0 ATP-Mg, 0.5 Na-GTP, and 10 QX314 (adjusted to pH 7.25 with 1.0 M CsOH, 280 -300 mosM).…”

Section: Removal Of Trpv1-expressing Dorsal Root Ganglion Neurons Andmentioning

confidence: 99%

Chronic Opioid Potentiates Presynaptic but Impairs Postsynaptic N-Methyl-d-aspartic Acid Receptor Activity in Spinal Cords

Zhao

Journal of Biological Chemistry

et al. 2012

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116

Background:We determined the role of presynaptic N-methyl-D-aspartate receptor (NMDAR) activity in spinal cords in opioid-induced hyperalgesia and tolerance. Results: Chronic opioid increases presynaptic NMDAR activity at primary sensory nerve terminals through protein kinase C. Conclusion: Increased presynaptic NMDAR activity potentiates nociceptive input and is responsible for opioid hyperalgesia and tolerance. Significance: Understanding mechanisms of increased NMDAR activity is important for improving opioid therapies.