Endogenous transient receptor potential ankyrin 1 and vanilloid 1 activity potentiates glutamatergic input to spinal lamina I neurons in inflammatory pain

Huang, Yuying; Chen, Shao Rui; Chen, Hong; Pan, Hui Lin

doi:10.1111/jnc.14677

Cited by 40 publications

(28 citation statements)

References 71 publications

(96 reference statements)

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“…However, bath application of AP5 has no effect on the CFA-induced increase in the frequency of spontaneous EPSCs in lamina I neurons. Furthermore, the amplitude of puff NMDA currents in lamina I neurons is similar in vehicle-and CFA-treated rats [76]. These findings suggest that chronic inflammatory pain is not associated with an increase in presynaptic or postsynaptic NMDAR activity in the spinal dorsal horn.…”

Section: Chronic Inflammatory Pain Is Not Associated With Increased Pmentioning

confidence: 63%

“…A recent study examined changes in presynaptic and postsynaptic NMDAR activity of spinal dorsal horn neurons in rats 10−16 days after induction of tissue inflammation with complete Freund's adjuvant (CFA). Interestingly, the glutamatergic input, measured by the frequency of mEPSCs and spontaneous EPSCs, is markedly increased in lamina I, but not lamina II, neurons in CFAtreated rats [76]. However, bath application of AP5 has no effect on the CFA-induced increase in the frequency of spontaneous EPSCs in lamina I neurons.…”

Section: Chronic Inflammatory Pain Is Not Associated With Increased Pmentioning

confidence: 88%

“…These findings suggest that chronic inflammatory pain is not associated with an increase in presynaptic or postsynaptic NMDAR activity in the spinal dorsal horn. Instead, presynaptic TRPA1 and TRPV1 channels play a major role in the augmented glutamatergic input to spinal lamina I neurons in chronic inflammatory pain [76]. It has been shown that CFA-induced pain hypersensitivity in the hindpaw is attenuated only for the first 2 days in mice in which spinal cord GluN1 is ablated [77].…”

Section: Chronic Inflammatory Pain Is Not Associated With Increased Pmentioning

confidence: 99%

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Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain

Deng

Chen

Pan

2019

Cell. Mol. Life Sci.

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Chronic neuropathic pain is a debilitating condition that remains challenging to treat. Glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been used to treat neuropathic pain, but the exact sites of their actions have been unclear until recently. Although conventionally postsynaptic, NMDARs are also expressed presynaptically, particularly at the central terminals of primary sensory neurons, in the spinal dorsal horn. However, presynaptic NMDARs in the spinal cord are normally quiescent and are not actively involved in physiological nociceptive transmission. In this review, we describe the emerging role of presynaptic NMDARs at the spinal cord level in chronic neuropathic pain and the implications of molecular mechanisms for more effective treatment. Recent studies indicate that presynaptic NMDAR activity at the spinal cord level is increased in several neuropathic pain conditions but not in chronic inflammatory pain. Increased presynaptic NMDAR activity can potentiate glutamate release from primary afferent terminals to spinal dorsal horn neurons, which is crucial for the synaptic plasticity associated with neuropathic pain caused by traumatic nerve injury and chemotherapy-induced peripheral neuropathy. Furthermore, α2δ-1, previously considered a calcium channel subunit, can directly interact with NMDARs through its C-terminus to increase presynaptic NMDAR activity by facilitating synaptic trafficking of α2δ-1-NMDAR complexes in neuropathic pain caused by chemotherapeutic agents and peripheral nerve injury. Targeting α2δ-1-bound NMDARs with gabapentinoids or α2δ-1 C-terminus peptides can attenuate nociceptive drive form primary sensory nerves to dorsal horn neurons in neuropathic pain.

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Section: Chronic Inflammatory Pain Is Not Associated With Increased Pmentioning

confidence: 63%

Section: Chronic Inflammatory Pain Is Not Associated With Increased Pmentioning

confidence: 88%

Section: Chronic Inflammatory Pain Is Not Associated With Increased Pmentioning

confidence: 99%

See 1 more Smart Citation

Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain

Deng

Chen

Pan

2019

Cell. Mol. Life Sci.

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“…We recorded lamina II outer neurons identified using infrared illumination and differential interference contrast under a microscope. EPSCs were recorded using whole-cell patch clamp at a holding potential of À60 mV (S. R. Chen et al, 2014b;Huang et al, 2019). The glass pipette electrode (4-7 MV) was filled with the internal solution containing the following (in mM): 135 K-gluconate, 5 KCl, 2 MgCl 2 , 0.5 CaCl 2 , 5 EGTA, 5 HEPES, 0.5 Na 2 -GTP, 5 Mg-ATP, and 10 lidocaine N-ethyl bromide (QX314; 280-300 mOsm, pH 7.3).…”

Section: Electrophysiological Recordings In Spinal Cord Slicesmentioning

confidence: 99%

Calcineurin Inhibition Causes α2δ-1–Mediated Tonic Activation of Synaptic NMDA Receptors and Pain Hypersensitivity

Huang

Chen

et al. 2020

J. Neurosci.

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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 a2d-1-GluN1 complexes in the spinal cord and the level of a2d-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 a2d-1 with gabapentin or disrupting the a2d-1-NMDAR interaction with a2d-1Tat peptide completely reversed the effects of FK506. In a2d-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDARmediated 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 a2d-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or a2d-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that a2d-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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“…Exemplos de tais receptores incluem a família de canais iônicos de potencial de receptor transitório (TRPtransient receptor potential) -TRPV1, TRPV2, TRPV3 e TRPV4 (Nishida et al, 2015;Huang et al, 2019), canais de sódio -NaV1.1, NaV1.3, NaV1.6, NaV1.7, NaV1.8 e NaV1.9 (Wood et al, 2004;Priestley, 2017), receptores purinérgicos ionotrópicos ativados por trifosfato de adenosina (Borea et al, 2018) e membros da família de receptores associados à proteína G relacionados ao Mas (Mrg -Mas-related G protein-coupled receptor) que são ativados por ligandos peptídicos (Tiwari et al, 2016;Li et al, 2017).…”

Section: Neurobiologia Da Dorunclassified

Papel da via succinato/GPR91 no desenvolvimento da dor neuropática induzida por paclitaxel

Gomes¹

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Endogenous transient receptor potential ankyrin 1 and vanilloid 1 activity potentiates glutamatergic input to spinal lamina I neurons in inflammatory pain

Cited by 40 publications

References 71 publications

Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain

Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain

Calcineurin Inhibition Causes α2δ-1–Mediated Tonic Activation of Synaptic NMDA Receptors and Pain Hypersensitivity

Papel da via succinato/GPR91 no desenvolvimento da dor neuropática induzida por paclitaxel

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