Cellular and Molecular Life Sciences

, Volume 76, Issue 10, pp 1889–1899 | Cite as

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

  • Meichun Deng
  • Shao-Rui Chen
  • Hui-Lin PanEmail author


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.


Calcineurin K+–Cl cotransporter-2 Synaptic plasticity Dorsal root ganglion Gabapentin Pregabalin 



2-Amino-5-phosphonopentanoic acid


Complete Freund’s adjuvant


Calcineurin inhibitor-induced pain syndrome


Dorsal root ganglion


Excitatory postsynaptic current


Miniature excitatory postsynaptic current


N-Methyl-d-aspartate receptor


Protein kinase C



Work conducted in the authors’ laboratory was funded by the National Institutes of Health (Grants R01 GM120844 and R01 NS101880).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.


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Authors and Affiliations

  1. 1.Department of Anesthesiology and Perioperative Medicine, Center for Neuroscience and Pain ResearchThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Biochemistry and Molecular Biology, School of Life SciencesCentral South UniversityChangshaChina

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