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

Abstract

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.

Streptozotocin-Induced Diabetic Neuropathic Pain Is Associated with Potentiated Calcium-Permeable AMPA Receptor Activity in the Spinal Cord

“…Diabetic Neuropathy Does Not Change Spinal NMDA Receptor Activity at Presynaptic and Postsynaptic Sites. NMDA receptors expressed presynaptically in the spinal cord are not activated under normal conditions but are spontaneously activated in neuropathic pain after peripheral nerve injury and treatment with calcineurin inhibitors and certain chemotherapeutics (Chen et al, 2014a(Chen et al, ,b, 2018Xie et al, 2016Xie et al, , 2017Deng et al, 2019). To determine whether painful diabetic neuropathy is associated with increased presynaptic NMDA receptor activity in the spinal dorsal horn, we first recorded mEPSCs of lamina II neurons, which represent glutamate release from presynaptic terminals (Chen et al, 2014a(Chen et al, , 2018, and examined the effect of blocking NMDA receptors with AP5.…”

“…Spinal cord NMDA receptors are generally thought to be central for neuropathic pain development (Zhou et al, 2011;Deng et al, 2019). For example, nerve ligation in rats potentiates the activity of both presynaptic and postsynaptic NMDA receptors in the spinal dorsal horn (Chen et al, 2014b(Chen et al, , 2018.…”

Distinct mechanisms of signal processing by lamina I spino-parabrachial neurons

“…NMDA receptors are expressed at primary afferent synapses on SPNs and also play an important role in a polysynaptic drive to these neurons 13,14 . To study whether the signal processing in the HO-SPNs depends on NMDA receptors, we analyzed effects of their specific blocker AP-5.…”

Capturing Novel Non-opioid Pain Targets

“…Peripheral axonal injury results in profound gene-expression changes in injured primary sensory neurons (40). One such change is upregulation of some analgesic target proteins such as the a2d subunit of calcium channels on which gabapentinoids act to reduce calcium channel trafficking to the membrane to reduce synaptic drive (41,42); another is an action on N-methyl D-aspartic acid receptors (43,44). The extent, nature, and duration of the changes in the nervous system underlying neuropathic pain represent a disease state of the nervous system (34,45).…”