NMDA Receptors at Primary Afferent–Excitatory Neuron Synapses Differentially Sustain Chemotherapy- and Nerve Trauma-Induced Chronic Pain

The Journal of Neuroscience, 2023 · DOI: https://doi.org/10.1523/JNEUROSCI.0183-23.2023 · Published: May 24, 2023

Simple Explanation

This study investigates how NMDARs, which are important for nerve pain, affect the communication between nerve cells in the spinal cord. The research shows that chemotherapy and nerve injuries increase NMDAR activity at synapses connecting primary afferent (sensory) and excitatory neurons, but not inhibitory neurons. The research indicates that NMDARs in sensory neurons are crucial for chemotherapy-induced pain, whereas postsynaptic NMDARs in spinal excitatory neurons are dominant in nerve trauma pain.

Study Duration

Not specified

Participants

C57BL/6 mice (8-14 weeks old, sex- and age-matched)

Evidence Level

Not specified

Key Findings

1
Paclitaxel treatment or spared nerve injury (SNI) similarly increased the NMDAR-mediated mEPSC frequency and dorsal root-evoked EPSCs in VGluT2 dorsal horn neurons.
2
Presynaptic NMDARs are required for chemotherapy-induced pain hypersensitivity, postsynaptic NMDARs in spinal excitatory neurons play a dominant role in traumatic nerve injury-induced chronic pain.
3
Traumatic nerve injury potentiates postsynaptic NMDAR activity in spinal VGluT2 neurons independently of NMDARs in primary sensory neurons.

Research Summary

This study demonstrates, for the first time, that chemotherapy and traumatic nerve injury preferentially enhance the NMDAR activity at primary afferent–excitatory neuron synapses but have no effect on primary afferent input to spinal inhibitory neurons. NMDARs in primary sensory neurons are essential for chemotherapy-induced chronic pain, whereas nerve trauma causes pain hypersensitivity predominantly via postsynaptic NMDARs in spinal excitatory neurons. Thus, presynaptic and postsynaptic NMDARs at primary afferent–excitatory neuron synapses are differentially engaged in chemotherapy- and nerve injury-induced chronic pain and could be targeted respectively for treating these painful conditions.

Practical Implications

Targeted Pain Treatment

Identifies specific NMDAR subtypes in different locations (presynaptic vs. postsynaptic) as potential targets for treating chemotherapy-induced vs. nerve injury-induced pain.

Cell-Specific Therapies

Suggests that therapies could be designed to target VGluT2-expressing excitatory neurons in the spinal dorsal horn for more effective pain management.

Understanding Neuropathic Pain

Provides a deeper understanding of the mechanistic differences in how different neuropathic pain conditions develop, specifically regarding the role of NMDARs.

Study Limitations

1
The study uses animal models, so the findings may not directly translate to humans.
2
The study focuses on specific types of neurons (VGluT2 and VGAT), and other cell types may also contribute to neuropathic pain.
3
The study doesn't fully elucidate the subtypes of DRG neurons synaptically connected to VGluT2 dorsal horn neurons.

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