Integrative Mechanisms and Translational Outcomes of Excitatory–Inhibitory Neurotransmission Switching in Neuropathic Pain
A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".
Deadline for manuscript submissions: 31 May 2026 | Viewed by 22
Special Issue Editor
2. National Coalition of Independent Scholars (NCIS), Brattleboro, VT 05301, USA
Interests: integrative medicine; neurophysiology; neuropsychiatry; omics; neuroinflammation; neural circuit plasticity; translational biomarkers; computational neuroscience
Special Issues, Collections and Topics in MDPI journals
Special Issue Information
Dear Colleagues,
Unified understanding of neuropathic pain remains incomplete. Notwithstanding, converging evidence suggests a transition from acute to chronic neuropathic pain takes place through the maladaptive disruption of excitatory–inhibitory (E/I) neurotransmission balance (defined as the ratio of excitatory versus inhibitory signaling) across molecular, cellular, and circuit levels. Basic studies show that peripheral nerve injury triggers the microglial release of BDNF, which in turn downregulates KCC2 and reduces GABAergic inhibition. The outcome of this process is the conversion of inhibitory inputs from GABAergic interneurons into excitatory output from dorsal horn projection neurons, thereby enhancing nociceptive signaling and the experience of pain. The structural remodeling of spinal dorsal horn circuits, including the selective pruning of GABAergic inhibitory synapses, further shifts the E/I balance, as demonstrated by Copeland and colleagues (2021). Circuit-level and supraspinal investigations have further revealed altered E/I ratios in emotion neural networks, such as the prefrontal cortex and amygdala, which in turn contribute to persistent hyperexcitability and negative affect, as summarized by Llorca-Torralba and colleagues (2022) and Prescott (2020). Experimental optogenetic studies and complementary computational modeling highlight dynamic state transitions that may underlie broader neurotransmission switching mechanisms.
Recent work continues to advance and refine our understanding with elegant experimentation. Wong and colleagues (2024) identified distinct roles of mTORC2 signaling in excitatory versus inhibitory neurons in neuropathic pain models, emphasizing molecular switches that regulate E/I balance. Gil Ávila and colleagues (2025) quantified the E/I balance non-invasively using human EEG, demonstrating its potential as a translational biomarker. Beckers and colleagues (2024) identified the cystine–glutamate exchanger (system xc−) as a modulator of neuroinflammation and elevated glutamatergic signaling, which may contribute to neuronal hyperexcitability in pain pathways and experience. Tian and colleagues (2025) report that botulinum toxin A reduces neuropathic pain through the suppression of microglial pyroptosis. Moreover, Liu and colleagues (2025) demonstrated that FGF8–FGFR3 signaling in astrocytes reduces neurotoxicity in dorsal horn neurons, suggesting a potential intervention to restore inhibitory tone. Collectively, these findings highlight specific molecular, cellular, and glial pathways as potential targets to enhance inhibitory tone, rebalance E/I neurotransmission ratios, and ameliorate the maladaptive circuit reorganization that sustains neuropathic pain.
This Special Issue has an integrative and multiscale scope that welcomes interdisciplinary contributions in line with the above. Researchers working with preclinical models are invited to submit work on molecular, synaptic, and circuit-level mechanisms that define or reconfigure the E/I ratio balance. Clinical and applied science researchers are encouraged to contribute studies on correlates, biomarkers, and system-level dysfunction in humans, including neuroimaging, electrophysiology, and behavioral phenotypes. Computational and AI researchers are welcomed for their value in developing models of neurotransmission switching, the integration of multiscale datasets, and mechanistic inferences where invasive measurements/data collection are not presently feasible.
Dr. Poppy Schoenberg
Guest Editor
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Keywords
- neuropathic pain
- excitatory–inhibitory balance (E/I balance)
- neurotransmission switching
- microglia
- spinal dorsal horn
- circuit remodeling
- translational biomarkers
- computational modeling
- glutamatergic signaling
- neuromodulation
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