Dysregulated Synaptic Plasticity in Chronic Pain: Molecular Mechanisms, Circuit Dysfunction, and Translational Approaches

Dear Colleagues,

Description

Chronic pain is increasingly recognized not just as a prolonged sensory state but as a disorder of maladaptive synaptic plasticity and dysfunctional neural circuits. Affecting over 20% of the global population, it disrupts quality of life and imposes a heavy socio-economic burden. While early studies focused on peripheral nociceptive pathways, growing evidence highlights central mechanisms including persistent alterations in glutamatergic signaling, the excitatory–inhibitory balance, and long-term potentiation/depression as key contributors to pain chronicity. This Special Issue aims to bring together cutting-edge research that elucidates the molecular and cellular mechanisms underlying synaptic plasticity in pain-related circuits, the resulting functional disruptions, and translational strategies to target these changes. We seek to foster interdisciplinary contributions that bridge basic mechanisms and potential therapeutic interventions, providing a platform for both emerging and established researchers to discuss novel insights and future directions in the field.

Goal

The goal of this Special Issue is to address the central role of dysregulated synaptic plasticity in the persistence and complexity of chronic pain. Despite advances in understanding peripheral mechanisms, effective long-term treatments remain elusive, in part due to our incomplete knowledge of how central circuits become and remain dysfunctional. By exploring changes in synaptic strength, receptor dynamics, intracellular signaling, and neural network connectivity, this Special Issue aims to uncover how pain reshapes the brain and spinal cord. Ultimately, the goal is to identify circuit-specific, mechanism-based strategies ranging from molecular therapies to neuromodulatory interventions that can reverse maladaptive plasticity and restore healthy function.

Background

Chronic pain arises from more than just injury or inflammation; it reflects long-lasting changes in the nervous system’s structure and function. At the core of this reorganization is synaptic plasticity, the process by which neurons adapt their communication strength. In pain circuits, plasticity can become maladaptive, amplifying pain signals and disrupting emotional and cognitive processes. This involves diverse mechanisms, including alterations in glutamate receptor signaling, changes in inhibitory control, neuroimmune interactions, and epigenetic reprogramming. These changes affect key brain regions such as the dorsal horn, thalamus, amygdala, and prefrontal cortex. Understanding these mechanisms is essential to advancing the development of precision-based therapeutics for chronic pain conditions.

Scope and Information for Authors

This Special Issue welcomes original research, reviews, mini-reviews, and perspectives that explore the molecular, synaptic, and circuit-level mechanisms underlying chronic pain. Key areas of interest include the following:

• Excitatory–inhibitory imbalance in pain circuits;
• Long-term potentiation/depression in nociceptive and affective pathways;
• Non-canonical glutamate receptor signaling and metaplasticity;
• Transcriptomic, proteomic, and epigenetic changes driving pain plasticity;
• Glial-neuronal interactions and neuroinflammation;
• Circuit-selective pharmacological, gene therapy, and neuromodulatory strategies;
• Biomarker discovery and precision medicine approaches;
• Integration of AI/machine learning in pain prediction and intervention.

We encourage contributions using innovative techniques such as optogenetics, chemogenetics, in vivo imaging, and computational modeling. Authors should aim to connect mechanistic insights to translational relevance, paving the way for future therapeutic developments.

Dr. Neeraj Soni
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

• chronic pain
• synaptic plasticity
• circuit dysfunction