Mechanisms of Central and Peripheral Sensitization in Neuropathic Pain: Insights into Neuronal Injury and Cellular Plasticity

Abstract

Neuropathic pain arises from injury or dysfunction within the somatosensory nervous system, leading to both central and peripheral sensitization. These mechanisms contribute significantly to the persistence and intensity of pain, characterized by spontaneous pain, hyperalgesia, and allodynia. Peripheral sensitization occurs at the site of injury due to increased responsiveness of primary sensory neurons, often driven by inflammatory mediators and changes in ion channel expression. Central sensitization, on the other hand, involves increased excitability of neurons within the spinal dorsal horn and higher brain centers, often due to long-lasting changes in synaptic plasticity. Key molecular pathways, including the activation of N-methyl-D-aspartate (NMDA) receptors, calcium signaling, and intracellular cascades like MAPK and NF-$\kappa$B, play a crucial role in maintaining these sensitized states. Additionally, the role of glial cells, particularly microglia and astrocytes, is increasingly recognized as critical in modulating both peripheral and central responses to nerve injury. This review explores the cellular and molecular mechanisms underlying central and peripheral sensitization in neuropathic pain, focusing on the interplay between neuronal injury and cellular plasticity. We discuss how these processes contribute to the transition from acute to chronic pain and highlight potential therapeutic targets aimed at modulating sensitization processes. By understanding these mechanisms, new therapeutic strategies can be developed to mitigate chronic pain and improve the quality of life for patients with neuropathic conditions.