Molecular and Cellular Mechanisms Governing Axonal Degeneration and Synaptic Plasticity in the Context of Neuropathic Pain and Neuronal Injury

Abstract

Axonal degeneration and synaptic plasticity are critical processes underlying the pathophysiology of neuropathic pain and neuronal injury. Axonal degeneration involves a cascade of molecular events leading to the disintegration of axons following injury, contributing to the loss of neuronal connectivity and chronic pain. Concurrently, synaptic plasticity, including both structural and functional changes in synapses, plays a pivotal role in altering pain pathways, thereby facilitating the transition from acute to chronic pain states. These processes are regulated by complex interactions among signaling pathways, including Wallerian degeneration, calcium influx, activation of calpains, and mitochondrial dysfunction. Additionally, molecular pathways such as the ubiquitin-proteasome system (UPS), axonal transport mechanisms, and neurotrophic factors like brain-derived neurotrophic factor (BDNF) are key regulators of axonal integrity and synaptic modifications. In the context of neuropathic pain, maladaptive synaptic plasticity at the level of the dorsal horn and supraspinal structures leads to central sensitization, contributing to heightened pain sensitivity and persistent pain states. This review explores the molecular and cellular mechanisms governing axonal degeneration and synaptic plasticity, emphasizing their roles in the onset and maintenance of neuropathic pain. Understanding these mechanisms offers insights into potential therapeutic strategies aimed at preventing axonal degeneration, modulating synaptic changes, and ultimately improving outcomes for individuals suffering from neuropathic pain and neuronal injury. By targeting specific molecular pathways, it may be possible to attenuate chronic pain and enhance neuronal resilience, offering new avenues for the treatment of neuropathic conditions.