Investigating the Molecular Pathways of Neuronal Apoptosis and Necroptosis in Response to Peripheral Nerve Injury and Neuropathic Pain

Abstract

Neuropathic pain, a chronic pain state resulting from peripheral nerve injury, involves complex cellular and molecular mechanisms, including the activation of neuronal cell death pathways. Two major forms of programmed cell death—apoptosis and necroptosis—play critical roles in the progression of neuronal damage and the persistence of pain. Apoptosis, characterized by caspase activation and cellular shrinkage, serves as a controlled mechanism for eliminating damaged neurons, but its excessive activation can lead to significant neuronal loss in the dorsal root ganglia (DRG) and spinal cord. Necroptosis, a form of regulated necrosis driven by receptor-interacting protein kinases (RIPK1 and RIPK3), results in cell membrane rupture and the release of damage-associated molecular patterns (DAMPs) that can exacerbate inflammation and pain. The balance between apoptosis and necroptosis is influenced by various signaling pathways, including the tumor necrosis factor (TNF) signaling cascade, mitochondrial dysfunction, and the activation of the c-Jun N-terminal kinase (JNK) pathway. This review explores the molecular mechanisms underlying neuronal apoptosis and necroptosis in the context of peripheral nerve injury and neuropathic pain. We examine the roles of key regulatory proteins such as caspases, RIPKs, and mixed lineage kinase domain-like protein (MLKL) in driving these cell death processes. Additionally, we discuss potential therapeutic strategies targeting these pathways to preserve neuronal survival and alleviate chronic pain. Understanding the interplay between apoptosis and necroptosis in response to nerve injury may provide new insights into the development of treatments for neuropathic pain and improve outcomes for affected patients.