The Role of Autophagy and Apoptosis in Neuropathic Pain Formation

Abstract

Neuropathic pain indicates pain caused by damage to the somatosensory system and is difficult to manage and treat. A new treatment strategy urgently needs to be developed. Both autophagy and apoptosis are critical adaptive mechanisms when neurons encounter stress or damage. Recent studies have shown that, after nerve damage, both autophagic and apoptotic activities in the injured nerve, dorsal root ganglia, and spinal dorsal horn change over time. Many studies have shown that upregulated autophagic activities may help myelin clearance, promote nerve regeneration, and attenuate pain behavior. On the other hand, there is no direct evidence that the inhibition of apoptotic activities in the injured neurons can attenuate pain behavior. Most studies have only shown that agents can simultaneously attenuate pain behavior and inhibit apoptotic activities in the injured dorsal root ganglia. Autophagy and apoptosis can crosstalk with each other through various proteins and proinflammatory cytokine expressions. Proinflammatory cytokines can promote both autophagic/apoptotic activities and neuropathic pain formation, whereas autophagy can inhibit proinflammatory cytokine activities and further attenuate pain behaviors. Thus, agents that can enhance autophagic activities but suppress apoptotic activities on the injured nerve and dorsal root ganglia can treat neuropathic pain. Here, we summarized the evolving changes in apoptotic and autophagic activities in the injured nerve, dorsal root ganglia, spinal cord, and brain after nerve damage. This review may help in further understanding the treatment strategy for neuropathic pain during nerve injury by modulating apoptotic/autophagic activities and proinflammatory cytokines in the nervous system.

Apoptosis and (in) Pain—Potential Clinical Implications

“…It should also be noted that apoptosis is also regulated by proinflammatory cytokines, such as Interferon gamma (IFN-g), tumor necrosis factor-α (TNF-α), interleukina-1 beta (IL-1 b), and IL-6 [ 35 ]. The roles of IL-1 and TNF- α in apoptosis in neurodegenerative diseases such as Alzheimer’s disease were previously described [ 35 , 36 ]. More importantly, it is known that these proinflammatory cytokines have crucial roles in the modulation of neuropathic pain [ 35 , 37 ].…”

“…The roles of IL-1 and TNF- α in apoptosis in neurodegenerative diseases such as Alzheimer’s disease were previously described [ 35 , 36 ]. More importantly, it is known that these proinflammatory cytokines have crucial roles in the modulation of neuropathic pain [ 35 , 37 ].…”

Expression Profiles of Circulating MicroRNAs in XELOX-Chemotherapy-Induced Peripheral Neuropathy in Patients with Advanced Gastric Cancer

“…Apoptosis plays significant roles in cancer, the immune system, and the response to chemotherapy [ 34 , 35 , 36 ]. Additionally, apoptosis participates in nerve injury and the formation of neuropathic pain [ 37 , 38 ]. However, the specific mechanism of the apoptosis in CIPN ought to be investigated in the future.…”

Interplay between exosomes and autophagy machinery in pain management: State of the art

“…In this era, proinflammatory cytokines can encourage autophagic/apoptotic function and subsequent NP formation. Autophagy per se quenches the proinflammatory cytokine activities and further modulates pain behavior ( Liao et al, 2022 ).…”

“…Similarly, these features in glial cells can contribute to worsening outcomes in NP ( Jang et al, 2016 ). It has been documented that autophagy modulation in the DRG neurons can relieve peripheral nerve pain and promote neuronal healing to some extent ( Liao et al, 2022 ). In a recent study, it was suggested that the production of nerve growth factor substantially accelerates debris clearance and improves axonal regeneration via the stimulation of autophagy in a rat model of sciatic nerve crush injury and in vitro Schwann cell culture ( Jadli et al, 2020 ).…”