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.

Keywords: apoptosis; autophagy; neuropathic pain; proinflammatory cytokines.

Figure 1

Crosstalk between autophagy, apoptosis, and proinflammatory cytokines during neuropathic pain formation. Autophagy plays an important role in inflammation and proinflammatory cytokine regulation. Furthermore, proinflammatory cytokines directly influence apoptosis in non-neuronal cells and probably neurons of the central nervous system. The crosstalk or interaction of autophagy and apoptosis in neuropathic pain formation occurs mainly through the modulation of proinflammatory cytokines. (Blue lines: activation; Red lines: inhibition).

Figure 2

Schematic diagram showing the underlying mechanisms of autophagic and apoptotic activities in the nerve injury. Summary of autophagic/apoptotic activity changes in the injured axon, Schwann cell, spinal dorsal horn, and brain after nerve injury, and the effects after modulating autophagic/apoptotic and proinflammatory cytokines activities after nerve injury. (CCI: chronic constriction injury, SCI: spinal cord injury, SNC: sciatic nerve crush injury, SNI: spared nerve injury, SNL: spinal nerve ligation, ↑: activities increase, ↓: activities decrease, -: activities do not change. *: studies showed that autophagy is a pain inducer.).