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.
Highlights
Neuropathic pain is induced by damage to the somatosensory nervous system [1].Neuropathic pain is difficult to manage, and epidemiological studies have shown that the prevalence of neuropathic pain ranges from 3 to 17% [2–4]
Many studies that used different animal models (including chronic constriction injury (CCI), sciatic nerve transection (SNT), spinal nerve ligation (SNL), and sciatic nerve crush injury (SNC)) have shown consistent results that the elevated autophagic activities are measured by different autophagic proteins (Beclin-1, autophagy-related protein 5 (Atg5), Atg7, LC3II) in the injured nerve axons, Schwann cells, and dorsal root ganglia from 6 h to 21 days after nerve injury [23–29]
We found that granulocyte-colony-stimulating factor (G-CSF) treatment can suppress pain behavior, upregulate autophagic activities, suppress proinflammatory cytokine expression, and downregulate apoptotic activities in the injured nerve and dorsal root ganglia
Summary
Neuropathic pain is induced by damage to the somatosensory nervous system [1]. Neuropathic pain is difficult to manage, and epidemiological studies have shown that the prevalence of neuropathic pain ranges from 3 to 17% [2–4]. Studies have found that different interventions, including medicines and hyperbaric oxygen therapy, can simultaneously attenuate neuropathic pain and suppress apoptotic activities in the dorsal root ganglia or spinal cord [14,15,19–22]. Many studies with different animal models have shown changed autophagic activities in the injured nerve [23–29], spinal cord [30–42], and even brain [43] after nerve injury. These studies showed that upregulated autophagic activities can directly alleviate neuropathic pain [24,26,27,32,33,37,38]. We will discuss autophagic/apoptotic activity changes and their interactions with proinflammatory cytokines based on the different anatomical locations of the nervous system, including the injured nerve, Schwann cells, dorsal root ganglion, spinal cord, and brain. We will summarize the alteration of pain behaviors after modulating autophagic/apoptotic activities
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