Abstract
Neuropathic pain (NP) is caused by lesions of the peripheral fibers and central neurons in the somatosensory nervous system and affects 7–10% of the general population. Although the distinct cause of neuropathic pain has been investigated in primary afferent neurons over the years, pain modulation by central sensitization remains controversial. NP is believed to be driven by cell type-specific spinal synaptic plasticity in the dorsal horn. Upon intense afferent stimulation, spinothalamic tract neurons are potentiated, whereas GABAergic interneurons are inhibited leading to long-term depression. Growing evidences suggest that the inhibition of GABAergic neurons plays pivotal roles in the manifestation of neuropathic and inflammatory pain states. Downregulation of GABA transmission and impairment of GABAergic interneurons in the dorsal horn are critical consequences after spinal cord and peripheral nerve injuries. These impairments in GABAergic interneurons may be associated with dysfunctional autophagy, resulting in neuropathic pain. Here, we review an emerging number of investigations that suggest a pivotal role of impaired autophagy of GABAergic interneurons in NP. We discuss relevant research spurring the development of new targets and therapeutic agents of NP and emphasize the need for a multidisciplinary approach to manage NP in the future.
Highlights
More than 20 million individuals have neuropathic pain (NP) worldwide and suffer from highly acute diseases, greater healthcare costs, and lower quality of life [1,2,3]
We demonstrated that brain-derived neurotrophic factor (BDNF) is expressed at higher levels in fat-1 mice, suggesting that BDNF and its associated proteins Akt and CREB, may be therapeutic targets for NP, because BDNF might be a neuroprotective factor by potentially upregulating autophagic flux activity
PINK1 is expressed in neurons in the spinal dorsal horn, but not in astrocytes or microglia [45]. us, we demonstrated that mitophagy may play a role in NP-related processes, but further studies are needed to clarify the function of mitophagy in NP, especially in GABAergic interneurons
Summary
More than 20 million individuals have neuropathic pain (NP) worldwide and suffer from highly acute diseases, greater healthcare costs, and lower quality of life [1,2,3]. L4 and L5 bilateral dorsal rhizotomy increases extracellular concentrations of excitatory amino acids in the dorsal horn and reduces the sensory glutamate-induced decreases in the expression of GABA-synthesizing enzymes and presynaptic inhibition [34, 35] Taken together, both autophagic impairment and ER stress contribute to dysfunction of dorsal horn GABAergic neurons in patients with NP. The levels of LC3 and Beclin 1 were significantly increased in GABAergic interneurons of the spinal dorsal horn following PNI [20]. Taken together, these studies suggest that autophagy is involved in the induction and maintenance of NP. The analysis of LC3, Beclin 1, and p62 indicates that impaired autophagy in CCI-induced NP may result from blocking the late phase, rather than the induction phase of autophagic flux
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