Endoplasmic reticulum stress impairment in the spinal dorsal horn of a neuropathic pain model

Abstract

Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, but its role in neuropathic pain remains unclear. In this study, we examined the ER stress and the unfolded protein response (UPR) activation in a L5 spinal nerve ligation (SNL)-induced rat neuropathic pain model. SNL-induced neuropathic pain was assessed behaviorally using the CatWalk system, and histologically with microglial activation in the dorsal spinal horn. L5 SNL induced BIP upregulation in the neuron of superficial laminae of dorsal spinal horn. It also increased the level of ATF6 and intracellular localization into the nuclei in the neurons. Moreover, spliced XBP1 was also markedly elevated in the ipsilateral spinal dorsal horn. The PERK-elF2 pathway was activated in astrocytes of the spinal dorsal horn in the SNL model. In addition, electron microscopy revealed the presence of swollen cisternae in the dorsal spinal cord after SNL. Additionally, inhibition of the ATF6 pathway by intrathecal treatment with ATF6 siRNA reduced pain behaviors and BIP expression in the dorsal horn. The results suggest that ER stress might be involved in the induction and maintenance of neuropathic pain. Furthermore, a disturbance in UPR signaling may render the spinal neurons vulnerable to peripheral nerve injury or neuropathic pain stimuli.

Standardized Profiling of The Membrane-Enriched Proteome of Mouse Dorsal Root Ganglia (DRG) Provides Novel Insights Into Chronic Pain

“…Here, we report highly reproducible DIA-proteome profiling of 2526 proteins, which granted unique insights into significant alterations of candidate proteins belonging to distinct cellular signaling networks. These data are not only in agreement with previous studies implicating mitochondrial (33, 80 -82) and ER (77,79,83) abnormalities in neuropathic pain, but importantly (i) identify affected members of these protein networks and (ii) provide evidence for their differential involvement also in inflammatory pain. Indeed, we could demonstrate attenuation of fully established chronic inflammatory pain by application of mitochondrial complex I or protein disulfide isomerase inhibitors in vivo.…”

“…This is in stark contrast to the emerging importance of "network medicine" as a powerful strategy to correct functional misalignments of complex cellular processes (2,76,95). Consequently, it might provide promising tools for achieving analgesia as exemplified by studies linking mitochondrial dysfunction (33, 80 -82) and ER stress to neuropathic pain (77,79,83). However, the underlying molecular changes and altered proteins are only scarcely understood preventing the design of targeted interventions with therapeutic potential.…”

“…Similarly, mitochondrial fission represents a crucial step for cellular homeostasis and has recently been implicated in painful neuropathies brought on by cancer chemotherapy and anti-HIV medication (41). ER stress represents another significant driver of pain in diverse neuropathic models such as diabetic neuropathy (77,79,83). ER stress may be caused by a disequilibrium in ER homeostasis regarding protein demand, synthesis and folding.…”

“…Both cellular pathways are crucially interconnected determinants of apoptosis, energy metabolism as well as oxidative and ER stress (76 -79). Furthermore, the notion is evolving that mitochondrial abnormality (33, 80 -82) and ER stress (77,79,83) contribute to several forms of neuropathic pain. Mitochondrial dysfunction in painful conditions appears to be multifactorial as it may arise from changes in the activity of the electron transport chain (ETC) (33, 80 -82), a concomitant increase of reactive oxygen species leading to oxidative stress (84) or mitochondrial calcium handling (85).…”

Ryanodine Receptor 2 Plays a Critical Role in Spinal Cord Injury via Induction of Oxidative Stress

“…Especially, mitochondrial dysfunction is believed to be an important contributor to SCI [25][26][27]. In addition, ER stress participates in various types of damage after traumatic injury of spinal cord [28][29][30]. In the current study, we found that downregulation of RyR2 significantly ameliorated mitochondrial dysfunction and ER stress, as evidenced by increased oxygen consumption rate and decreased expression of GRP78, ATF3 and ATF6.…”