Endoplasmic reticular stress as an emerging therapeutic target for chronic pain: a narrative review

Abstract

Chronic pain is a severely debilitating condition with enormous socioeconomic costs. Current treatment regimens with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or opioids have been largely unsatisfactory with uncertain benefits or severe long-term side effects. This is mainly because chronic pain has a multifactorial aetiology. Although conventional pain medications can alleviate pain by keeping several dysfunctional pathways under control, they can mask other underlying pathological causes, ultimately worsening nerve pathologies and pain outcome. Recent preclinical studies have shown that endoplasmic reticulum (ER) stress could be a central hub for triggering multiple molecular cascades involved in the development of chronic pain. Several ER stress inhibitors and unfolded protein response modulators, which have been tested in randomised clinical trials or apprpoved by the US Food and Drug Administration for other chronic diseases, significantly alleviated hyperalgesia in multiple preclinical pain models. Although the role of ER stress in neurodegenerative disorders, metabolic disorders, and cancer has been well established, research on ER stress and chronic pain is still in its infancy. Here, we critically analyse preclinical studies and explore how ER stress can mechanistically act as a central node to drive development and progression of chronic pain. We also discuss therapeutic prospects, benefits, and pitfalls of using ER stress inhibitors and unfolded protein response modulators for managing intractable chronic pain. In the future, targeting ER stress to impact multiple molecular networks might be an attractive therapeutic strategy against chronic pain refractory to steroids, NSAIDs, or opioids. This novel therapeutic strategy could provide solutions for the opioid crisis and public health challenge.

Keywords: animal model; apoptosis; chronic pain; endoplasmic reticulum stress; inflammation; ion channel; mitochondrial dysfunction; unfolded protein response.

Fig 1

Three branches of the UPR triggered by ER stress. (a) IRE1α pathway. Upon sensing misfolded proteins, cytosolic kinase domains of IRE1α dimerise, leading to their trans-autophosphorylation. Subsequently, cytosolic RNase domains of IRE1α become activated, causing excision of intron from the mRNA encoding the transcription factor, X-box-binding protein 1 (XBP1). The spliced XBP1 (XBP1-s) is then translated into the active form, which upregulates genes important for folding, export, and degradation of misfolded proteins. IRE1α also cleaves several other mRNAs via regulated IRE1-dependent decay (RIDD). RIDD decreases the ER protein load by lowering mRNA abundance. (b) PERK pathway. In response to ER stress, PERK oligomerises and becomes autophosphorylated, which in turn inactivates eukaryotic translation initiation factor 2α (eIF2α) via phosphorylation. This attenuates global mRNA translation, reduces the protein influx to ER, and ultimately alleviates ER stress. eIF2α phosphorylation also selectively upregulates translation of genes important for stress responses mainly via ATF4-dependent translation. (c) ATF6 pathway. Under ER stress, ATF6 pinches off from the ER membrane to form a vesicle and enters Golgi. There, its luminal and transmembrane domains are cleaved by proteases S1P and S2P, respectively. The resulting N-terminal cytosolic fragment (ATF6p50) translocates into nucleus and triggers transcription of UPR target genes involved in folding, secretion, and degradation of misfolded proteins. ATF6, activating transcription factor 6; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; IRE1α, inositol requiring enzyme 1α; mRNA, messenger RNA; PERK, protein kinase-like endoplasmic reticulum kinase; UPR, unfolded protein response.

Fig 2

Schematic representations of ER stress-sensing mechanisms. (a) Competition model (binding immunoglobulin protein (BiP)-dependent indirect sensing mechanism). Under normal conditions, IRE1α/PERK/ATF6 are maintained in inactive states as their ER luminal domains (LDs) bind to the substrate binding domain (SBD) of BiP. However, under ER stress, unfolded/misfolded proteins bind to the BiP SBD, thereby releasing IRE1α/PERK LDs to dimerise for activation and enabling ATF6 to translocate to Golgi. (b) Allosteric model (BiP-dependent indirect sensing mechanism). Misfolded proteins bind to SBD of BiP whereas IRE1α/PERK/ATF6 LDs bind to the nucleotide binding domain (NBD) of BiP without competition. Binding of misfolded proteins to BiP SBD causes conformational changes, leading to dissociation of LDs of UPR transducers from BiP NBD. (c) BiP independent direct sensing mechanism. LDs of UPR transducers have binding pockets that directly send and bind to misfolded proteins, triggering UPR activation. ATF6, activating transcription factor 6; ER, endoplasmic reticulum; IRE1α, inositol requiring enzyme 1α; PERK, protein kinase-like endoplasmic reticulum kinase; UPR, unfolded protein response.

Fig 3

Types of chronic pain that may be driven by ER stress. DM, diabetes mellitus; ER, endoplasmic reticulum; MS, multiple sclerosis.