title: 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.
authors.affiliation: 1] Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, South Korea [2] Department of Anesthesiology, Yanbian University Hospital, Yanbian, 133000, China.
authors.forename: Enji
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Yi
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Nara
authors.initials: N
authors.lastname: Shin
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Baek
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Sena
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Eunjee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Kisang
authors.initials: K
authors.lastname: Kwon
authors.affiliation: Department of Anesthesia and Pain Medicine, Chungnam National University Hospital, Daejeon 301-721, South Korea.
authors.forename: Sunyeul
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Physiology, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Department of Oral Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, South Korea.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chul Bae
authors.affiliation: Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL, USA.
authors.forename: Yonghyun
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: O-Yu
authors.initials: OY
authors.lastname: Kwon
authors.affiliation: Department of Anesthesia and Pain Medicine, Chungnam National University Hospital, Daejeon 301-721, South Korea.
authors.forename: Won Hyung
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, South Korea.
authors.forename: Dong Woon
authors.initials: DW
authors.lastname: Kim
mesh_terms: D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D009437:Neuralgia / Q000378:metabolism / Q000473:pathology*; D017288:Pain Threshold; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism* / Q000473:pathology; D013127:Spinal Nerves / Q000293:injuries; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C497113:Atf6 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C000605545:Xbp1 protein, rat