Advanced oxidation protein products sensitized the transient receptor potential vanilloid 1 via NADPH oxidase 1 and 4 to cause mechanical hyperalgesia.
Oxidative stress is a possible pathogenesis of hyperalgesia. Advanced oxidation protein products (AOPPs), a new family of oxidized protein compounds, have been considered as a novel marker of oxidative stress. However, the role of AOPPs in the mechanism of hyperalgesia remains unknown. Our study aims to investigate whether AOPPs have an effect on hyperalgesia and the possible underlying mechanisms. To identify the AOPPs involved, we induced hyperalgesia in rats by injecting complete Freund's adjuvant (CFA) in hindpaw. The level of plasma AOPPs in CFA-induced rats was 1.6-fold in comparison with what in normal rats (P<0.05). After intravenous injection of AOPPs-modified rat serum albumin (AOPPs-RSA) in Sprague-Dawley rats, the paw mechanical thresholds, measured by the electronic von Frey system, significantly declined. Immunofluorescence staining indicated that AOPPs increased expressions of NADPH oxidase 1 (Nox1), NADPH oxidase 4 (Nox4), transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in the dorsal root ganglia (DRG) tissues. In-vitro studies were performed on primary DRG neurons which were obtained from both thoracic and lumbar DRG of rats. Results indicated that AOPPs triggered reactive oxygen species (ROS) production in DRG neurons, which were significantly abolished by ROS scavenger N-acetyl-l-cysteine (NAC) and small-interfering RNA (siRNA) silencing of Nox1 or Nox4. The expressions of Nox1, Nox4, TRPV1 and CGRP were significantly increased in AOPPs-induced DRG neurons. And relevant siRNA or inhibitors notably suppressed the expressions of these proteins and the calcium influxes in AOPPs-induced DRG neurons. In conclusion, AOPPs increased significantly in CFA-induced hyperalgesia rats and they activated Nox1/Nox4-ROS to sensitize TRPV1-dependent Ca2+ influx and CGRP release which led to inducing mechanical hyperalgesia.
Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
Ruoting
R
Ding
Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
Hui
H
Jiang
Department of Plastic and Aesthetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
Baihui
B
Sun
Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
Xiaoliang
X
Wu
Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
Wei
W
Li
Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
Siyuan
S
Zhu
Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
Congrui
C
Liao
Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: chenjt99@tom.com.
Zhaoming
Z
Zhong
Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: chenjt99@tom.com.
Jianting
J
Chen
D061605:Administration, Intravenous; D062107:Advanced Oxidation Protein Products / Q000378:metabolism*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000009:adverse effects; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D000074624:NADPH Oxidase 1 / Q000378:metabolism*; D000074663:NADPH Oxidase 4 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*
D062107:Advanced Oxidation Protein Products; D017382:Reactive Oxygen Species; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D005620:Freund's Adjuvant; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; C000614712:NOX1 protein, rat; C498911:Nox4 protein, rat; D015740:Calcitonin Gene-Related Peptide
Advanced oxidation protein products; Dorsal root ganglion; Hyperalgesia; NADPH oxidase; TRPV1
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