title: Dose Optimization for Single Intradiscal Administration of the Tumor Necrosis Factor-α Inhibitor, Etanercept, in Rat Disc Injury Models.
abstract: METHODS
  Experimental animal study.
  
  
  OBJECTIVE
  We aimed to determine the optimal dose of a single direct injection of the tumor necrosis factor (TNF)-α inhibitor, etanercept, by using the rat model of degenerative intervertebral disc from injury.
  
  
  BACKGROUND
  The pain-related peptide expression was suppressed in the etanercept (100 µg and 1,000 µg)-administered groups in a dose-dependent manner.
  
  
  METHODS
  The neurotracer FluoroGold (FG) was applied to the surfaces of L4/5 discs to label their innervating dorsal root ganglion (DRG) neurons (n=50). Ten rats were included in the nonpunctured disc sham surgery control group, whereas the other 40 were included in the experimental group in which intervertebral discs were punctured with a 23-gauge needle. Saline or etanercept (10 µg, 100 µg, or 1,000 µg) was injected into the punctured discs (n=10 for each treatment). After 14 days of surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for calcitonin gene-related peptide (CGRP). The proportion of FG-labeled CGRP-immunoreactive DRG neurons was evaluated in all the groups.
  
  
  RESULTS
  There were no significant differences between the puncture+saline group and the puncture+10-µg etanercept group (p >0.05). However, a significant decrease in the percentage of FG and CGRP double-positive cells in FG-positive cells was observed in the etanercept (100 µg and 1,000 µg)-administered groups in a dose-dependent manner (p <0.05).
  
  
  CONCLUSIONS
  When a low dose of the TNF-α inhibitor (10 µg of etanercept) was directly administered to the rat intervertebral disc in the rat model of degenerative intervertebral disc from injury, no suppressive effect on the pain-related peptide expression was observed. However, when a higher dose of etanercept (100 µg and 1,000 µg) was administered, the pain-related peptide expression was suppressed in a dose-dependent manner.
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Kazuhide
authors: K
authors: Inage
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Sumihisa
authors: S
authors: Orita
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Kazuyo
authors: K
authors: Yamauchi
authors: Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Takane
authors: T
authors: Suzuki
authors: Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Miyako
authors: M
authors: Suzuki
authors: Department of Orthopaedic Surgery, National Hospital Organization Chiba Medical Center, Chiba, Japan.
authors: Yoshihiro
authors: Y
authors: Sakuma
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Go
authors: G
authors: Kubota
authors: Department of Orthopaedic Surgery, Chiba Children's Hospital, Chiba, Japan.
authors: Yasuhiro
authors: Y
authors: Oikawa
authors: Department of Orthopaedic Surgery, Sainou Hospital, Toyama, Japan.
authors: Takeshi
authors: T
authors: Sainoh
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Jun
authors: J
authors: Sato
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Kazuki
authors: K
authors: Fujimoto
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Yasuhiro
authors: Y
authors: Shiga
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Koki
authors: K
authors: Abe
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Hirohito
authors: H
authors: Kanamoto
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Masahiro
authors: M
authors: Inoue
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Hideyuki
authors: H
authors: Kinoshita
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Kazuhisa
authors: K
authors: Takahashi
authors: Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Seiji
authors: S
authors: Ohtori
keywords: Degenerative intervertebral disc; Dose; Etanercept; Optimization; Tumor necrosis factor-alpha