1. Academic Validation
  2. Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain

Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain

  • Acta Pharmacol Sin. 2020 Aug;41(8):1041-1048. doi: 10.1038/s41401-020-0394-6.
Ya-Qun Zhou 1 Dai-Qiang Liu 1 Shu-Ping Chen 1 Nan Chen 1 Jia Sun 1 Xiao-Mei Wang 1 Fei Cao 2 Yu-Ke Tian 3 Da-Wei Ye 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2 Department of Psychiatry, UMKC School of Medicine, Kansas City, MO, 64108, USA.
  • 3 Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. yktian@tjh.tjmu.edu.cn.
  • 4 Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. dy0711@gmail.com.
Abstract

Paclitaxel-induced neuropathic pain (PINP) is refractory to currently used analgesics. Previous studies show a pivotal role of oxidative stress in PINP. Because the nuclear factor erythroid-2-related factor 2 (Nrf2) has been considered as the critical regulator of endogenous antioxidant defense, we here explored whether activation of Nrf2 could attenuate PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to assess mechanical allodynia. We showed that a single dose of Nrf2 activator, oltipraz (10, 50, and 100 mg/kg), dose-dependently attenuated established mechanical allodynia, whereas repeated injection of oltipraz (100 mg· kg-1· d-1, i.p. from d 14 to d 18) almost abolished the mechanical allodynia in PINP rats. The antinociceptive effect of oltipraz was blocked by pre-injection of Nrf2 inhibitor trigonelline (20 mg/kg, i.p.). Early treatment with oltipraz (100 mg· kg-1· d-1, i.p. from d 0 to d 6) failed to prevent the development of the PINP, but delayed its onset. Western blot and immunofluorescence analysis revealed that the expression levels of Nrf2 and HO-1 were significantly upregulated in the spinal cord of PINP rats. Repeated injection of oltipraz caused further elevation of the expression levels of Nrf2 and HO-1 in the spinal cord of PINP rats, which was reversed by pre-injection of trigonelline. These results demonstrate that oltipraz ameliorates PINP via activating Nrf2/HO-1-signaling pathway in the spinal cord.

Keywords

HO-1; Nrf2; neuropathic pain; oltipraz; oxidative stress; paclitaxel.

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