Article

Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain

Authors: Ya-qun Zhou1, Dai-qiang Liu1, Shu-ping Chen1, Nan Chen1, Jia Sun1, Xiao-mei Wang1, Fei Cao2, Yu-ke Tian1, Da-wei Ye3
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 Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Correspondence to: Yu-ke Tian: yktian@tjh.tjmu.edu.cn, Da-wei Ye: dy0711@gmail.com,
DOI: 10.1038/s41401-020-0394-6
Received: 15 September 2019
Accepted: 5 March 2020
Advance online: 19 March 2020

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

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