Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain

• 作者: Da-wei Ye Dai-qiang Liu Fei Cao Jia Sun Nan Chen Shu-ping Chen Xiao-mei Wang Ya-qun Zhou Yu-ke Tian
• 来源期刊: 中国药理学报（英文版）
• 关键词: paclitaxel neuropathic pain oxidative stress Nrf2 HO-1 oltipraz
• 年，卷（期）: 2020,（8）
• 页码范围: 1041-1048
• 页数: 8页
• 语种: 英文

摘要

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.