Analgesic and Antidepressant Effects of Oltipraz on Neuropathic Pain in Mice by Modulating Microglial Activation

Abstract

Nerve injury provokes microglial activation, contributing to the sensory and emotional disorders associated with neuropathic pain that do not completely resolve with treatment. In C57BL/6J mice with neuropathic pain induced by chronic constriction of the sciatic nerve (CCI), we evaluated the effects of oltipraz, an antioxidant and anticancer compound, on (1) allodynia and hyperalgesia, (2) microglial activation and pain signaling pathways, (3) oxidative stress, and (4) depressive-like behaviors. Twenty-eight days after surgery, we assessed the effects of oltipraz on the expression of CD11b/c (a microglial marker), phosphoinositide 3-kinase (PI3K)/ phosphorylated protein kinase B (p-Akt), nuclear factor-κB (NF-κB) transcription factor, and mitogen activated protein kinases (MAPK) in the spinal cord, hippocampus, and prefrontal cortex. Our results show that oltipraz alleviates neuropathic pain by inhibiting microglial activation and PI3K/p-Akt, phosphorylated inhibitor of κBα (p-IκBα), and MAPK overexpression, and by normalizing and/or enhancing the expression of antioxidant proteins, nuclear factor erythroid derived-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO1) in the spinal cord. The inhibition of microglial activation and induction of the Nrf2/HO-1/NQO1 signaling pathway in the hippocampus and/or prefrontal cortex may explain the antidepressant effects of oltipraz during neuropathic pain. These data demonstrate the analgesic and antidepressant effects of oltipraz and reveal its protective and antioxidant properties during chronic pain.

Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain

“…However, microglia are not activated in the spinal cord after paclitaxel treatment, thus excluding their role in the pathogenesis of PINP [ 40 ]. In a very recent study, Díaz et al claimed that oltipraz possesses analgesic and antidepressant effects in a mouse model of neuropathic pain induced by chronic constriction of the sciatic nerve [ 41 ]. They found that the inhibition of microglial activation and induction of the Nrf2/HO-1-signaling pathway in the hippocampus and/or prefrontal cortex contributes to the protective effects of oltipraz.…”

<p>Risk of Postoperative Hyperalgesia in Adult Patients with Preoperative Poor Sleep Quality Undergoing Open-heart Valve Surgery</p>

“…23 Moreover, systemic and central nervous system inflammatory responses promoted by sleep disturbances increase pain sensitivity through multiple signaling pathways. [24][25][26][27] In addition, long-term poor sleep quality can continuously activate the hypothalamus-pituitaryadrenal axis, which produces a large amount of corticotropin and cortisol. 28 Study on healthy volunteers has reported that high corticosteroid levels in the body could enhance pain sensitivity.…”

Protective Effect of Sphaerococcus coronopifolius Crude Extract in Combination with Bacillus Calmette-Guerin on Ligature-Induced Depression in Female Wistar Rats

“…34 Furthermore, persistent neuropathic pain is associated with emotional disorders, such as anxiety and depression. 1,2 Previous reports using rodents have shown that pain lasting more than 4 weeks induces emotional dysfunction, such as anxiety or depression-like behavior. 35,36 In the present work, depression-like behavior was observed in female Wistar rats 3 weeks after sciatic nerve injury.…”

“…Chronic neuropathic pain caused by nerve injury provokes peripheral and central sensitization. 1 That is, patients with neuropathic pain involve emotional disorders such as anxiety and depression. 2 As well, depression is an outspread chronic psychiatric disorder that interferes with social life and work performance.…”