Peripheral and central oxidative stress in chemotherapy-induced neuropathic pain

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse side effect of many anti-cancer chemotherapeutic treatments. CIPN often causes neuropathic pain in extremities, and oxidative stress has been shown to be a major contributing factor to this pain. In this study, we determined the site of oxidative stress associated with pain (specifically, mechanical hypersensitivity) in cisplatin-and paclitaxel-treated mouse models of CIPN and investigated the neurophysiological mechanisms accounting for the pain. C57BL/6N mice that received either cisplatin or paclitaxel (2 mg/kg, once daily on four alternate days) developed mechanical hypersensitivity to von Frey filament stimulations of their hindpaws. Cisplatininduced mechanical hypersensitivity was inhibited by silencing of Transient Receptor Potential channels V1 (TRPV1)-or TRPA1-expressing afferents, whereas paclitaxel-induced mechanical hypersensitivity was attenuated by silencing of Ab fibers. Although systemic delivery of phenyl N-tert-butylnitrone, a reactive oxygen species scavenger, alleviated mechanical hypersensitivity in both cisplatin-and paclitaxel-treated mice, intraplantar phenyl N-tert-butylnitrone was effective only in cisplatin-treated mice, and intrathecal phenyl N-tert-butylnitrone, only in paclitaxel-treated mice. In a reactive oxygen species-dependent manner, the mechanosensitivity of Ad/C fiber endings in the hindpaw skin was increased in cisplatintreated mice, and the excitatory synaptic strength in the spinal dorsal horn was potentiated in paclitaxel-treated mice. Collectively, these results suggest that cisplatin-induced mechanical hypersensitivity is attributed to peripheral oxidative stress sensitizing mechanical nociceptors, whereas paclitaxel-induced mechanical hypersensitivity is due to central (spinal) oxidative stress maintaining central sensitization that abnormally produces pain in response to Ab fiber inputs.

Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways

“…These drugs are accumulated in DRG neurons, thereby causing damage to neurons [16]. However, the types of pain induced in CIPN model animals by each of these drugs are different [19,[21][22][23][24][25][27][28][29][30][31][32][33]. In the present study, carboplatin induced mechanical allodynia and cold hyperalgesia in mice (Figure 1), both of which were significantly suppressed by a TRPA1 inhibitor, HC-030031 ( Figure 2).…”

“…Many reports have shown that oxaliplatin induces both cold hyperalgesia and mechanical allodynia through TRPA1 activation [18, 19, 21-25, 27, 33]. On the contrary, cisplatin induces not only mechanical allodynia and cold hyperalgesia but also heat hyperalgesia via other TRP channels, such as TRPV1, instead of TRPA1 [18,21,[27][28][29][30][31][32]. Taken together, these reports suggested that carboplatin was more similar to oxaliplatin than to cisplatin, although further studies are needed to clear such difference occurs.…”

“…Some reports have shown that the activity of DRG neurons expressing TRP channels was enhanced in CIPN model animals [16,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Therefore, we investigated the effects of carboplatin on TRPA1 activation in hTRPA1-expressing HEK293 cells using a Ca 2+ imaging assay.…”

“…TRPA1 is activated by noxious stimulus, including cold temperature (< 17°C), alkaline condition, and inflammatory mediators, such as oxidative stress [10][11][12]14]. Many studies have indicated that TRPA1 is also involved in allodynia and hyperalgesia development [15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Moreover, recent reports have shown that TRPA1 plays an important role in CIPN caused by cisplatin or oxaliplatin, both of which are platinum-based drugs [16,[18][19][20][21][22][23][24][25][26][27][28].…”

Inhibition of microRNA-155 Reduces Neuropathic Pain During Chemotherapeutic Bortezomib via Engagement of Neuroinflammation

“…In general, cytotoxic drugs used for chemotherapy activate oxidative stress signals and thereby induce peripheral neuropathy (35,54,55). The previous study has demonstrated that TRPA1 is activated in the process of BTZ-induced pain and oxidative stress is involved in activation of the signal pathways (55).…”