Etodolac, a Cyclooxygenase-2 Inhibitor, Attenuates Paclitaxel-Induced Peripheral Neuropathy in a Mouse Model of Mechanical Allodynia

Abstract

The effect of the cyclooxygenase-2 (COX-2) inhibitor etodolac on the mechanical allodynia induced by paclitaxel was investigated in mice and compared with the effects of the nonselective COX inhibitors indomethacin and diclofenac, the selective COX-2 inhibitor celecoxib, the calcium channel ␣ 2 ␦ subunit inhibitor pregabalin, the sodium channel blocker mexiletine, and the serotonin-norepinephrine reuptake inhibitor duloxetine. The decrease in the paw-withdrawal threshold induced by paclitaxel was reversed by oral administration of etodolac at 10 mg/kg but was not affected by indomethacin, diclofenac, or celecoxib. The antiallodynic effect of etodolac gradually increased during repeated administration, and after 2 weeks the paw-withdrawal threshold at the preadministration point was significantly increased. Pregabalin, duloxetine, and mexiletine also showed an antiallodynic effect in this model. Whereas pregabalin had a preadministration effect similar to that of etodolac during repeated administration, mexiletine or duloxetine had no such effect. There was almost no difference in the distribution of etodolac and diclofenac in nervous tissue, indicating that COX inhibition is unlikely to be involved in the antiallodynic effect of etodolac. Etodolac did not show a neuroprotective effect against morphological transformations such as the axonal degeneration induced by paclitaxel. Instead, etodolac probably acts at the level of functional changes accompanying paclitaxel treatment, such as alterations in the activation state of components of the pain transmission pathway. Our findings suggest that etodolac attenuates paclitaxel-induced peripheral neuropathy by a COX-independent pathway and that it might be useful for the treatment of paclitaxel-induced peripheral neuropathy.

Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture

“…Using this approach, investigators have examined the efficacy of antidepressants, gabapentin, COX inhibitors, antioxidants, mitochondrial protective agents, and immune suppressing drugs to reverse paclitaxel-induced mechanical hypersensitivity and cold allodynia (Boyette-Davis et al, 2011; Flatters et al, 2006; Ito et al, 2012; Jin et al, 2008; Kim et al, 2010; Xiao et al, 2007). Although these putative therapeutics are moderately successful in the animal model, they fall short in translation into the clinical setting (Hershman et al, 2012; Kautio et al, 2009; Kottschade et al, 2011; Rao et al, 2008; Rao et al, 2007; Smith et al, 2013).…”

Effects of natural and synthetic isothiocyanate-based H 2 S-releasers against chemotherapy-induced neuropathic pain: Role of Kv7 potassium channels

“…Effects of these reference compounds on paclitaxel-induced neuropathic pain are already published. In particular, pregabalin and duloxetin showed similar efficacy than in oxaliplatin model (Ito et al, 2012); on the contrary, morphine (Xu et al, 2011) was partially active against paclitaxel (differently from oxaliplatin) whereas celecoxib did not (Ito et al, 2012). P-ITC, CP-ITC and NaHS showed similar efficacy against paclitaxel-and oxaliplatin-dependent hypersensitivity when evoked by mechanical stimulus (Von Frey test, Supplementary Figs.…”

Involvement of TRPM2 in a wide range of inflammatory and neuropathic pain mouse models

“…Male WT and TRPM2-KO mice were injected with paclitaxel (4 mg/kg; i.p.) once daily on day 0, 3, 5, and 7, as previously described, with slight modifications (27).…”