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Etodolac, a cyclooxygenase-2 inhibitor, attenuates paclitaxel-induced peripheral neuropathy in a mouse model of mechanical allodynia.

The Journal of pharmacology and experimental therapeutics (2012-03-31)
Sunao Ito, Koyuki Tajima, Masaki Nogawa, Naoki Inoue, Takashi Kyoi, Yosuke Takahashi, Takahiro Sasagawa, Akio Nakamura, Takashi Kotera, Makoto Ueda, Yasuhiro Yamashita, Kouji Banno
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 α(2)δ 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Mexiletine hydrochloride, powder
Sigma-Aldrich
Etodolac
Etodolac for peak identification, European Pharmacopoeia (EP) Reference Standard
Etodolac, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
1-(2,6-Dimethylphenoxy)-2-propanamine hydrochloride, 97%

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