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.

Abstract. Cyclooxygenase (COX) contributes to neuropathic pain after peripheral nerve injury, yet COX inhibitors are generally ineffective against mechanical allodynia and hyperalgesia in neuropathic pain patients and animal models. In the present study, we investigated the effects of etodolac, a selective COX-2 inhibitor, on mechanical allodynia in mice after partial sciatic nerve ligation (PSNL) compared to indomethacin (a nonselective COX inhibitor) or celecoxib (a selective COX-2 inhibitor). PSNL decreased the paw-withdrawal threshold (PWT) as assessed by the von Frey hair test, and etodolac, but not indomethacin or celecoxib, administered daily for two weeks, partially or wholly reversed the decrease. The efficacy of etodolac gradually increased throughout the administration period, and the higher dosages restored preligation PWT values by day 21. The positive control pregabalin also partially or wholly reversed the decrease in PWT, but in contrast to etodolac, it showed no increase in efficacy throughout the administration period. In normal mice, etodolac did not affect the PWT, whereas pregabalin increased it. These findings suggest that the mechanisms of inhibition of mechanical allodynia by etodolac and pregabalin are different and demonstrate that in contrast to other COX inhibitors, etodolac is effective against mechanical allodynia in a mouse neuropathic pain model.

The therapeutic effects of non-steroidal anti-inflammatory drugs (NSAIDs) include anti-pyretic, analgesic and anti-inflammatory effects, while their adverse effects are primarily gastrointestinal (GI) and renal toxicity. The major therapeutic and adverse effects are mediated by the inhibition of cyclooxygenase (COX), which catalyzes the rate-limiting step in the formation of prostanoids from arachidonic acid. [1][2][3] There are two membrane-bound COX isoenzymes, the constitutively expressed COX-1 and the highly inducible COX-2. 4) COX inhibitors include conventional NSAIDs and COX-2-selective inhibitors. Conventional NSAIDs, at therapeutic doses, are non-selective COX inhibitors and inhibit both isoenzymes. The anti-inflammatory benefits of NSAIDs are primarily due to COX-2 inhibition, while inhibition of COX-1 often elicits GI toxicity. Etodolac is widely known as a COX-2-selective inhibitor. 5-7) It has good clinical anti-inflammatory efficacy and a good safety profile for the GI tract. 8) Many NSAIDs are chiral and are marketed as the racemate (which contains equal amounts of each enantiomer). The anti-inflammatory activity of NSAIDs and their inhibition of prostaglandin synthetase is largely stereospecific in favor of the S-enantiomer. 9) Etodolac too is a racemate consisting of S-and R-enantiomers, and S-etodolac inhibits prostaglandin synthesis in sheep vesicular glands and decreases hind-paw volume in established adjuvant arthritic rats. 10) Neuropathic pain is a common symptom caused by injury to peripheral or central nerves, and it can result from pathological changes induced by metabolic disease, viral infection, traumatic injury or chemotherapeutically induced nerve damage. Clinically, neuropathic pain is characterized by mechanical and thermal allodynia, hyperalgesia and spontaneous ongoing pain that are often refractory to treatment. 11) Patients with neuropathic pain do not respond to NSAIDs, and resistance or insensitivity to opiates is common. 12) We recently reported that etodolac attenuates allodynia in a mouse model of neuropathic pain. 13) The mechanism of the anti-allodynic effects of etodolac has not yet been established, but COX inhibition is unlikely to be involved because the COX inhibitors indomethacin and celecoxib do not attenuate the allodynia. There is still a question which enantiomer of etodolac produces the anti-allodynic effect in mice. And there is also a question whether the ulcerogenic activity of etodolac is attributable to the S-enantiomer alone.In the present study, we evaluated the inhibitory effects of the enantiomers of etodolac on COX-1 and COX-2. We also investigated the beneficial actions of racemic etodolac and its enantiomers, especially their anti-inflammatory effects, antiallodynic effects and ulcerogenic activity, in mouse and rat models. S-Etodolac, but not R-etodolac, inhibited COX-2 and showed anti-inflammatory and anti-allodynic effects, while R-etodolac showed a gastroprotective effect that may explain the low GI toxicity of racemic etodolac. MATERIALS AND...

To clarify neuronal networks controlling swallowing water, inhibitory neurotransmitters were searched on the glossopharyngeal-vagal motor complex (GVC) of the medulla oblongata (MO), which is proposed as a motor nucleus controlling swallowing. Spontaneous firing (20-30 Hz) in the GVC was inhibited by adrenaline (AD), noradrenaline (NA) and dopamine (DA). The inhibitory effects of these catecholamines (CAs) were dose-dependent, and the effects of AD and NA were completely blocked by phenoxybenzamine or yohimbine, indicating that at least these two CAs act on the same receptor, presumably on alpha(2)-adrenoceptor. Even after blocking the alpha(2)-adrenoceptor with yohimbine, the inhibitory effect of DA still remained, indicating separate action of DA from AD or NA. Although DA receptor type was not determined in the present study, these results suggest existence of CA receptors in the GVC neurons. Almost 70% GVC neurons were inhibited by CAs. The CA-sensitive neurons were specifically restricted in the middle part of the GVC area. There were many tyrosine hydroxylase (TH)-immunoreactive somata and fibers in the eel MO. Among these TH-immunoreactive nuclei, the area postrema (AP) and the commissural nucleus of Cajal (NCC) appeared to project to the GVC morphologically. Significance of the catecholaminergic inhibition in the GVC activity is discussed in relation to controlling swallowing water.

Background and Purpose: The excitability of nociceptors is modulated by the transient receptor potential cation channel, ankyrin subfamily, member 1 (TRPA1). We have previously reported that etodolac, a nonsteroidal anti-inflammatory drug, attenuates mechanical allodynia in a mouse model of neuropathic pain by a mechanism that is independent of cyclooxygenase inhibition. Here, we investigate the role of TRPA1 in the mechanism of the antinociceptive action of etodolac in vitro and in vivo. Experimental Approach: Ca²⁺ influx was measured in HEK-293 cells expressing mouse TRPA1 and in mouse dorsal root ganglion (DRG) neurons. The effect of etodolac on the nociceptive behavior induced in mice by the TRPA1 agonist allyl isothiocyanate (AITC) was also measured. Results: Etodolac induced Ca²⁺ influx in HEK-293 cells expressing mouse TRPA1 and in mouse DRG neurons. The Ca²⁺ influx induced by etodolac was inhibited by pretreatment with the TRPA1-specific antagonist HC-030031. In contrast, etodolac did not induce Ca²⁺ influx in cells expressing TRPV1, TRPV2 or TRPM8. In addition, pretreatment with etodolac inhibited the Ca²⁺ influx induced by AITC. Conclusion and Implication: Etodolac showed a selective TRPA1 agonist action, providing evidence that etodolac desensitizes nociceptors by the selective activation of TRPA1. Etodolac may be clinically useful in the treatment of neuropathic pain.