Etodolac Attenuates Mechanical Allodynia in a Mouse Model of Neuropathic Pain

Inoue, Naoki; Ito, Sunao; Tajima, Koyuki; Nogawa, Masaki; Takahashi, Yosuke; Sasagawa, Takahiro; Nakamura, Akio; Kyoi, Takashi

doi:10.1254/jphs.08287fp

Cited by 26 publications

(18 citation statements)

References 22 publications

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“…15) We have previously reported that etodolac, but not indomethacin or celecoxib, attenuates allodynia in PSNL mice. 13) In the present study, neither diclofenac nor meloxicam showed anti-allodynic effects in the PSNL model. Taken together, these results suggest that the anti-allodynic mechanism of etodolac is not mediated by COX-2 inhibition.…”

Section: Discussioncontrasting

confidence: 67%

“…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.…”

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confidence: 99%

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The Enantiomers of Etodolac, a Racemic Anti-inflammatory Agent, Play Different Roles in Efficacy and Gastrointestinal Safety

Inoue

Nogawa

Ito

et al. 2011

Biological & Pharmaceutical Bulletin

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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...

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Section: Discussioncontrasting

confidence: 67%

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confidence: 99%

The Enantiomers of Etodolac, a Racemic Anti-inflammatory Agent, Play Different Roles in Efficacy and Gastrointestinal Safety

Inoue

Nogawa

Ito

et al. 2011

Biological & Pharmaceutical Bulletin

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“…55) However, NSAIDs are reported to be ineffective against neuropathic pain, including CPSP in basic or clinical study. 14,56,57) Indomethacin, an NSAID, had no effect on the paw withdrawal threshold throughout the assessment period.…”

Section: )mentioning

confidence: 99%

“…14,56,57) Indomethacin, an NSAID, had no effect on the paw withdrawal threshold throughout the assessment period. 55) Additionally, another NSAID, diclofenac, had no effect on oxaliplatin-induced cold hypersensitivity. 14) In the present study, we also found that administration of the NSAID indomethacin had no effect on the BCAO-induced mechanical allodynia, suggesting that NSAIDs are not useful in CPSP treatment.…”

Section: )mentioning

confidence: 99%

Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia

Matsuura

Harada

Tokuyama

2016

Biological & Pharmaceutical Bulletin

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Central post-stroke pain (CPSP), a potential sequela of stroke, is classified as neuropathic pain. Although we recently established a CPSP-like model in mice, the effects of adjuvant analgesics as therapeutic drugs for neuropathic pain in this model are unknown. Hence, the aim of the present study was to assess the usefulness of our model by evaluating the effects of adjuvant analgesics used for treating neuropathic pain in this mouse model of CPSP. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). The development of hind paw mechanical allodynia was measured after BCAO using the von Frey test. The mechanical allodynia was significantly increased on day 3 after BCAO compared with that during the pre-BCAO assessment. BCAO-induced mechanical allodynia was significantly decreased by intraperitoneal injections of imipramine (a tricyclic antidepressant), mexiletine (an antiarrhythmic), gabapentin (an antiepileptic), or a subcutaneous injection of morphine (an opioid receptor agonist) compared with that following vehicle treatment in BCAO-mice. By contrast, milnacipran (a serotonin and norepinephrine reuptake inhibitor), paroxetine (selective serotonin reuptake inhibitor), carbamazepine (antiepileptic), and indomethacin (nonsteroidal anti-inflammatory drug) did not affect the BCAO-induced mechanical allodynia. Our results show that BCAO in mice may be useful as an animal model of CPSP. In addition, BCAO-induced mechanical allodynia may be suppressed by some adjuvant analgesics used to treat neuropathic pain.Key words central post-stroke pain; global ischemia; allodynia; neuropathic pain Pain may occur with actual substantial or even potential histologic lesions, producing uncomfortable sensory and emotional experiences, according to the definition by the International Association for the Study of Pain. One type of pain, neuropathic pain, is caused by dysfunctional peripheral or central nerves and results in the appearance of allodynia and hypersensitivity to pain.1,2) Cerebral stroke patients may experience several types of pain, including musculoskeletal pain, headache, and neuropathic central post-stroke pain (CPSP).Among the different types of neuropathic pain, CPSP is an especially intractable condition to treat. CPSP is associated with various symptoms, such as burning and lancinating pain, and the incidence of CPSP after cerebral stroke is reportedly 1-14%. 3,4) In clinical studies, the risk factors associated with CPSP are the degree of brain infarction, sexual dimorphism, alcohol intake, depression anamnesis, statin use, dyslipidemia, diabetes, and peripheral vascular disorder.5) The pathogenic mechanisms for CPSP and neuropathic pain appear similar at the point of excitation of primary afferent fibers and for epistatic or central excitation or suppression pathway disorders. Recently, we established a CPSP-like animal model by experimentally inducing focal (middle cerebral artery occlusion model) or global cerebral ischemia (bilateral carotid artery occlusion model; BCAO). 6,...

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“…It is caused by damage to the nervous system and is characterized by spontaneous pain, hyperalgesia and allodynia [1]. We have previously reported that etodolac, a nonsteroidal anti-inflammatory drug (NSAID) and selective cyclooxygenase-2 (COX-2) inhibitor, attenuates allodynia in a mouse model of neuropathic pain [2]. The mechanism of the antiallodynic effect of etodolac has not yet been established, but COX inhibition is unlikely to be involved because other COX inhibitors do not attenuate the allodynia [2,3].…”

Section: Introductionmentioning

confidence: 99%

Etodolac Blocks the Allyl Isothiocyanate-Induced Response in Mouse Sensory Neurons by Selective TRPA1 Activation

et al. 2012

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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.

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Etodolac Attenuates Mechanical Allodynia in a Mouse Model of Neuropathic Pain

Cited by 26 publications

References 22 publications

The Enantiomers of Etodolac, a Racemic Anti-inflammatory Agent, Play Different Roles in Efficacy and Gastrointestinal Safety

The Enantiomers of Etodolac, a Racemic Anti-inflammatory Agent, Play Different Roles in Efficacy and Gastrointestinal Safety

Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia

Etodolac Blocks the Allyl Isothiocyanate-Induced Response in Mouse Sensory Neurons by Selective TRPA1 Activation

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