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

Abstract

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.

TRPA1 and other TRP channels in migraine

“…In addition, TRPA1 antagonists could represent novel therapeutic strategies of CIPN. In this context, it could be better understood that the unexpected attenuation by etodolac, a nonsteroidal anti-inflammatory drug of mechanical allodynia in a mouse model of neuropathic pain, might be due to its ability to inhibit TRPA1 [67]. In addition, to contribute to mechanical hyperalgesia, TRPA1 seems to be involved in the development of cold allodynia [68].…”

Inhibitory Actions of Clinical Analgesics, Analgesic Adjuvants, and Plant-Derived Analgesics on Nerve Action Potential Conduction

“…NSAIDs globally downregulate nociception through multiple mechanisms, including: inhibited production of prostaglandins from arachidonic acid by the suppression of the cyclooxygenase enzyme ( [34,35]; refer to reviews [36][37][38][39]); activation of several potassium channels ( [40][41][42][43][44]; refer to reviews [45,46]); suppression of acid-sensitive ion channels [47] and transient receptor potential (TRP) channels [48,49]; substance P depletion [50]; interaction with the adrenergic nervous system [51]; opioid receptor activation [52,53]; and cannabinoid receptor activation and increase in endocannabinoid level [54]. The idea that antinociception is produced by effects other than the suppression of cyclooxygenase is consistent with the experimental result which showed a difference between the antinociceptive and anti-inflammatory effects of NSAIDs [55].…”

Inhibition of Fast Nerve Conduction Produced by Analgesics and Analgesic Adjuvants—Possible Involvement in Pain Alleviation

“…Antinociception produced by NSAIDs is mediated by various mechanisms such as (1) inhibition of the synthesis of prostaglandins from arachidonic acid by inhibiting the cyclooxygenase enzyme ([ 87 , 88 ]; see [ 89 , 90 , 91 ] for reviews), (2) inhibition of acid-sensitive ion channels [ 92 ] and transient receptor potential (TRP) channels [ 93 , 94 ], (3) activation of several K + channels ([ 95 , 96 , 97 , 98 , 99 ]; see [ 100 , 101 ] for reviews), (4) substance P depletion [ 102 ], (5) an interaction with the adrenergic system [ 103 ] and (6) an involvement of opioids [ 104 , 105 ] and endocannabinoids (see [ 106 ] for review). The idea about an involvement of mechanisms other than cyclooxygenase inhibition in antinociception is supported by the observation that there is a dissociation between anti-inflammation and antinociception produced by NSAIDs [ 107 ].…”