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

  title={Etodolac Blocks the Allyl Isothiocyanate-Induced Response in Mouse Sensory Neurons by Selective TRPA1 Activation},
  author={Naoki Inoue and Sunao Ito and Masaki Nogawa and Koyuki Tajima and Takashi Kyoi},
  pages={47 - 54}
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… 
Etodolac activates and desensitizes transient receptor potential ankyrin 1
It is found that etodolac at higher doses could activate and then desensitize TRPA1 channels in heterologous expressing HEK293 cells as well as in DRG neurons, which indicates a novel mechanism of the anti‐inflammatory and analgesic clinical effects of etdolac.
TRPA1 and other TRP channels in migraine
TRP channels, and particularly TRPA1, may be proposed as novel pathways in migraine pathophysiology and as possible new targets for its treatment.
The transient receptor potential channel TRPA1: from gene to pathophysiology
Based on localization and functional properties, TRPA1 is considered a key player in acute and chronic (neuropathic) pain and inflammation, and its role in the (patho)physiology of nearly all organ systems is anticipated, and will be discussed along with the potential ofTRPA1 as a drug target for the management of various pathological conditions.
Non-steroidal anti-inflammatory drugs attenuate agonist-evoked activation of transient receptor potential channels.
It is shown for the first time that local administration of NSAIDs reduces thermal and mechanical hyperalgesia following TRPA1 or TRPV1 activation.
The transient receptor potential channel TRPA 1 : from gene to pathophysiology
The Transient Receptor Potential Ankyrin 1 channel (TRPA1), is a member of the large TRP family of ion channels, and functions as a Ca permeable non-selective cation channel in many different cell
Inhibition by non-steroidal anti-inflammatory drugs of compound action potentials in frog sciatic nerve fibers.
At least a part of antinociception produced by NSAIDs used as a dermatological drug to alleviate pain may be attributed to their inhibitory effects on nerve conduction, which depend on the chemical structures of NSAIDs.
Inhibition of Fast Nerve Conduction Produced by Analgesics and Analgesic Adjuvants—Possible Involvement in Pain Alleviation
The inhibitory actions of the antinociceptive compounds on CAPs in frog and mammalian peripheral nerves and on voltage-gated Na+ and K+ channels involved in AP production are mentioned.
Recent Progress in the Discovery and Development of TRPA1 Modulators.
  • S. Skerratt
  • Medicine
    Progress in medicinal chemistry
  • 2017
The recent TRPA1 cryogenic electron microscopy structure from the Cheng and Julius labs determined the structure of full-length human TRpa1 at up to 4Å resolution in the presence ofTRPA1 ligands, paving the way to enable structure-based drug design within the TRPA2 field.
Modulators of Transient Receptor Potential (TRP) Channels as Therapeutic Options in Lung Disease
This review will focus on TRP channels (TRPA1, TRPC6, TRPV1, andTRPV4), predominantly expressed in non-neuronal lung tissues and their involvement in pathways associated with diseases like asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), lung Fibrosis, and edema formation.
TRPs: modulation by drug-like compounds.
  • M. Schaefer
  • Medicine, Chemistry
    Handbook of experimental pharmacology
  • 2014
Drug-like compounds that exert biological activity towards TRP channels are either being used as cell biological tools or further developed into pharmacological lead structures aiming at therapeutic


Molecular characterization of TRPA1 channel activation by cysteine-reactive inflammatory mediators
It is shown that a variety of inflammatory mediators (15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), nitric oxide (NO), hydrogen peroxide (H2O2), and proton (H+) activate human TRPA1 heterologously expressed in HEK cells.
Activation of TRPA1 channels by fenamate nonsteroidal anti-inflammatory drugs
It is concluded that fenamate NSAIDs are a novel class of potent and reversible direct agonists of TRPA1, and should provide a structural basis for developing novel ligands that noncovalently interact withTRPA1 channels.
HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity
Using oral administration of the selective TRPA1 antagonist HC-030031, the results demonstrated that TRPA 1 plays an important role in the mechanisms responsible for mechanical hypersensitivity observed in inflammatory and neuropathic pain models and suggested thatTRPA1 antagonism may be a suitable new approach for the development of a potent and selective therapeutic agent to treat both inflammatory and Neuropathic pain.
Etodolac attenuates mechanical allodynia in a mouse model of neuropathic pain.
The 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, etodobolac is effective against mechanicalAllodynia in a mouse neuropathic pain model.
TRPA1 mediates formalin-induced pain
It is shown that TRPA1 is the principal site of formalin's pain-producing action in vivo, and that activation of this excitatory channel underlies the physiological and behavioral responses associated with this model of pain hypersensitivity.
A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition
A specific small molecule TRPA1 inhibitor (AP18) is developed that can reduce cinnameldehyde-induced nociception in vivo and is capable of reversing CFA-induced mechanical hyperalgesia in mice.
Attenuation of Mechanical Hypersensitivity by an Antagonist of the TRPA1 Ion Channel in Diabetic Animals
Reduction of pain-related behavior by a lower dose of the TRPA1 channel antagonist in the diabetic than in the control group suggests that endogenous compounds resulting from diabetes mellitus and acting on the TRpa1 channel contribute to diabetic hypersensitivity.
Antisense knock down of TRPA1, but not TRPM8, alleviates cold hyperalgesia after spinal nerve ligation in rats
The data suggest that increased TRPA1 in uninjured primary afferent neurons may contribute to the exaggerated response to cold observed in the neuropathic pain model.
TRPA1 Contributes to Cold, Mechanical, and Chemical Nociception but Is Not Essential for Hair-Cell Transduction
TRPA1 is apparently not essential for hair-cell transduction but contributes to the transduction of mechanical, cold, and chemical stimuli in nociceptor sensory neurons.
TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents
Using TRPA1-deficient mice, it is shown that this channel is the sole target through which mustard oil and garlic activate primary afferent nociceptors to produce inflammatory pain.