Abstract
Current medications inadequately treat the symptoms of chronic pain experienced by over 50 million people in the United States, and may come with substantial adverse effects signifying the need to find novel treatments. One novel therapeutic target is the Transient Receptor Potential A1 channel (TRPA1), an ion channel that mediates nociception through calcium influx of sensory neurons. Drug discovery still relies heavily on animal models, including zebrafish, a species in which TRPA1 activation produces hyperlocomotion. Here, we investigated if this hyperlocomotion follows zebrafish TRPA1 pharmacology and evaluated the strengths and limitations of using TRPA1-mediated hyperlocomotion as potential preclinical screening tool for drug discovery. To support face validity of the model, we pharmacologically characterized mouse and zebrafish TRPA1 in transfected HEK293 cells using calcium assays as well as in vivo. TRPA1 agonists and antagonists respectively activated or blocked TRPA1 activity in HEK293 cells, mice, and zebrafish in a dose-dependent manner. However, our results revealed complexities including partial agonist activity of TRPA1 antagonists, bidirectional locomotor activity, receptor desensitization, and off-target effects. We propose that TRPA1-mediated hyperlocomotion in zebrafish larvae has the potential to be used as in vivo screening tool for novel anti-nociceptive drugs but requires careful evaluation of the TRPA1 pharmacology.
Highlights
Nociception plays an active role in the defense against injury; persisting pain may become maladaptive and significantly impact an individual’s daily activity and the quality of life
The limitations associated with using a mouse model early in the drug discovery process motivated us to search for an alternative animal model that could expedite the process of validating in vivo Transient Receptor Potential subfamily A1 (TRPA1) ligand efficacy
We investigated if locomotor behavior of zebrafish larvae adheres to TRPA1 channel pharmacology
Summary
Nociception plays an active role in the defense against injury; persisting pain may become maladaptive and significantly impact an individual’s daily activity and the quality of life. Chronic pain, defined as unrelieved and persistent, lasting longer than 3 months, is usually treated by non-steroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, tricyclic antidepressants, and opioids. Despite these treatment options, many patients still complain that their pain is insufficiently managed[1]. Drug development targeting TRPA1 is still in its infancy, and far no TRPA1 ligand has been approved by the Food and Drug Administration This may be in part because using the rodent models to establish in vivo efficacy of drug candidates can be very expensive and time-consuming. The mouse TRPA1 pharmacology in HEK293 cells and nocifensive behavior in mice were examined upon TPRA1 activation to support the face validity of the zebrafish model. We evaluated dose-dependent changes of nocifensive swimming behavior in zebrafish larvae following the exposure to TRPA1 ligands
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