A Human TRPA1-Specific Pain Model

Area of Science:

• Neuroscience
• Pain Research
• Pharmacology

Background:

• The cation channel transient receptor potential ankyrin 1 (TRPA1) is crucial for sensing harmful stimuli.
• Significant species differences in TRPA1 function and the lack of TRPA1-specific agonists in humans have hindered translational research.
• The precise sensation evoked by isolated TRPA1 activation in humans remained unknown due to confounding targets of previously tested agonists.

Purpose of the Study:

• To determine if isolated TRPA1 activation elicits pain in humans.
• To validate the specificity of a novel TRPA1 agonist, JT010, using a TRPA1 antagonist, A-967079.
• To establish a TRPA1-specific pain model for future research applications.

Main Methods:

• A double-blind, placebo-controlled, crossover study involving 16 healthy volunteers.
• Intraepidermal injections of varying concentrations of the TRPA1 agonist JT010, alone and in combination with the antagonist A-967079.
• Pain ratings by participants and quantification of JT010 levels using High-Performance Liquid Chromatography (HPLC).

Main Results:

• Intraepidermal injection of JT010 dose-dependently induced pain in humans, with a half-maximal effective concentration of 0.31 μm.
• The TRPA1 antagonist A-967079 dose-dependently inhibited and, at high concentrations, abolished JT010-induced pain, confirming JT010's specificity.
• Handling procedures were optimized to overcome JT010 adsorption to polypropylene surfaces, ensuring accurate quantification.

Conclusions:

• Isolated activation of the TRPA1 channel in humans is sufficient to cause pain.
• Intradermal JT010 injection provides a validated tool for assessing TRPA1 antagonist target engagement in vivo.
• This TRPA1-specific pain model facilitates the quantification of TRPA1's role in physiological and pathophysiological processes, aiding in understanding diseases and developing targeted therapies.