Abstract
ObjectiveTransient receptor potential ankyrin 1 (TRPA1) is an excitatory ion channel expressed on a subset of sensory neurons. TRPA1 is activated by a host of noxious stimuli including pollutants, irritants, oxidative stress and inflammation, and is thought to play an important role in nociception and pain perception. TRPA1 is therefore a therapeutic target for diseases with nociceptive sensory signaling components. TRPA1 orthologs have been shown to have differential sensitivity to certain ligands. Cinnamaldehyde has previously been shown to activate sensory neurons via the selective gating of TRPA1. Here, we tested the sensitivity of cinnamaldehyde-evoked responses in mouse and guinea pig sensory neurons to the pore blocker ruthenium red (RuR).ResultsCinnamaldehyde, the canonical TRPA1-selective agonist, caused robust calcium fluxes in trigeminal neurons dissociated from both mice and guinea pigs. RuR effectively inhibited cinnamaldehyde-evoked responses in mouse neurons at 30 nM, with complete block seen with 3 μM. In contrast, responses in guinea pig neurons were only partially inhibited by 3 μM RuR. We conclude that RuR has a decreased affinity for guinea pig TRPA1 compared to mouse TRPA1. This study provides further evidence of differences in ligand affinity for TRPA1 in animal models relevant for drug development.
Highlights
Transient Receptor Potential Ankyrin 1 (TRPA1) is a homo-tetrameric, non-selective cation channel belonging to the superfamily of TRP channels
To study the differences between the sensitivity of guinea pig TRPA1 and mouse TRPA1 to ruthenium red (RuR) we compared its effect on the Ca2+ responses of sensory neurons dissociated from mouse and guinea pig trigeminal ganglia to the TRPA1 selective agonist cinnamaldehyde [3, 34]
Previous studies have shown that guinea pig and mouse nociceptive sensory nerves and nocifensive reflexes are activated by known TRPA1 agonists such as cinnamaldehyde and other unsaturated aldehydes and allyl isothiocyanate [3, 4, 8, 10, 11, 13, 39,40,41]
Summary
Cinnamaldehyde, the canonical TRPA1-selective agonist, caused robust calcium fluxes in trigeminal neurons dissociated from both mice and guinea pigs. RuR effectively inhibited cinnamaldehyde-evoked responses in mouse neurons at 30 nM, with complete block seen with 3 μM. Responses in guinea pig neurons were only par‐ tially inhibited by 3 μM RuR. We conclude that RuR has a decreased affinity for guinea pig TRPA1 compared to mouse TRPA1. This study provides further evidence of differences in ligand affinity for TRPA1 in animal models relevant for drug development
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