Abstract | BACKGROUND: RESULTS: Activation of the nociceptive transient receptor potential (TRP) ion channels TRPA1 and TRPV1 was studied in a transfected HEK293t cell line by whole-cell voltage clamp recordings of induced inward ion currents. Calcium influx in sensory neurons of wild-type and trp knockout mice was ratiometrically measured by Fura2-AM staining. Stimulated calcitonin gene-related peptide release from mouse sciatic nerves was detected by enzyme immunoassay. Painfulness of different etomidate formulations was tested in a translational human pain model. Etomidate as well as propylene glycol proved to be effective agonists of TRPA1 and TRPV1 ion channels at clinically relevant concentrations. Etomidate consistently activated TRPA1, but there was also evidence for a contribution of TRPV1 in dependence of drug concentration ranges and species specificities. Distinct N-terminal cysteine and lysine residues seemed to mediate gating of TRPA1, although the electrophile scavenger N-acetyl-L-cysteine did not prevent its activation by etomidate. Propylene glycol-induced activation of TRPA1 and TRPV1 appeared independent of the concomitant high osmolarity. Intradermal injections of etomidate as well as propylene glycol evoked severe burning pain in the human pain model that was absent with emulsification of etomidate. CONCLUSIONS: Data in our study provided evidence that pain upon injection of clinical aqueous etomidate formulations is not an unspecific effect of hyperosmolarity but rather due to a specific action mediated by activated nociceptive TRPA1 and TRPV1 ion channels in sensory neurons.
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Authors | Florian Niedermirtl, Mirjam Eberhardt, Barbara Namer, Andreas Leffler, Carla Nau, Peter W Reeh, Katrin Kistner |
Journal | Molecular pain
(Mol Pain)
2018 Jan-Dec
Vol. 14
Pg. 1744806918811699
ISSN: 1744-8069 [Electronic] United States |
PMID | 30345869
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- TRPV Cation Channels
- Transient Receptor Potential Channels
- Calcitonin Gene-Related Peptide
- Calcium
- Etomidate
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Topics |
- Animals
- Calcitonin Gene-Related Peptide
(metabolism)
- Calcium
(metabolism)
- Etomidate
(pharmacology)
- Female
- Ganglia, Spinal
(drug effects, metabolism)
- HEK293 Cells
- Humans
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Pain
(chemically induced, metabolism, physiopathology)
- Sensory Receptor Cells
(drug effects, metabolism)
- TRPV Cation Channels
(drug effects, metabolism)
- Transient Receptor Potential Channels
(drug effects, metabolism)
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