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[EXPRESS] Etomidate and propylene glycol activate nociceptive TRP ion channels.

A new interesting article has been published in Mol Pain. 2018 Oct 22:1744806918811699. doi: 10.1177/1744806918811699. [Epub ahead of print] and titled:

[EXPRESS] Etomidate and propylene glycol activate nociceptive TRP ion channels.

Authors of this article are:

Niedermirtl F, Eberhardt M, Namer B, Leffler A, Nau C, Reeh PW, Kistner K.

A summary of the article is shown below:

Etomidate is a preferred drug for induction of general anesthesia in cardiovascular risk patients. As with propofol and other perioperatively used anesthetics the application of aqueous etomidate formulations causes an intensive burning pain upon injection. Such algogenic properties of etomidate have been attributed to the solubilizer propylene glycol (PG) which represents 35 % of the solution administered clinically. The aim of this study was to investigate the underlying molecular mechanisms which lead to injection pain of aqueous etomidate formulations. 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 CGRP release from mouse sciatic nerves was detected by EIA. Painfulness of different etomidate formulations was tested in a translational human pain model. Etomidate as well as PG 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 (NAC) did not prevent its by etomidate. PG-induced activation of TRPA1 and TRPV1 appeared independent of the concomitant high osmolarity. Intradermal injections of etomidate as well as PG evoked severe burning pain in the human pain model that was absent with emulsification of etomidate. 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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