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Etomidate and propylene glycol activate nociceptive TRP ion channels.
Mol Pain. 2018 Jan-Dec; 14:1744806918811699.MP

Abstract

BACKGROUND

Etomidate is a preferred drug for the 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 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.

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.

Authors+Show Affiliations

1 Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany.2 Department for Anaesthesia and Critical Care Medicine, Hannover Medical School, Hannover, Germany.1 Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany.2 Department for Anaesthesia and Critical Care Medicine, Hannover Medical School, Hannover, Germany.3 Department of Anesthesiology and Intensive Care, University of Lübeck, Lübeck, Germany.1 Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany.1 Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30345869

Citation

Niedermirtl, Florian, et al. "Etomidate and Propylene Glycol Activate Nociceptive TRP Ion Channels." Molecular Pain, vol. 14, 2018, p. 1744806918811699.
Niedermirtl F, Eberhardt M, Namer B, et al. Etomidate and propylene glycol activate nociceptive TRP ion channels. Mol Pain. 2018;14:1744806918811699.
Niedermirtl, F., Eberhardt, M., Namer, B., Leffler, A., Nau, C., Reeh, P. W., & Kistner, K. (2018). Etomidate and propylene glycol activate nociceptive TRP ion channels. Molecular Pain, 14, 1744806918811699. https://doi.org/10.1177/1744806918811699
Niedermirtl F, et al. Etomidate and Propylene Glycol Activate Nociceptive TRP Ion Channels. Mol Pain. 2018 Jan-Dec;14:1744806918811699. PubMed PMID: 30345869.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Etomidate and propylene glycol activate nociceptive TRP ion channels. AU - Niedermirtl,Florian, AU - Eberhardt,Mirjam, AU - Namer,Barbara, AU - Leffler,Andreas, AU - Nau,Carla, AU - Reeh,Peter W, AU - Kistner,Katrin, Y1 - 2018/10/22/ PY - 2018/10/23/pubmed PY - 2019/3/21/medline PY - 2018/10/23/entrez KW - Etomidate KW - TRPA1 KW - TRPV1 KW - anesthetic KW - human pain model KW - injection pain KW - nociception KW - propylene glycol KW - sensory neuron KW - transient receptor potential ion channel SP - 1744806918811699 EP - 1744806918811699 JF - Molecular pain JO - Mol Pain VL - 14 N2 - BACKGROUND: Etomidate is a preferred drug for the 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 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. 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. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/30345869/Etomidate_and_propylene_glycol_activate_nociceptive_TRP_ion_channels_ L2 - https://journals.sagepub.com/doi/10.1177/1744806918811699?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -