Etomidate and propylene glycol activate nociceptive TRP ion channels

Abstract

BackgroundEtomidate 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.ResultsActivation 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.ConclusionsData 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.

What are the respiratory effects of e-cigarettes?

“…However, this label does not apply to inhalational safety, and short term occupational exposures to propylene glycol caused irritation and either mild or no objective effects on pulmonary function, suggesting that propylene glycol may act as a sensory irritant 116118132133. Propylene glycol activated TRPV1 and TRPA1, two irritant receptors expressed in sensory nerves innervating the airways 134135. These receptors promote asthmatic inflammation and airway hyper-reactivity in asthma models 136.…”

“… 116 118 132 133 Propylene glycol activated TRPV1 and TRPA1, two irritant receptors expressed in sensory nerves innervating the airways. 134 135 These receptors promote asthmatic inflammation and airway hyper-reactivity in asthma models. 136 MUC5AC protein concentrations were increased in the lungs of chronic vapers.…”

Comparison of the injection‐site experience of semaglutide in a single‐dose and a multidose pen‐injector

“…Propylene glycol at a concentration of 35% injected intradermally induces burning pain that subsides within minutes. 12 That concentration, however, is much higher than the 1.9% in semaglutide C.…”

“…Semaglutide D differs from semaglutide C in that the tonicity regulator propylene glycol has been replaced with sodium chloride. Propylene glycol at a concentration of 35% injected intradermally induces burning pain that subsides within minutes 12 . That concentration, however, is much higher than the 1.9% in semaglutide C.…”

Chemosensory Contributions of E-Cigarette Additives on Nicotine Use

“…Furthermore, PG, sometimes used as a vehicle solution for intravenous drug delivery, can induce burning or stinging sensations during injection ( Doenicke et al, 1999 ). As a possible explanation of its nociceptive effects, PG activates heterologously expressed human TRPA1 and rat TRPV1 receptors ( Niedermirtl et al, 2018 ). However, the interaction between PG and TRPA1 in e-cigarette users is currently unknown.…”