Authors: Kale KM et al.
Source: Anesthesia & Analgesia. 2026;142(6):1039-1049.
Summary:
This article questions whether it is accurate to describe common anesthetic agents as “GABAergic,” “NMDAergic,” or otherwise tied mainly to one receptor target. The authors reviewed data from 310 in vitro studies and found that most anesthetic agents are not highly selective for one molecular target. Instead, they often affect several receptors and ion channels at similar concentrations.
The article explains that terms such as “GABAergic anesthetic” may imply that a drug’s hypnotic effect is caused mainly or exclusively by GABA-A receptor activity. The authors argue that this is too simplistic. For example, propofol is often described as a typical GABAergic anesthetic, but the review found that propofol may show greater potency at neuronal nicotinic acetylcholine receptors and HCN ion channels than at GABA-A receptors.
The authors also found that molecular targets themselves are “promiscuous,” meaning a single receptor or ion channel can be influenced by multiple anesthetic agents. This mutual promiscuity makes it difficult to support a single-site theory of anesthesia. Instead, the evidence supports a multi-site hypothesis in which each anesthetic produces its clinical effect through a unique spectrum of molecular interactions.
Etomidate and dexmedetomidine were partial exceptions because they appeared more selective for GABA-A receptors and alpha-2 adrenoceptors, respectively. Ketamine also showed a relatively stronger relationship with NMDA receptors. Even so, the overall conclusion was that most anesthetics are much less receptor-selective than common terminology suggests.
Clinical importance:
For anesthesia clinicians, this article is important because it reminds us that anesthetic pharmacology should not be oversimplified. A drug may have a dominant or well-known receptor effect, but the actual anesthetic state likely results from activity at multiple molecular sites and neural circuits. This may help explain why different agents produce different combinations of hypnosis, amnesia, immobility, hemodynamic effects, respiratory depression, and EEG patterns.
Bottom line:
The authors argue that calling drugs “GABAergic” may be misleading when used too literally. General anesthesia is more likely a multi-target phenomenon than a single-receptor process.
Thank you to Anesthesia & Analgesia and IARS for publishing this important review on anesthetic mechanisms and the limitations of single-receptor explanations for general anesthesia.