Why anesthetic mechanism research has failed, and what to do about it

Despite 170 years of research, we as a specialty are clueless as to how anesthetics cause reversible loss of consciousness, behavior and memory. We know HOW to safely deliver anesthesia, but quite literally, we don’t know WHAT we are doing! How did we get in this embarrassing predicament? In the 19 th century Claude Bernard showed that anesthetic gases cause reversible cessation of purposeful cytoplasmic streaming inside amoeboid cells. Bernard saw purposeful cytoplasm as an essential feature of living systems, with anesthesia acting in a common, unitary fashion to prevent it. We now know purposeful cytoplasm in amoeba, and brain neurons, depends on cycles of assembly/disassembly of cytoskeletal proteins comprising actin filaments and microtubules Following Bernard, the next major research into anesthetic mechanisms occurred at the turn of the 20 th century. Meyer and Overton found a striking correlation between potency of anesthetics, and their solubility in a non-polar, lipid-like, ‘hydrophobic ’ environment, binding there (it was later discovered) by van der Waals London forces, extremely weak quantum-level electron cloud dipole couplings. Because neuronal membranes convey signals, and are largely lipid, anesthetics were assumed through much of the 20 th century to act in a unitary fashion in lipid regions of brain neuronal surface membranes. Claude Bernard’s work on purposeful cytoplasm in cell interiors was forgotten. In the mid-20 th century, characterization of the ‘Hodgkin-Huxley neuron ’ showed signaling along membranes of integrate-and-fire neurons to be conveyed by depolarization waves caused by dynamics of receptors and ion channel proteins. In th