The worm sheds light on anesthetic mechanisms.

One hundred and sixty five years have passed since the first documented use of volatile anesthetics to aid in surgery, but we have yet to understand the underlying mechanism of action of these drugs. There is no question that, in vitro, volatile anesthetics can affect the function of numerous neuronal and non-neuronal proteins. In fact, volatile anesthetics are capable of binding such diverse proteins as albumin and bacterial luciferase. The promiscuity of volatile anesthetic binding makes it difficult to determine which proteins are modulated by anesthetics to cause the state of anesthesia. Consequently, despite a great deal of in vitro data, the fundamental physiological process that volatile anesthetics perturb to effect neuronal silencing is not yet identified. Recently, data has increasingly indicated that membrane leak channels may play a role in the anesthetic response. Here we comment on the use of optogenetics to further support such a model.

Optical reversal of halothane-induced immobility in C. elegans.

Volatile anesthetics (VAs) cause profound neurological effects, including reversible loss of consciousness and immobility. Despite their widespread use, the mechanism of action of VAs remains one of the unsolved puzzles of neuroscience [1, 2]. Genetic studies in Caenorhabditis elegans [3, 4], Drosophila [3, 5], and mice [6-9] indicate that ion channels controlling the neuronal resting membrane potential (RMP) also control anesthetic sensitivity. Leak channels selective for K(+) [10-13] or permeable to Na(+) [14] are critical for establishing RMP. We hypothesized that halothane, a VA, caused immobility by altering the neuronal RMP. In C. elegans, halothane-induced immobility is acutely and completely reversed by channelrhodopsin-2 based depolarization of the RMP when expressed specifically in cholinergic neurons. Furthermore, hyperpolarizing cholinergic neurons via halorhodopsin activation increases sensitivity to halothane. The sensitivity of C. elegans to halothane can be altered by 25-fold by either manipulation of membrane conductance with optogenetic methods or generation of mutations in leak channels that set the RMP. Immobility induced by another VA, isoflurane, is not affected by these treatments, thereby excluding the possibility of nonspecific hyperactivity. The sum of our data indicates that leak channels and the RMP are important determinants of halothane-induced general anesthesia.