Drug therapy: Mechanisms of actions of inhaled anesthetics

Simplifying assumptions such as the unitary hypothesis led early research on anesthesia to focus on nonspecific biophysical mechanisms. Reevaluation of the actions of anesthetics on a variety of neurobiologic-systems levels has revealed important new insights into mechanisms that contradict these nonspecific hypotheses. Thus, although all inhaled general anesthetics produce amnesia and suppress motor responses to noxious stimuli, their actions on other behavioral and physiological responses vary. The suppression of nociceptive motor responses by anesthetics is mediated primarily by the spinal cord, whereas hypnosis and amnesia are mediated within the brain. These actions may also be associated with separate molecular targets. Important actions of inhaled anesthetics are associated with altered activity of neuronal ion channels, particularly the fast synaptic neurotransmitter receptors such as nicotinic acetylcholine, GABAA, and glutamate receptors. There is also growing evidence that anesthetics affect neuronal ion channels by binding directly to protein sites. Different ion channels display strikingly unique sensitivities to various inhaled anesthetics, suggesting that different channels are involved in distinct behavioral effects of anesthetics and that several mechanistic pathways may converge to produce similar anesthetic states. Neuroanatomical differences in the distribution of various ion channels and their specific subunits are likely to influence specific behavioral effects of inhaled anesthetics. This emerging view of the specific neurobiologic actions of inhaled anesthetics suggests that these widely used drugs should be amenable to improvements by rational design.