Anesthetics and control of breathing

Abstract

An important side effect of general anesthetics is respiratory depression. Anesthetics have multiple membrane targets of which ionotropic receptors such as gamma-aminobutyric acid-A (GABA_A), glycine, N-methyl-d-aspartate and nicotinic acetylcholinergic (nACh) receptors are important members. GABA, glutamate and ACh are crucial neurotransmitters in the respiratory neuronal network, and the ability of anesthetics to modulate their release and interact with their receptors implies complex effects on respiration. Metabotropic receptors and intracellular proteins are other important targets for anesthetics suggesting complex effects on intracellular signaling pathways. Here we briefly overview the effects of general anesthetics on protein targets as far as these are relevant for respiratory control. Subsequently, we describe some methods with which the overall effect of anesthetics on the control of breathing can be measured, as well as some promising in vivo approaches to study their synaptic effects. Finally, we summarize the most important respiratory effects of volatile anesthetics in humans and animals and those of some intravenous anesthetics in animals.

Introduction

The invasive nature of many animal studies requires the use of general anesthetics. Many, if not all, anesthetic regimens cause a dose-dependent depression of the cardiorespiratory system. Depending on the dose, anesthetics have multiple sites of action within the respiratory system such as the suprapontine structures involved in the volitional control of breathing, respiratory brain stem neurons that generate, shape, modulate and integrate respiratory activity, efferent nerves from the brain stem, spinal motoneurones, the diaphragm, intercostal and upper airway muscles, neuromuscular junctions, lung and chest wall mechanics, airway smooth muscle, vagal control mechanisms and finally all structures conveying afferent input to the central nervous system (CNS) including the carotid bodies. It is very difficult to design paradigms to study the relative contribution of all these structures to the net effect of anesthetics on respiration. The effects on respiratory parameters and the contribution of separate structures will critically depend on the specific experimental conditions: arousal state (is there a background anesthesia or are animals decerebrated), artificially ventilated vs. spontaneous breathing, paralyzed or not, tracheotomy vs. intact upper airways, intact vs. denervated vagus and/or glossopharyngeal nerves, etc.

Numerous studies have shown that, apart from having complex peripheral effects, general anesthetics act on both pre- and postsynaptic membranes of respiratory (pre)motoneurones, alter their excitability and modulate both the release and efficacy of neurotransmitters (e.g. Stuth et al., 2005, Stuth et al., 2008). In studies on the pharmacological control of breathing it is therefore of crucial importance to interpret experimental findings in light of the mechanisms of action of the particular anesthetic used, or, even better, to design paradigms to avoid or minimize confounding effects by anesthetics. Studying ventilatory effects of anesthetics (e.g. volatile anesthetics) at a background of intravenous anesthesia is problematic since most general anesthetics have common molecular targets, acting on the same ligand-gated and other ion channels. Part of these problems can be avoided by employing decerebration which provides a means of performing pharmacological studies without the confounding background of anesthesia.

Here we will briefly summarize the current state of knowledge on the molecular targets of the most important intravenous and volatile anesthetics used in animal research and clinical medicine and place these in the context of respiratory control. In subsequent sections we will then briefly summarize the methods that can be used to determine drug effects on respiratory control and finally discuss known effects of volatile and some intravenous anesthetics on breathing.