Multiple ionic mechanisms mediate inhibition of rat motoneurones by inhalation anaesthetics

Inhalation anaesthetics have been used in surgical procedures for more than a century but their mechanism of action remains incompletely understood. Traditionally, hypotheses concerning anaesthetic mechanisms have focused on the ability of these compounds to disrupt the fluidity of the plasma membrane (Gruner & Shyamsunder, 1991), since anaesthetic potency seemed to be a linear function of hydrocarbon solubility, as described by the Meyer-Overton rule (Meyer, 1899). However, in many cases the membrane partitioning of compounds does not correlate well with anaesthetic potency (Koblin et al. 1994) and clinically effective concentrations of anaesthetic produce little or no change in membrane fluidity (Harris & Groh, 1985), indicating that a simple alteration of membrane lipids is probably not responsible for anaesthetic action. A popular alternative hypothesis that may represent an important mechanism of anaesthetic action involves alterations in synaptic transmission. For example, there is now substantial evidence that anaesthetics potentiate the effects of some inhibitory neurotransmitters (e.g. γ-aminobutyric acid, GABA) and attenuate the effects of excitatory neurotransmitters (e.g. glutamate), presumably contributing to an overall depression of central nervous system function (see Franks & Lieb, 1994, for review). Although effects of anaesthetics on synaptic transmission are undoubtedly important, it is unlikely that these actions alone are sufficient to produce surgical anaesthesia and additional mechanisms of anaesthetic action have been sought (Lynch & Pancrazio, 1994). In this respect, attention has been given to the possibility that anaesthetics may modulate intrinsic ionic conductances and, because they are primarily responsible for controlling membrane potential, K+ channels represent an obvious potential candidate to mediate anaesthetic effects. Indeed, a number of different K+ channels have been shown to be modulated by inhalation anaesthetics. In coronary artery preparations, antagonists of the sulfonylurea receptor prevent isoflurane-induced vasodilatation, suggesting that ATP-sensitive K+ (KATP) channels are a target for anaesthetic effects in those cells (Cason et al. 1994; Kersten et al. 1996). Interestingly, in a number of different in vitro central nervous system preparations, volatile anaesthetics produce a hyperpolarization of neuronal membrane potential (Nicoll & Madison, 1982; Berg-Johnsen & Langmoen, 1987; Takenoshita & Takahashi, 1987; Sugiyama et al. 1992), which in some, but not all, cases has been shown to be due to the activation of a K+ conductance (Franks & Lieb, 1988; Winegar et al. 1996). Of particular relevance, halothane causes membrane hyperpolarization in motoneurones and it was suggested, based on indirect evidence, that this effect was mediated via activation of a K+ conductance (Takenoshita & Takahashi, 1987). However, further details regarding the nature of the halothane-sensitive conductance were not determined and additional mechanisms of halothane action were not explored. The immobilization (i.e. the lack of movement in response to painful stimuli) that accompanies the anaesthetic state is a desirable effect, distinct from loss of consciousness and amnesia (Eger et al. 1997). Thus, the ability of volatile anaesthetics to modulate motoneuronal excitability may be an important consequence of the use of inhalation anaesthetics and a detailed understanding of the mechanisms underlying those effects is warranted. We therefore used whole-cell voltage clamp techniques in a neonatal rat brainstem slice preparation to test the effects of volatile anaesthetics on hypoglossal motoneurones. Hypoglossal motoneurones control the tongue musculature and participate in a number of motor activities, including regulation of airway patency during inspiration; they represent an ideal model system for study because much is known regarding the intrinsic properties and neuromodulation of this group of motoneurones (see Berger et al. 1996; Bayliss et al. 1997, for review). We report here that multiple mechanisms contribute to the effects of inhalation anaesthetics on hypoglossal motoneurones. Thus, halothane activated a Ba2+-sensitive K+ conductance and inhibited two cationic currents: a hyperpolarization-activated mixed cationic current (Ih) and a TTX-resistant, persistent Na+ current. The membrane hyperpolarization and decreased motoneuronal excitability produced by these effects, observed directly under current clamp conditions, could contribute to the immobilizing effect of inhalation anaesthetics.