Model of anaesthetic induction by unilateral intracerebral microinjection of GABAergic agonists.

General anaesthetic agents induce loss of consciousness coupled with suppression of movement, analgesia and amnesia. Although these diverse functions are mediated by neural structures located in wide-ranging parts of the neuraxis, anaesthesia can be induced rapidly and reversibly by bilateral microinjection of minute quantities of γ-aminobutyric acid (GABA)A -R agonists at a small, focal locus in the mesopontine tegmentum (MPTA). State switching under these circumstances is presumably executed by dedicated neural pathways and does not require widespread distribution of the anaesthetic agent itself, the classical assumption regarding anaesthetic induction. Here it was asked whether these pathways serve each hemisphere independently, or whether there is bilateral redundancy such that the MPTA on each side is capable of anaesthetizing the entire brain. Either of two GABAA -R ligands were microinjected unilaterally into the MPTA in awake rats, the barbiturate modulator pentobarbital and the direct receptor agonist muscimol. Both agents, microinjected on either side, induced clinical anaesthesia, including bilateral atonia, bilateral analgesia and bilateral changes in cortical activity. The latter was monitored using c-fos expression and electroencephalography. This action, however, was not simply a consequence of suppressing spike activity in MPTA neurons, as unilateral (or bilateral) microinjection of the local anaesthetic lidocaine at the same locus failed to induce anaesthesia. A model of the state-switching circuitry that accounts for the bilateral action of unilateral microinjection and also for the observation that inactivation with lidocaine is not equivalent to inhibition with GABAA -R agonists was proposed. This is a step in defining the overall switching circuitry that underlies anaesthesia.

Cerebral activity during the anesthesia-like state induced by mesopontine microinjection of pentobarbital.

Microinjection of pentobarbital into a restricted region of rat brainstem, the mesopontine tegmental anesthesia area (MPTA), induces a reversible anesthesia-like state characterized by loss of the righting reflex, atonia, antinociception, and loss of consciousness as assessed by electroencephalogram synchronization. We examined cerebral activity during this state using FOS expression as a marker. Animals were anesthetized for 50 min with a series of intracerebral microinjections of pentobarbital or with systemic pentobarbital and intracerebral microinjections of vehicle. FOS expression was compared with that in awake animals microinjected with vehicle. Neural activity was suppressed throughout the cortex whether anesthesia was induced by systemic or MPTA routes. Changes were less consistent subcortically. In the zona incerta and the nucleus raphe pallidus, expression was strongly suppressed during systemic anesthesia, but only mildly during MPTA-induced anesthesia. Dissociation was seen in the tuberomammillary nucleus where suppression occurred during systemic-induced anesthesia only, and in the lateral habenular nucleus where activity was markedly increased during systemic-induced anesthesia but not following intracerebral microinjection. Several subcortical nuclei previously associated with cerebral arousal were not affected. In the MPTA itself FOS expression was suppressed during systemic anesthesia. Differences in the pattern of brain activity in the two modes of anesthesia are consistent with the possibility that anesthetic endpoints might be achieved by alternative mechanisms: direct drug action for systemic anesthesia or via ascending pathways for MPTA-induced anesthesia. However, it is also possible that systemically administered agents induce anesthesia, at least in part, by a primary action in the MPTA with cortical inhibition occurring secondarily.

Reversible analgesia, atonia, and loss of consciousness on bilateral intracerebral microinjection of pentobarbital.

Concussion, asphyxia, and systemically administered general anesthetics all induce reversible depression of the organism's response to noxious stimuli as one of the elements of loss of consciousness. This is so even for barbiturate anesthetics, which have only modest analgesic efficacy at subanesthetic doses. Little is known about the neural circuits involved in this form of antinociception, although for anesthetic agents, at least, it is usually presumed that the drugs act in widely distributed regions of the nervous system. We now report the discovery of a focal zone in the brainstem mesopontine tegmentum in rats at which microinjection of minute quantities of pentobarbital induces a transient, reversible anesthetic-like state with non-responsiveness to noxious stimuli, flaccid atonia, and absence of the righting reflex. The behavioral suppression is accompanied by slow-wave EEG and, presumably, loss of consciousness. This zone, which we refer to as the mesopontine tegmental anesthesia locus (MPTA), apparently contains a barbiturate-sensitive 'switch' for both cortical and spinal activity. The very existence of the MPTA locus has implications for an understanding of the neural circuits that control motor functions and pain sensation, and for the cerebral representation of consciousness.