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What can in vivo electrophysiology in animal models tell us about mechanisms of anaesthesia?

2002; Elsevier BV; Volume: 89; Issue: 1 Linguagem: Inglês

10.1093/bja/aef166

1471-6771

Christiane Vahle-Hinz, O. Detsch,

Pain Mechanisms and Treatments

The search for the mechanisms of anaesthesia has resulted in an overwhelming multitude of cellular and subcellular sites identified as potential targets of anaesthetic action. Attempts to define a unitary mechanism of action for the diverse types of chemicals with anaesthetic potency have failed, and it is now recognized that agent-specific effects on defined neuronal sites, including the constituents of synaptic transmission, may underlie their actions. The next step in answering the question ‘how do anaesthetics cause anaesthesia?’ is to associate these cellular mechanisms of action'most of which were described using in vitro experiments'with areas and neuronal networks within the nervous system (‘where do anaesthetics cause anaesthesia?’) using preparations with fully intact pathways. Combining the knowledge gained from in vitro experiments with clinical experience, animal experiments can be designed to take the questions about anaesthetic actions to the level of the living organism. This approach is important, as it is controversial which of the many effects of anaesthetics demonstrated in vitro are important for producing relevant in vivo effects, such as hypnosis, amnesia, analgesia/antinociception, and the suppression of movement in response to noxious stimulation.44Franks NP Lieb WR Which molecular targets are most relevant to general anaesthesia?.Toxicol Lett. 1998; 100/101: 1-8Crossref Scopus (115) Google Scholar 114Urban BW Friederich P Anesthetic mechanisms in-vitro and in general anesthesia.Toxicol Lett. 1998; 100/101: 9-16Crossref Scopus (28) Google Scholar The production of unconsciousness (hypnosis) and inhibition of memory formation (amnesia) require effects on cortical function;118Veselis RA Reinsel RA Feshchenko VA Drug-induced amnesia is a separate phenomenon from sedation: electrophysiologic evidence.Anesthesiology. 2001; 95: 896-907Crossref PubMed Google Scholar 120Webb AC Consciousness and the cerebral cortex.Br J Anaesth. 1983; 55: 209-219Crossref PubMed Google Scholar on the other hand, the suppression of motor and autonomic responses to noxious stimuli and the inhibition of sensory processing may well occur at subcortical sites. Many anaesthetic agents, in clinically used doses, can produce several components of anaesthesia, but they typically show a profile of preferred actions. Moreover, neurotransmitter receptors and other putative neuronal targets of anaesthetics (such as voltage-gated or background ion channels) have a distinct distribution and density in the central nervous system (CNS). For example, the GABAA receptors in different regions of the CNS are composed of varying combinations of subunits which differ in their sensitivity to anaesthetics.88Olsen RW The molecular mechanism of action of general anesthetics: structural aspects of interactions with GABA(A) receptors.Toxicol Lett. 1998; 100/101: 193-201Crossref Scopus (40) Google Scholar Therefore, anaesthetics may preferentially affect certain regions of the CNS and may show, for example, a ‘top-down’ or ‘bottom-up’ effectiveness with increasing dose within the hierarchically organized neural systems. This review will focus on in vivo animal studies recording neuronal activity in the peripheral nervous system (PNS) and CNS involved in the different aspects of the anaesthetic state induced by general anaesthetics. We discuss a selection of studies undertaken with this aim, but further data can be hidden especially in electrophysiological investigations on CNS functioning, where the anaesthesia of the experimental animal is a necessary but not central issue. A common end point for studies on anaesthetic mechanisms is the withdrawal response to noxious stimulation, which comprises a motor and a sensory component and some information processing with all three readily assessable in electrophysiological recordings. The suppression of sensory perception is accessible for study in animal models; the site within the ascending sensory pathways and the neuronal networks affected by anaesthetics and their targets among the constituents of synaptic transmission can be explored. As suppression of pain is one of the major goals of anaesthesia and, indeed, most in vivo studies on the mechanisms of anaesthesia address questions about processing of pain and touch, this review will focus on the somatosensory system (see Fig. 1). There are few studies on suppression of hearing, another interesting aspect of anaesthesia in the operating room. Hypnosis and amnesia are difficult to assess in animal models and are not covered in this review. Methods used in in vivo animal studies on neuronal activity are: (1) evoked potential recordings of peripheral nerves, central fibre tracts or nuclei, and cortical areas; (2) extracellular single neurone recordings of action potential (spike) discharges which reflect the excitability of the neurone above its firing threshold; and (3) intracellular recordings of postsynaptic potentials and action potentials. The two questions, the ‘where?’ and the ‘how?’ of anaesthetic action may be answered to a varying extent with these methods. From latency measurements of evoked potentials, whether elicited by electrical or natural stimulation, the regions involved within the hierarchically organized systems of the CNS can be detected; electrical stimulation procedures can differentiate the fibre types involved in the PNS and to a certain degree also in the CNS; and stimuli such as non-noxious mechanical or noxious laser-heat stimuli can discriminate between sensory modalities. Evoked potentials of the CNS originate from a large population of neurones and reflect postsynaptic, rather than spike, events. Hence, they reflect a gross average of the net population activity, obscuring differential functions within the network. Therefore, details of the transmission and processing of stimulus information necessary for sensory perception of, for example, intensity, quality, duration, and velocity, cannot be assessed. Extracellular single neurone recordings, in contrast, are ideally suited to provide this kind of information. Several caveats, however, have to be considered. (1) To infer from one neurone to the population within the system requires data from larger numbers collected sequentially or simultaneously from multi-electrode arrays. (2) An electrode introduced into a CNS nucleus picks up action potentials from different parts of a neurone: the soma and dendritic branches, and the axon. Axons found within a nucleus typically may originate from three sources: ascending and descending input fibres and fibres from the neurones of the nucleus itself, traversing it en route to their termination fields. Soma and fibre recordings can be distinguished electrophysiologically by their form and duration. The sources of fibres can be identified by orthodromic and antidromic electrical stimulation. (3) Two types of neurones usually comprise a CNS nucleus: neurones projecting to one or several other brain regions and interneurones making connections within the nuclear boundaries. Projection neurones can be positively identified by electrophysiological means (antidromic activation from the site of their axonal projection), interneurones cannot. In the spinal dorsal horn the situation is particularly complex, as not only neurones belonging to different ascending and descending systems occur in close proximity or may even feed into several systems, but also those mediating different modalities/submodalities (touch, proprioception, visceroception, pain). Within the somatosensory system, low-threshold mechanoreceptive (LTM), wide dynamic range (WDR), and high-threshold (HT), that is nociceptive-specific, neurones may occur intermingled also at higher CNS stages (for definition of neuronal classes, see below). These, however, can be identified by use of stimuli known to activate adequately the sensory receptors within their peripheral receptive field (RF) (see also Fig. 2). Even more complicated than in the ‘specific’ sensory CNS areas, is the situation in the ‘non-specific’ areas, that is modulatory regions such as, for example, the brain stem reticular formation or cortical association areas, where the association between neuronal activity and experimental stimuli is not always clearly discernible (see below). These cortical regions, however, are considered to be the sites responsible for conscious perception and hence those most interesting to study in the context of mechanisms of anaesthesia. Apart from certain neurosurgical procedures, single neurone recordings in humans are difficult to obtain and obviously not suitable for systematic study.71Lenz FA Dostrovsky JO Kwan HC Tasker RR Yamashiro K Murphy JT Methods for microstimulation and recording of single neurons and evoked potentials in the human central nervous system.J Neurosurg. 1988; 68: 630-634Crossref PubMed Google Scholar 112Tsoukatos J Kiss ZH Davis KD Tasker RR Dostrovsky JO Patterns of neuronal firing in the human lateral thalamus during sleep and wakefulness.Exp Brain Res. 1997; 113: 273-282Crossref PubMed Scopus (0) Google Scholar Studies in humans using recordings of gross neuronal signalling activity (EEG and MEG) or imaging techniques which are based on cerebral metabolic (CMR) or blood flow (CBF) changes associated with neuronal function (fMRI, SPECT, PET) have highlighted brain areas involved in anaesthesia, that is the ‘where?’ of anaesthetic action. An implicit but pivotal assumption for this type of imaging study, and for many in vivo electrophysiological studies in animals, is that an anaesthetic-induced change in neuronal activity (as measured by neuronal activity or CBF/CMR change) results from the local effect of the drug at the site where the measurement is taken. This, however, is not necessarily so: on the contrary, the effects measured may reflect anaesthetic action at a quite distant site.76Menon DK Mapping the anatomy of unconsciousness'imaging anaesthetic action in the brain.Br J Anaesth. 2001; 86: 607-610Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar For example, an anaesthetic-induced decrease in cortical activity may result from suppression of the transfer of information at cortical, thalamic, brain stem, spinal, and/or peripheral sites. The ideal method, therefore, would be to record neuronal activity simultaneously at all of these sites; an approach hindered among other things, when natural stimulation is used by the requirement to match RFs. An approach to investigate the spinal actions of anaesthetics is to isolate the spinal cord by proximal spinal cooling, transection, or decerebration; these manoeuvres, however, may produce their own alterations (see below). An elegant method to circumvent the difficulty to pinpoint the site of anaesthetic action is to record from a single neurone and, simultaneously, locally administer drugs to the neurone's vicinity (using microiontophoresis or picoejection) that activate or inhibit membrane receptors/channels. This method in addition provides information about the ‘how?’ of anaesthetic action. Nearly all anaesthetics and agonists/antagonists at their potential targets (such as presynaptic and postsynaptic neurotransmitter receptors, ion channels, or uptake mechanisms) can be administered by microiontophoresis or picoejection. The pitfalls of these techniques, for example, unspecific neuronal excitation by current, pH, or high doses of ejected drugs, have to be controlled carefully. The dose of the ejected drug is difficult to determine as it depends on the time and current of application or the ejection pressure, the duration, and frequency of the pulses. Furthermore, the dose depends on the distance and geometry of the pipette tips with respect to the recorded neurone, the diffusion within the tissue and the uptake or metabolic mechanisms present; thus, the dose has to be adapted to each individual recording situation. Quantification of the effects of ejected drugs, therefore, warrants careful interpretation.59Hicks TP The history and development of microiontophoresis in experimental neurobiology.Prog Neurobiol. 1984; 22: 185-240Crossref PubMed Scopus (63) Google Scholar 73Lipski J Bellingham MC West MJ Pilowsky P Limitations of the technique of pressure microinjection of excitatory amino acids for evoking responses from localized regions of the CNS.J Neurosci Methods. 1988; 26: 169-179Crossref PubMed Google Scholar Intracellular recordings address the ‘how?’ in even more detail; however, in vivo the recording time is limited and usually cannot be extended to the several hours necessary to permit repeated systematic changes in experimental conditions. In single neurone recordings the traditional measure taken is the action potential discharge rate (expressed as impulses or spikes or events per unit of time). In studies using experimental stimuli, a distinction is made between the ongoing (‘spontaneous’) activity, that is the discharge activity in the absence of experimental stimulation, and the response activity evoked by electrical stimulation of afferent inputs or ‘natural’ stimulation of the RF of the neurone using stimuli adequate for the sensory modality under study (see Fig. 2). Normally, the response rate is determined by stimulation of the centre of the RF, which is the peripheral area from which the highest response rate can be elicited. Another measure of response activity is the size of the RF, which is determined by mapping the boundaries of the RF area. RFs of CNS neurones may be larger or smaller than those of primary afferents because of convergence and differential organization of centre/surround areas. The discharge pattern, such as tonic or burst firing, or after-discharges, is also considered to hold important information. In contrast to stimulus-evoked response discharges, the biological significance of the ongoing activity is not readily discernible under most experimental conditions. Many attempts based on sophisticated mathematics have been applied to decipher these spike train patterns.49Gruneis F Nakao M Yamamoto M Counting statistics of 1/f fluctuations in neuronal spike trains.Biol Cybern. 1990; 62: 407-413Crossref Scopus (23) Google Scholar 91Perkel DH Gerstein GL Moore GP Neuronal spike trains and stochastic point processes. I. The single spike train.Biophys J. 1967; 7: 391-418Abstract Full Text PDF PubMed Google Scholar 120Webb AC Consciousness and the cerebral cortex.Br J Anaesth. 1983; 55: 209-219Crossref PubMed Google Scholar 125Yamamoto M Nakahama H Shima K Kodama T Mushiake H Markov-dependency and spectral analyses on spike-counts in mesencephalic reticular neurons during sleep and attentive states.Brain Res. 1986; 366: 279-289Crossref PubMed Google Scholar The question remains whether changes in discharge rate adequately reflect the neuronal processes underlying the anaesthetic-induced suppression of sensory perception, hypnosis, and amnesia. The effects of anaesthetics have been studied in animal models using a background anaesthetic for ‘baseline’ recordings followed either by the administration of another anaesthetic or higher doses of the initial anaesthetic; with this preparation, the production of anaesthesia per se cannot be studied. The need for a reliable drug-free baseline has resulted in the use of decerebrate animal models that limit experiments mostly to studies on spinal cord mechanisms. As the gross surgical intervention of decerebration again results in an unphysiological state (for further discussion, see below), chronic preparations have been established where rats, cats, and monkeys were trained to accept a recording and stimulation session while being restrained. Again, training and the experimental situation might impact on the results. Recently, models of unrestrained animals have been developed, which, in turn, suffer from problems of inconsistent stimulus presentations. While the possibility to compare the activity of individual neurones in the awake and anaesthetized animal is appealing, to maintain a recording from the same neurone under both conditions is technically challenging; therefore, some authors prefer the comparison of the activity between two sets of neurones, one ‘awake’ and one ‘anaesthetized’. Furthermore, the ‘awake’ condition does not necessarily reflect a uniform state of neuronal activity, but it is subject to shifts in arousal and attention (e.g.42Fanselow EE Nicolelis MA Behavioral modulation of tactile responses in the rat somatosensory system.J Neurosci. 1999; 19: 7603-7616Crossref PubMed Google Scholar 82Morrow TJ Casey KL State-related modulation of thalamic somatosensory responses in the awake monkey.J Neurophysiol. 1992; 67: 305-317Crossref PubMed Scopus (42) Google Scholar). Apart from different preparations, a reason for incongruent results in animal studies may be species differences. Furthermore, translating results from animals to the situation in humans may suffer from similar constraints. The somatosensory system comprises touch and pain modalities. Figure 1 shows a simplified diagram of the major pathways. The peripheral sensors in the skin, muscles, joints, and internal organs are terminals of Aβ-fibres and classified as LTM (SA, RA, and PC); terminals of Aδ- and C-fibres constitute the nociceptors. Tactile events are encoded in trains of action potentials that contain information about stimulus features (intensity, duration, velocity, and location on the body surface). Nociceptors of the skin are activated by mechanical, thermal, or chemical noxious stimuli, which are those damaging or threatening to damage the integrity of the body surface. Nociceptive and tactile information from the body periphery is conveyed via the spinal cord (dorsal horn, extracranial areas; spinal trigeminal nucleus, cranial areas) and brain stem (dorsal column nuclei; principal trigeminal nucleus), respectively, to the posterior (PO) and ventrobasal (VB) complexes of the thalamus and further on to the primary somatosensory cortex. Throughout the ascending pathways, the body surface is represented in somatotopic order. These lateral thalamic and cortical areas are the targets of the sensory-discriminative aspects of pain, whereas the motivational-affective aspect of pain is mediated in medial regions, mostly via the brain stem reticular formation and medial thalamic nuclei. Primary and secondary sensory cortices receive inputs from the lateral system, while the medial system projects to other cortical regions'for example, the cingulate gyrus, or the prefrontal cortex. Information is not merely relayed in the different stages of the ascending pathways, but processed by local networks involving intrinsic interneurones and modulated by descending connections from the cortex, and from thalamic and brain stem regions for which the thalamic reticular nucleus (TRN), the mesencephalic reticular formation (MRF), and the periaqueductal grey (PAG) are shown as examples in Figure 1. In vivo studies on the effects of general anaesthetics on sensory receptors or peripheral nerve fibres are sparse. Axonal conduction of action potentials, even in fine unmyelinated nerve fibres, appears largely to be unaltered by anaesthetics as much higher (supraclinical) concentrations of anaesthetics are necessary to produce any effect compared with those altering synaptic transmission (for review see95Richards CD Actions of general anaesthetics on synaptic transmission in the CNS.Br J Anaesth. 1983; 55: 201-207Crossref PubMed Google Scholar 96Richards CD The synaptic basis of general anaesthesia.Eur J Anaesthesiol. 1995; 12: 5-19PubMed Google Scholar).15Bosnjak ZJ Seagard JL Wu A Kampine JP The effects of halothane on sympathetic ganglionic transmission.Anesthesiology. 1982; 57: 473-479Crossref PubMed Google Scholar 69Larrabee MG Pasternak JM Selective action of anesthetics on synapses and axons in mammalian sympathetic ganglia.J Neurophysiol. 1952; 15: 91-114Crossref PubMed Google Scholar As early as 1967, de Jong and Nace32De Jong RH Nace RA Nerve impulse conduction and cutaneous receptor responses during general anesthesia.Anesthesiology. 1967; 28: 851-855Crossref PubMed Google Scholar studied the effects of ether, methoxyflurane, halothane, and nitrous oxide on the compound action potential of the saphenous branch after electrical stimulation of the femoral nerve, and on action potential responses to mechanical stimulation of the nerve fibres’ cutaneous RFs. They used concentrations up to ranges where the EEG and/or the arterial pressure were profoundly depressed. The only significant change seen was a small increase of the C-wave under ether. Intravenously administered pentobarbital had no effect. They concluded from their study that volatile anaesthetics in usual anaesthetic concentrations have no important effect on conduction in the peripheral nerve or on generation of impulses in cutaneous receptors. Correspondingly, the tuning curves of auditory nerve fibres in the gecko were best (lowest thresholds, highest discharge rates) under pentobarbital and decreased only with high doses of isoflurane or ketamine.40Dodd F Capranica RR A comparison of anesthetic agents and their effects on the response properties of the peripheral auditory system.Hear Res. 1992; 62: 173-180Crossref PubMed Scopus (24) Google Scholar Using intracellular recordings, Puil and Gimbarzevsky94Puil E Gimbarzevsky B Modifications in membrane properties of trigeminal sensory neurons during general anesthesia.J Neurophysiol. 1987; 58: 87-104PubMed Google Scholar studied anaesthetic effects on membrane potentials and electrical properties of trigeminal root ganglion neurones in decerebrate guinea pigs. In more than two-thirds of the neurones, isoflurane (2–3% for 0.5–3 min) caused no consistent alterations of electrical neuronal properties; in the remaining neurones, isoflurane (2–4%) modestly reduced neuronal excitability as reflected in a reduction in spike electrogenesis and repetitive firing. In contrast, nitrous oxide had predominantly excitatory effects with increased repetitive firing. Some anaesthetics, however, seem to cause sensitization of cutaneous nociceptors innervated by Aδ- and C-fibres. This was demonstrated for halothane (0.8%)/nitrous oxide (67%) as opposed to barbiturate anaesthesia in monkeys.18Campbell JN Raja SN Meyer RA Halothane sensitizes cutaneous nociceptors in monkeys.J Neurophysiol. 1984; 52: 762-770Crossref PubMed Google Scholar It is interesting to note that the threshold to heat stimuli decreased and the responses increased (2-fold for C-fibre afferents; 5-fold for A-fibre afferents), whereas no changes to innocuous mechanical stimulation were seen in these mechanosensitive and heat-sensitive fibres. This implies a differential effect of halothane on the different types of transduction mechanisms recently shown to underlie heat and mechanical nociceptors.20Caterina MJ Schumacher MA Tominaga M Rosen TA Levine JD Julius D The capsaicin receptor: a heat-activated ion channel in the pain pathway.Nature. 1997; 389: 816-824Crossref PubMed Scopus (5263) Google Scholar A similar excitatory effect of halothane, isoflurane, and enflurane was demonstrated for C-fibres in an in vitro rabbit corneal preparation.74MacIver MB Tanelian DL Volatile anesthetics excite mammalian nociceptor afferents recorded in vitro.Anesthesiology. 1990; 72: 1022-1030Crossref PubMed Google Scholar However, these excitatory effects on peripheral nociceptors cannot account for the suppressive effects of volatile anaesthetics on CNS neurones. This is also supported by a study in dogs,8Antognini JF Kien ND Potency (minimum alveolar anesthetic concentration) of isoflurane is independent of peripheral anesthetic effects.Anesth Analg. 1995; 81: 69-72PubMed Google Scholar where the authors determined the minimum alveolar concentration (MAC) of isoflurane (as tested with noxious stimulation at the tail), and showed that MAC is independent of peripheral isoflurane effects when isolated perfusion of hind limbs and tail was used to allow the selective reduction of isoflurane concentration. At the level of the spinal cord, two systems are of interest: the ventral horn with the motor neurones as the output side of motor reflexes and the dorsal horn with sensory neurones feeding into the motor reflexes and into the ascending sensory pathways. Somatosensory neurones are classified as LTM, WDR, and HT or NS (nociceptive-specific). LTM neurones respond maximally to low-threshold (innocuous) mechanical stimulation of their RF (light touch, pressure, hair movement, or vibration) without an increase with stimuli reaching the HT (noxious) range (Fig. 2a and b; see also Fig. 4). WDR neurones receive both low- and high-threshold input and thus respond with increasing discharges to mechanical stimuli from the innocuous to the noxious range (Fig. 2c). In addition to the mechanosensitivity, many of the WDR neurones also respond to noxious thermal stimuli and receive convergent input from muscle and viscera. HT neurones are activated only by stimuli of noxious strength (Fig. 2d). Studies on the mechanisms of suppression of pain-evoked movements have shown that the spinal cord contributes significantly (for review see28Collins JG Kendig JJ Mason P Anesthetic actions within the spinal cord: contributions to the state of general anesthesia.Trends Neurosci. 1995; 18: 549-553Abstract Full Text PDF PubMed Google Scholar). Volatile anaesthetics, barbiturates, nitrous oxide, and propofol depress reflex activity (nocifensive movements) by both suppression of the excitability of spinal motor neurones and by suppression of responses of spinal nociceptive neurones in rats, cats, and monkeys (Fig. 3).28Collins JG Kendig JJ Mason P Anesthetic actions within the spinal cord: contributions to the state of general anesthesia.Trends Neurosci. 1995; 18: 549-553Abstract Full Text PDF PubMed Google Scholar 84Namiki A Collins JG Kitahata LM Kikuchi H Homma E Thalhammer JG Effects of halothane on spinal neuronal responses to graded noxious heat stimulation in the cat.Anesthesiology. 1980; 53: 475-480Crossref PubMed Google Scholar The effects are dose-dependent and appeared to be largely independent of supraspinal actions, as has been demonstrated by the block of the descending modulatory influences through transection or reversible cooling of the spinal cord, or in decerebrate animals.33De Jong RH Wagman IH Block of afferent impulses in the dorsal horn of monkey. A possible mechanism of anesthesia.Exp Neurol. 1968; 20: 352-358Crossref PubMed Google Scholar, 34De Jong RH Robles R Corbin RW Nace RA Effect of inhalation anesthetics on monosynaptic and polysynaptic transmission in the spinal cord.J Pharmacol Exp Ther. 1968; 162: 326-330PubMed Google Scholar, 35De Jong RH Robles R Morikawa KI Actions of halothane and nitrous oxide on dorsal horn neurons (‘The Spinal Gate’).Anesthesiology. 1969; 31: 205-212Crossref PubMed Google Scholar, 36De Jong RH Robles R Heavner JE Suppression of impulse transmission in the cat's dorsal horn by inhalation anesthetics.Anesthesiology. 1970; 32: 440-445Crossref PubMed Google Scholar 68Kitahata LM Ghazi-Saidi K Yamashita M Kosaka Y Bonikos C Taub A The depressant effect of halothane and sodium thiopental on the spontaneous and evoked activity of dorsal horn cells: lamina specificity, time course and dose dependence.J Pharmacol Exp Ther. 1975; 195: 515-521PubMed Google Scholar 124Yamamori Y Kishikawa K Collins JG Halothane effects on low-threshold receptive field size of rat spinal dorsal horn neurons appear to be independent of supraspinal modulatory systems.Brain Res. 1995; 702: 162-168Crossref PubMed Scopus (0) Google Scholar Also, differential lamina-specific anaesthetic effects have been described in the dorsal horn.68Kitahata LM Ghazi-Saidi K Yamashita M Kosaka Y Bonikos C Taub A The depressant effect of halothane and sodium thiopental on the spontaneous and evoked activity of dorsal horn cells: lamina specificity, time course and dose dependence.J Pharmacol Exp Ther. 1975; 195: 515-521PubMed Google Scholar A different approach was taken in a preparation (goat model) where the circulation and hence anaesthetic supply to the brain and to the spinal cord was separated.7Antognini JF Schwartz K Exaggerated anesthetic requirements in the preferentially anesthetized brain.Anesthesiology. 1993; 79: 1244-1249Crossref PubMed Google Scholar In this model propofol and thiopental had a direct depressant effect on nociceptive responses of dorsal horn neurones, while administration of propofol or thiopental to the cranial circulation (hence to the brain) had no effect.12Antognini JF Wang XW Piercy M Carstens E Propofol directly depresses lumbar dorsal horn neuronal responses to noxious stimulation in goats.Can J Anaesth. 2000; 47: 273-279Crossref PubMed Google Scholar 110Sudo M Sudo S Chen XG Piercy M Carstens E Antognini JF Thiopental directly depresses lumbar dorsal horn neuronal responses to noxious mechanical stimulation in goats.Acta Anaesthesiol Scand. 2001; 45: 823-829Crossref PubMed Scopus (15) Google Scholar The suppression of nociceptive sensory transmission by general anaesthetics is similar to the effects of opioids administered to the spinal cord (e.g.60Homma E Collins JG Kitahata LM Matsumoto M Kawahara M Suppression of noxiously evoked WDR dorsal horn neuronal activity by spinally administered morphine.Anesthesiology. 1983; 58: 232-236Crossref PubMed Google Scholar 67Kitahata LM Kosaka Y Taub A Bonikos K Hoffert M Lamina-specific suppression of dorsal-horn unit activity by morphine sulfate.Anesthesiology. 1974; 41: 39-48Crossref PubMed Google Scholar 111Toyooka H Kitahata LM Dohi S Ohtani M Hanaoka K Taub A Effects of morphine on the rexed lamina VII spinal neuronal response to graded noxious radiant heat stimulation.Exp Neurol. 1978; 62: 146-158Crossref PubMed Google Scholar 123Yaksh TL Pharmacol