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• W2025751104 abstract "Modern anaesthetics are, in the main, safe and predictable in their use, and highly efficient. Moreover, it could be argued that without these properties major advances in surgical practice, so often highlighted in the media, could not have taken place. However, as an example of pharmacology, the production of the anaesthetic state remains somewhat of a mystery. This mystery results from the controversies related to the existence of a unitary anaesthetic target site. From direct observation of clinical anaesthesia, this seems unlikely as different anaesthetic agents produce different ‘types’ of anaesthesia. GABAA receptors have long been held as a unifying cellular target (with some exceptions), but others have also been suggested. In this editorial, we consider the evidence in support of a role for noradrenergic transmission as a ‘wiring’ target for anaesthetic action. The clear role of this system in analgesia is not considered. Norepinephrine is a major central nervous system neurotransmitter in the brainstem. Noradrenergic neurones are of great importance in the regulation of a range of behaviours including the sleep–wake cycle, feeding, thermoregulation, attention, motor activity, and growth and development.1Steriade M McCarley RW. Neurotransmitter-modulated ionic currents of brainstem neurons and some of their targets.in: Steriade M McCarley RW Brainstem Control of Wakefulness and Sleep. Plenum Press, New York1990: 164-203Crossref Google Scholar In addition, there are many studies suggesting that noradrenergic system(s) may be involved in the production of the ‘anaesthetic state’. In the brain, the A1, A2, A5, and A7 noradrenergic clusters constituting the lateral tegmental area, project to the thalamus and hypothalamus.2Nieuwenhuys R. Survey of chemically defined cell groups and pathways.in: Nieuwenhuys R Chemoarchitecture of the Brain. Springer-Verlag, Berlin1985: 7-113Crossref Google Scholar The locus coeruleus (A6 cluster), which is distinct from the lateral tegmental area, innervates the cerebral cortex, hippocampus, cerebellum, and spinal cord.2Nieuwenhuys R. Survey of chemically defined cell groups and pathways.in: Nieuwenhuys R Chemoarchitecture of the Brain. Springer-Verlag, Berlin1985: 7-113Crossref Google Scholar The activity of locus coeruleus neurones is slow and regular during wakefulness.3Berridge CW Abercrombie ED. Relationship between locus coeruleus discharge rates and rates of norepinephrine release within neocortex as assessed by in vivo microdialysis.Neuroscience. 1999; 93: 1263-1270Crossref PubMed Scopus (139) Google Scholar In contrast, when an animal becomes drowsy, entering slow wave and then REM sleep, there is a decrease in discharge rate such that during REM sleep these neurones are silent.3Berridge CW Abercrombie ED. Relationship between locus coeruleus discharge rates and rates of norepinephrine release within neocortex as assessed by in vivo microdialysis.Neuroscience. 1999; 93: 1263-1270Crossref PubMed Scopus (139) Google ScholarInterestingly, all noradrenergic projections to the cerebrocortex originate from the locus coeruleus.3Berridge CW Abercrombie ED. Relationship between locus coeruleus discharge rates and rates of norepinephrine release within neocortex as assessed by in vivo microdialysis.Neuroscience. 1999; 93: 1263-1270Crossref PubMed Scopus (139) Google Scholar The preoptic area receives input from both the locus coeruleus (A6), and the lateral tegmental group (A1, A2, A5, and A7) noradrenergic neurones.4Mizuno T Ito E Kimura F. Pentobarbital sodium inhibits the release of noradrenaline in the medial preoptic area.Neurosci Lett. 1994; 170: 111-113Crossref PubMed Scopus (18) Google Scholar In addition, neurones in the preoptic area project back to the locus coeruleus.5Osaka T Matsumura H. Noradrenergic inputs to sleep-related neurons in the preoptic area from the locus coeruleus and the ventrolateral medulla in the rat.Neurosci Res. 1994; 19: 39-50Crossref PubMed Scopus (60) Google Scholar This area plays an important role in sleep or hypnosis. What is the role of noradrenergic neurones in this area? Most of the previous studies6Osaka T Matsumura H. Noradrenaline inhibits preoptic sleep-active neurons through α2-receptors in the rat.Neurosci Res. 1995; 21: 323-330Crossref PubMed Scopus (47) Google Scholar suggest that norepinephrine neurones in the preoptic area may contribute to wakefulness, as direct activation or injection of norepinephrine into this area inhibits sleep. However, several studies also suggest that some norepinephrine neurones may be involved in the induction of sleep.7Mohan Kumar V Sharma R Wadhwa S Manchanda SK. Sleep-inducing function of noradrenergic fibers in the medial preoptic area.Brain Res Bull. 1993; 32: 153-158Crossref PubMed Scopus (38) Google Scholar 8Ramesh V Mohan Kumar V. Changes in sleep-wakefulness after 6-hydroxydopamine lesion of the preoptic area.Neuroscience. 2000; 98: 549-553Crossref PubMed Scopus (19) Google Scholar Mohan Kumar and colleagues7Mohan Kumar V Sharma R Wadhwa S Manchanda SK. Sleep-inducing function of noradrenergic fibers in the medial preoptic area.Brain Res Bull. 1993; 32: 153-158Crossref PubMed Scopus (38) Google Scholar reported that microinjection of norepinephrine into the medial preoptic area after destruction of the ventral noradrenergic bundle induced sleep. This group also reported that there was a mild reduction in sleep and an increase in wakefulness after destruction of catecholaminergic terminals at the medial preoptic area by bilateral intracerebral injection of 6-hydroxydopamine.8Ramesh V Mohan Kumar V. Changes in sleep-wakefulness after 6-hydroxydopamine lesion of the preoptic area.Neuroscience. 2000; 98: 549-553Crossref PubMed Scopus (19) Google Scholar Thus, it appears that noradrenergic fibres in the medial preoptic area may be hypnogenic. Central noradrenergic neurones are regulated by both α- and β-adrenergic receptors. It has been reported that the α1-adrenoceptor antagonist prazosin, given orally, increased active waking and slow wave sleep and decreased paradoxical sleep in the rat.9Kleinlogel H. Effects of the selective alpha 1-adrenoceptor blocker prazocin on EEG sleep and waking stages in the rat.Neuropsychobiology. 1989; 21: 100-103Crossref PubMed Scopus (25) Google Scholar In contrast, α1-adrenoceptor stimulation with systemic methoxamine, increased aroused wakefulness and decreased slow wave sleep and paradoxical sleep in cats.10Hilakivi I Leoppa¨vuori A. Effects of methoxamine, and alpha-1 adrenoceptor agonist, and prazosin, an alpha-1 antagonist, on the stages of the sleep–waking cycle in the cat.Acta Physiol Scand. 1984; 120: 363-372Crossref PubMed Scopus (59) Google Scholar In addition, prazosin increased but the α1-agonist ST 587 decreased the duration of thiopental anaesthesia in rats.11Mason ST Angel A. Anaesthesia: the role of adrenergic mechanisms.Eur J Pharmacol. 1983; 91: 29-39Crossref PubMed Scopus (33) Google Scholar Matsumoto and colleagues also reported that direct intracerebroventricular administration of methoxamine dose-dependently reduced pentobarbital anaesthesia time in mice.12Matsumoto K Kohno SI Ojima K Watanabe H. Flumazenil but not FG7142 reverses the decrease in pentobarbital sleep caused by activation of central noradrenergic systems in mice.Brain Res. 1997; 754: 325-328Crossref PubMed Scopus (14) Google Scholar Most of the central physiological effects of α2-agonists can be attributed to α2-adrenoceptors present in the locus coeruleus.13Callodo LF Stamford JA. Spatiotemporal interaction of α2 autoreceptors and noradrenaline transporters in the rat locus coeruleus: implications for volume transmission.J Neurochem. 2000; 74: 2350-2358Crossref PubMed Scopus (37) Google Scholar In rats, microinjection of the α2-agonist dexmedetomedine into the locus coeruleus per se produces anaesthesia (defined as a loss of righting reflex).14Nacif CoelhoC Correa Sales C Chang LL Maze M. Perturbation of ion channel conductance alters the hypnotic response to the α2-adrenergic agonist dexmedetomidine in the locus coeruleus of the rat.Anesthesiology. 1994; 81: 1527-1534Crossref PubMed Scopus (92) Google Scholar α2-Agonists also reduce anaesthetic requirement in human and many other species.15Maze M Tranquilli W. Alpha-2 adrenergic agonists: defining the role in clinical anesthesia.Anesthesiology. 1991; 74: 581-605Crossref PubMed Scopus (660) Google Scholar In contrast to these data, the α2-antagonist yohimbine decreases sleep,16Angel A Majeed AB. Alterations of ‘sleeping time’ in the rat induced by drugs which modulate central monoaminergic systems.Br J Anaesth. 1990; 64: 594-600Crossref PubMed Scopus (12) Google Scholar and anaesthesia time15Maze M Tranquilli W. Alpha-2 adrenergic agonists: defining the role in clinical anesthesia.Anesthesiology. 1991; 74: 581-605Crossref PubMed Scopus (660) Google Scholar in a variety of non-human species. The Angel group showed that propranolol, a non-selective β-antagonist, dose-dependently increased sleep time16Angel A Majeed AB. Alterations of ‘sleeping time’ in the rat induced by drugs which modulate central monoaminergic systems.Br J Anaesth. 1990; 64: 594-600Crossref PubMed Scopus (12) Google Scholar and thiopental anaesthesia time11Mason ST Angel A. Anaesthesia: the role of adrenergic mechanisms.Eur J Pharmacol. 1983; 91: 29-39Crossref PubMed Scopus (33) Google Scholar in rats. However, they failed to show an effect with the selective β1-antagonists metoprolol and atenolol.11Mason ST Angel A. Anaesthesia: the role of adrenergic mechanisms.Eur J Pharmacol. 1983; 91: 29-39Crossref PubMed Scopus (33) Google Scholar 17Mason ST Angel A. Brain noradrenaline and anaesthesia: further characterization of the beta-receptor.Neuropharmacology. 1983; 22: 1065-1069Crossref PubMed Scopus (15) Google Scholar They also studied the role of β2-adrenoceptors in sleep and general anaesthesia,11Mason ST Angel A. Anaesthesia: the role of adrenergic mechanisms.Eur J Pharmacol. 1983; 91: 29-39Crossref PubMed Scopus (33) Google Scholar 16Angel A Majeed AB. Alterations of ‘sleeping time’ in the rat induced by drugs which modulate central monoaminergic systems.Br J Anaesth. 1990; 64: 594-600Crossref PubMed Scopus (12) Google Scholar 17Mason ST Angel A. Brain noradrenaline and anaesthesia: further characterization of the beta-receptor.Neuropharmacology. 1983; 22: 1065-1069Crossref PubMed Scopus (15) Google Scholar and found that the selective β2-antagonist ICI 118551 increased sleep time16Angel A Majeed AB. Alterations of ‘sleeping time’ in the rat induced by drugs which modulate central monoaminergic systems.Br J Anaesth. 1990; 64: 594-600Crossref PubMed Scopus (12) Google Scholar and the duration of thiopental anaesthesia.17Mason ST Angel A. Brain noradrenaline and anaesthesia: further characterization of the beta-receptor.Neuropharmacology. 1983; 22: 1065-1069Crossref PubMed Scopus (15) Google Scholar Collectively, these data indicate that the effects of the non-selective antagonist, propranolol, may be mediated via β2-adrenoceptors. The recently identified (from rat hypothalamus) neuropeptides orexin A and B18Smart D. Orexins: a new family of neuropeptides.Br J Anaesth. 1999; 83: 695-697Crossref PubMed Scopus (24) Google Scholar are endogenous agonists for the G-protein-coupled orexin-1 (OX1) and OX2 receptors.18Smart D. Orexins: a new family of neuropeptides.Br J Anaesth. 1999; 83: 695-697Crossref PubMed Scopus (24) Google Scholar Orexin A has equal affinity for OX1 and OX2, while orexin B has a higher affinity for OX2. Orexins and their receptors are widely distributed in the brain.18Smart D. Orexins: a new family of neuropeptides.Br J Anaesth. 1999; 83: 695-697Crossref PubMed Scopus (24) Google Scholar Orexins activate the locus coeruleus noradrenergic system and this activation may increase arousal and locomotor activity.19Hagan JJ Leslie RA Patel S et al.Orexin A activates locus coeruleus cell firing and increases arousal in the rat.Proc Natl Acad Sci USA. 1999; 96: 10911-10916Crossref PubMed Scopus (1076) Google Scholar In addition, several reports20Lin L Faraco J Li R et al.The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.Cell. 1999; 98: 365-376Abstract Full Text Full Text PDF PubMed Scopus (2216) Google Scholar suggest a link between orexin receptors and narcolepsy. Therefore, modulation of noradrenergic neurones by orexins and their receptors may contribute to control of the sleep–wake cycle. Moreover, we suggest that these neuropeptides and their receptors may also be involved in general anaesthesia, although this remains to be examined. Based on these considerations, we and others have began a systematic evaluation of a range of anaesthetic agents on central norepinephrine release using in vivo microdialysis techniques. Mizuno and colleagues reported that intraperitoneal pentobarbital inhibited norepinephrine release from the medial preoptic area in rats.4Mizuno T Ito E Kimura F. Pentobarbital sodium inhibits the release of noradrenaline in the medial preoptic area.Neurosci Lett. 1994; 170: 111-113Crossref PubMed Scopus (18) Google Scholar In addition, we have shown that systemic administration of midazolam and propofol significantly reduced norepinephrine release from the medial prefrontal cortex,21Kubota K Hirota K Yoshida H et al.Effects of sedatives on noradrenaline release from the medial prefrontal cortex in rats. GABAAreceptor activator vs NMDA receptor inhibitor.Psychopharmacology. 1999; 146: 335-338Crossref PubMed Scopus (44) Google Scholar but pentobarbital was ineffective.22Kubota T Anzawa N Hirota K Yoshida H Matsuki A. Effects of ketamine and pentobarbital on norepinephrine release from the median frontal cortex in rats.Can J Anaesth. 1999; 46: 388-392Crossref PubMed Scopus (48) Google Scholar As noradrenergic neurones in the prefrontal cortex receive innervation from the locus coeruleus,3Berridge CW Abercrombie ED. Relationship between locus coeruleus discharge rates and rates of norepinephrine release within neocortex as assessed by in vivo microdialysis.Neuroscience. 1999; 93: 1263-1270Crossref PubMed Scopus (139) Google Scholar the activity of noradrenergic neurones in the prefrontal cortex indirectly reflects locus coeruleus activity. Thus, anaesthetics that activate or enhance GABAA receptors may reduce noradrenergic neuronal activity. In contrast, ketamine,21Kubota K Hirota K Yoshida H et al.Effects of sedatives on noradrenaline release from the medial prefrontal cortex in rats. GABAAreceptor activator vs NMDA receptor inhibitor.Psychopharmacology. 1999; 146: 335-338Crossref PubMed Scopus (44) Google Scholar 22Kubota T Anzawa N Hirota K Yoshida H Matsuki A. Effects of ketamine and pentobarbital on norepinephrine release from the median frontal cortex in rats.Can J Anaesth. 1999; 46: 388-392Crossref PubMed Scopus (48) Google Scholar nitrous oxide and xenon,23Yoshida H Kushikata T Kubota T Hirota K Ishihara H Matsuki A. Increased norepinephrine release from anterior and posterior hypothalamus following xenon inhalation.Can J Anesth. 2001; 48: 651-655Crossref PubMed Scopus (18) Google Scholar which have NMDA receptor antagonistic actions, markedly increased norepinephrine release from the prefrontal cortex and preoptic area in rats. Clearly, anaesthetic modulation of norepinephrine release depends on the type of anaesthetic. This might argue against noradrenergic transmission as an anaesthetic target. However, as we have already mentioned, a unitary site is highly unlikely. Loss of consciousness results not only from a reduction in cerebral activity, but also as a result of cerebral excitation such as occurs during convulsions. In addition, sleepiness is induced by not only hypothermia but also by increased body temperature that activates heat-sensitive neurones in the preoptic area.24Alam MN McGinity D Szymusiak R. Neuronal discharge of preoptic/anterior hypothalamus thermosensitive neurons: relation to NREM sleep.Am J Physiol. 1995; 269: R1240-R1249PubMed Google Scholar We feel that wakefulness may occur over a set range and that when this range is exceeded (above or below), unconsciousness may occur. In support of this hypothesis we found that physostigmine, which has been reported to antagonize ketamine anaesthesia, reduced both the duration of ketamine anaesthesia and ketamine-increased norepinephrine release from the rat prefrontal cortex.25Kubota K Hirota K Anzawa N Yoshida H Takahashi S Matsuki A. Physostigmine antagonizes ketamine-induced noradrenaline release from the medial prefrontal cortex in rats.Brain Res. 1999; 840: 175-178Crossref PubMed Scopus (24) Google Scholar Collectively, the data presented in this editorial provide compelling evidence in favour of a role for noradrenergic transmission in both the control of wakefulness and the production of the ‘mysterious’ anaesthetic state." @default.
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