Current assessment of targets and theories of anaesthesia B.W. Urban  British Journal of Anaesthesia  Volume 89, Issue 1, Pages 167-183 (July 2002) DOI: 10.1093/bja/aef165 Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 1 Direct and indirect molecular anaesthetic target sites on ion channels. British Journal of Anaesthesia 2002 89, 167-183DOI: (10.1093/bja/aef165) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 2 Meyer–Overton correlations for different ion channels, including sodium channels,10 13 15 16 36 38 41 51 70 87–90 104 113 potassium channels,13 15 25 39 40 42 43 46 52 70 calcium channels,18 19 54 105 106 nACh receptor channels,20 23 26 40 44 116–118 5-HT3 receptor channels10 58 69 124 and GABAA receptor channels.9 57 62 85 125 The number in parentheses after each channel name indicates the number of different ion channel subtypes contributing. Only anaesthetics in clinical use are included. British Journal of Anaesthesia 2002 89, 167-183DOI: (10.1093/bja/aef165) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 3 Periodic table of anaesthesia (table of molecular elements in anaesthesia). The table contains the molecular components involved in anaesthetic action, including the inhalation anaesthetics (Gas), the intravenous anaesthetics (I.V.), endogenous compounds (ENDO), noble gases (Inert), receptors as defined by the International Union of Pharmacology (IUPHAR) and ion channels as originally defined by the Ion Channel Network, including extracellular ligand-gated (ELG), intracellular ligand-gated (ILG), inward rectifying potassium (INR), junctional (JUN), voltage-gated (VLG), and miscellaneous (MIS) ion channels. Gas: (from left to right) nitrous oxide, diethyl ether, chloroform, halothane, enflurane, isoflurane, desflurane, sevoflurane, cyclopropane, divinyl ether, methoxyflurane, fluroxene, ethyl-chloride, trichloroethylene, alcohol. I.V.: (from left to right) thiopental, amobarbital, methohexital, propofol, etomidate, ketamine, midazolam, flunitrazepam, droperidol, morphine, fentanyl, remifentanil, cocaine, lidocaine, bupivacaine. ENDO: (Top to bottom) nitric oxide, carbon monoxide, carbon dioxide, endorphin, enkephalin. Ion channels (from the top of each column): ELG: 5-HT3, ATP-gated (P2X), AMPA, and kainate, NMDA glutamate receptor, nicotinic ACh receptor, GABAA receptor, glycine receptor. ILG: ryanodine, InsP3-sensitive Ca2+-release receptor, cAMP-activated cation channel, cGMP-activated cation channel, CFTR channel, Ca2+-activated K+ channel. INR: ATP-inhibited K+ channel, G/ACh muscarinic-activated K+channel Kirinwardly rectifying K+ channel, Ifhq native hyperpolarization-activated cation channel. JUN: connexins. VLG: Ca2+ channel, C1− channel, Ke (Keag, Kelk, Kerg) ether a-go-go K+ channel, Kv delayed rectifier K+ channel, Na+ channel. MIS: mechanosensitive channel; mitochondrial membrane channel, nuclear membrane channel; aquaporins; synaptophysin channel. IUPHAR receptors: (left to right, first row) muscarinic ACh receptor, adenosine receptor, adrenoceptors, angiotensin receptor, bradykinin receptor, cannabionoid receptor, chemokine receptor, cholecystokinin receptor, corticotropin-releasing factor receptor, dopamine receptor; (left to right, second row) endothelin receptor, excitatory amino acid receptor, histamine receptor, serotonin receptor, melanocortin receptor, melatonin receptor, neuropeptide Y receptor, nucleotide receptor (P2X receptor, P2Y receptor), opioid receptor, prostanoid receptor; (left to right, third row) protease-activated receptor, somatostatin, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptor, vasopressin and oxytocin receptor. British Journal of Anaesthesia 2002 89, 167-183DOI: (10.1093/bja/aef165) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 4 Anaesthetic actions on a hypothetical neurone. Anaesthetic responses depend on networks. This is illustrated here for the spatial and temporal integration of excitation and inhibition within a model neurone before and during anaesthesia. Resting fibres are shown grey, black indicates propagating excitation. The number of arrows indicates the frequency of incoming signals, and non-aligned arrows on incoming fibres indicate a temporal shift in incoming signals. Apart from receiving excitatory and inhibitory input, the excitability of the model neurone is assumed to be controlled by tonic modulatory input (no input=low excitability, high frequency input=high excitability). Anaesthetics may act on the neurone directly by modifying incoming signals (presynaptically or postsynaptically), indirectly by influencing some upstream component so that the incoming modulatory signal is modified, or by a combination of both types of action. Whether the model neurone fires action potentials depends on how the excitatory, inhibitory and modulatory inputs are connected; only an arbitrary sample of possible outcomes is shown. British Journal of Anaesthesia 2002 89, 167-183DOI: (10.1093/bja/aef165) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 4 Anaesthetic actions on a hypothetical neurone. Anaesthetic responses depend on networks. This is illustrated here for the spatial and temporal integration of excitation and inhibition within a model neurone before and during anaesthesia. Resting fibres are shown grey, black indicates propagating excitation. The number of arrows indicates the frequency of incoming signals, and non-aligned arrows on incoming fibres indicate a temporal shift in incoming signals. Apart from receiving excitatory and inhibitory input, the excitability of the model neurone is assumed to be controlled by tonic modulatory input (no input=low excitability, high frequency input=high excitability). Anaesthetics may act on the neurone directly by modifying incoming signals (presynaptically or postsynaptically), indirectly by influencing some upstream component so that the incoming modulatory signal is modified, or by a combination of both types of action. Whether the model neurone fires action potentials depends on how the excitatory, inhibitory and modulatory inputs are connected; only an arbitrary sample of possible outcomes is shown. British Journal of Anaesthesia 2002 89, 167-183DOI: (10.1093/bja/aef165) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 5 Correlation of IC50 for Kv3.1 potassium channels40 43 with clinical concentration. British Journal of Anaesthesia 2002 89, 167-183DOI: (10.1093/bja/aef165) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 6 How do molecular anaesthetic actions modify brain functions? The networks that are responsible for translating molecular effects into clinically observable effects are still unknown. British Journal of Anaesthesia 2002 89, 167-183DOI: (10.1093/bja/aef165) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 7 Meyer–Overton correlations of anaesthetic actions with octanol–water partition coefficients are observed at all six levels of CNS integration. (a) Molecular: inhibition of peak currents from sodium channels.87 88 90 (b) Subcellular: depression of compound action potentials from frog sciatic nerve.102 (c) Cellular: depression of firing rates of sensory neurones (muscle receptor organ) from crayfish.94 (d) Depression of spontaneous firing in rat neocortical brain slices.3 (e) Block of somatosensory potentials in rats.2 (f) Clinical concentrations in general anaesthetic procedures.75 British Journal of Anaesthesia 2002 89, 167-183DOI: (10.1093/bja/aef165) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions