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1.
Eur J Pharmacol ; 723: 29-37, 2014 Jan 15.
Article in English | MEDLINE | ID: mdl-24333550

ABSTRACT

N-methyl-d-aspartate (NMDA) receptors are important in mediating excitatory neurotransmission in the nervous system. They are preferentially inhibited by some general anesthetics and have, therefore, been implied in the mediation of their effects. This review summarizes the main research findings available related to NMDA receptors and their role in anesthesia. The contribution of NMDA receptors to the anesthetized state is discussed separately for each of its components: amnesia, analgesia, unconsciousness and immobility. Anesthetic-induced unconsciousness and immobility have received the most attention in the research community and are the main focus of this review. In the overall perspective, however, studies using pharmacological or electrophysiological approaches have failed to reach definitive conclusions regarding the contribution of NMDA receptors to these anesthetic endpoints. None of the studies have specifically addressed the role of NMDA receptors in the amnestic effect of general anesthetics, and the few available data are (at best) only indirect. NMDA receptor antagonism by general anesthetics may have a preventive anti-hyperalgesic effect. The only and most extensively used genetic tool to examine the role of NMDA receptors in anesthesia is global knockout of the GluN2A subunit of the NMDA receptor. These animals are resistant to many intravenous and inhalational anesthetics, but the interpretation of their phenotype is hindered by the secondary changes occurring in these animals after GluN2A knockout, which are themselves capable of altering anesthetic sensitivity. Generation of more sophisticated conditional knockout models targeting NMDA receptors is required to finally define their role in the mechanisms of anesthesia.


Subject(s)
Anesthesia , Anesthetics/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Anesthetics/therapeutic use , Animals , Humans , Protein Subunits , Receptors, N-Methyl-D-Aspartate/chemistry
2.
Eur J Pharmacol ; 698(1-3): 200-5, 2013 Jan 05.
Article in English | MEDLINE | ID: mdl-23123346

ABSTRACT

N-methyl-d-aspartate (NMDA) receptors can be inhibited by inhalational anesthetics in vitro at clinically relevant concentrations. Here, to clarify the role of NMDA receptors in anesthetic-induced unconsciousness, we examined the hypnotic properties of isoflurane, sevoflurane and nitrous oxide in NMDA receptor GluN2A subunit knockout mice. The hypnotic properties of inhalational anesthetics were evaluated in mice in the loss of righting reflex (LORR) assay by measuring the 50% concentration for LORR (LORR ED(50)). Knockout mice displayed isoflurane and sevoflurane LORR ED(50) values similar to wild-type controls, indicating no significant contribution of these receptors to the hypnotic action of halogenated anesthetics. However, compared with wild-type controls, mutant mice displayed larger isoflurane LORR ED(50) values in the presence of nitrous oxide, indicating a resistance to this gaseous anesthetic. Knockout mice have enhanced brain monoaminergic activity which occurs secondary to NMDA receptor dysfunction, and the observed resistance to the isoflurane LORR ED(50)-sparing effect of nitrous oxide could be abolished by pretreatment with the dopamine D(2) receptor antagonist droperidol or with the serotonin 5-HT(2A) receptor antagonist ketanserin. Thus, resistance to nitrous oxide in knockout mice appears to be a secondary phenomenon of monoaminergic origin and not a direct result of impaired NMDA receptor function. Our results indicate that NMDA receptors are not critically involved in the hypnotic action of conventionally-used inhalational anesthetics. Also, they suggest that increased brain monoaminergic tone can diminish the effects of general anesthesia. Finally, they provide further evidence that changes secondary to genetic manipulation can explain the results obtained in global knockouts.


Subject(s)
Biogenic Monoamines/metabolism , Brain/drug effects , Brain/metabolism , Drug Resistance/genetics , Nitrous Oxide/pharmacology , Receptors, N-Methyl-D-Aspartate/deficiency , Receptors, N-Methyl-D-Aspartate/genetics , Anesthetics/chemistry , Anesthetics/pharmacology , Animals , Biogenic Monoamines/antagonists & inhibitors , Droperidol/pharmacology , Gene Knockout Techniques , Halogenation , Hypnotics and Sedatives/chemistry , Hypnotics and Sedatives/pharmacology , Ketanserin/pharmacology , Male , Mice , Mice, Inbred C57BL , Nitrous Oxide/chemistry , Reflex, Righting/drug effects , Unconsciousness/chemically induced
3.
Anesth Analg ; 110(2): 461-5, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-19933527

ABSTRACT

BACKGROUND: Until recently, the N-methyl-D-aspartate (NMDA) receptor was considered to possibly mediate the immobility produced by inhaled anesthetics such as isoflurane and nitrous oxide. However, new evidence suggests that the role of this receptor in abolition of the movement response may be less important than previously thought. To provide further evidence supporting or challenging this view, we examined the anesthetic potencies of isoflurane and nitrous oxide in genetically modified animals with established NMDA receptor dysfunction caused by GluRepsilon1 subunit knockout. METHODS: The immobilizing properties of inhaled anesthetics in mice quantitated by the minimum alveolar anesthetic concentration (MAC) were evaluated using the classic tail clamp method. RESULTS: Compared with wild-type controls, NMDA receptor GluRepsilon1 subunit knockout mice displayed larger isoflurane MAC values indicating a resistance to the immobilizing action of isoflurane. Knockout mice were previously shown to have enhanced monoaminergic tone as a result of genetic manipulation, and this increase in MAC could be abolished in our experiments by pretreatment with the serotonin 5-hydroxytryptamine type 2A receptor antagonist ketanserin or with the dopamine D2 receptor antagonist droperidol at doses that did not affect MAC values in wild-type animals. Mutant mice also displayed resistance to the isoflurane MAC-sparing effect of nitrous oxide, but this resistance was similarly abolished by ketanserin and droperidol. Thus, resistance to the immobilizing action of inhaled anesthetics in knockout mice seems to be secondary to increased monoaminergic activation after knockout rather than a direct result of impaired NMDA receptor function. CONCLUSIONS: Our results confirm recent findings indicating no critical contribution of NMDA receptors to the immobility induced by isoflurane and nitrous oxide. In addition, they demonstrate the ability of changes secondary to genetic manipulation to affect the results obtained in global knockout studies.


Subject(s)
Anesthetics, Inhalation/pharmacology , Gene Knockout Techniques , Isoflurane/pharmacology , Movement/drug effects , Nitrous Oxide/pharmacology , Receptors, N-Methyl-D-Aspartate/genetics , Animals , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Droperidol/pharmacology , Isoflurane/pharmacokinetics , Ketanserin/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pain Threshold , Pulmonary Alveoli/chemistry , Serotonin Antagonists/pharmacology
4.
Eur J Neurosci ; 27(12): 3182-90, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18554299

ABSTRACT

Dexmedetomidine is a highly specific, potent and selective alpha(2)-adrenoceptor agonist. Although intrathecal and epidural administration of dexmedetomidine has been found to produce analgesia, whether this analgesia results from an effect on spinal cord substantia gelatinosa (SG) neurons remains unclear. Here, we investigated the effects of dexmedetomidine on postsynaptic transmission in SG neurons of rat spinal cord slices using the whole-cell patch-clamp technique. In 92% of the SG neurons examined (n = 84), bath-applied dexmedetomidine induced outward currents at -70 mV in a concentration-dependent manner, with the value of effective concentration producing a half-maximal response (0.62 microM). The outward currents induced by dexmedetomidine were suppressed by the alpha(2)-adrenoceptor antagonist yohimbine, but not by prazosin, an alpha(1)-, alpha(2B)- and alpha(2C)-adrenoceptor antagonist. Moreover, the dexmedetomidine-induced currents were partially suppressed by the alpha(2C)-adrenoceptor antagonist JP-1302, while simultaneous application of JP-1302 and the alpha(2A)-adrenoceptor antagonist BRL44408 abolished the current completely. The action of dexmedetomidine was mimicked by the alpha(2A)-adrenoceptor agonist oxymetazoline. Plots of the current-voltage relationship revealed a reversal potential at around -86 mV. Dexmedetomidine-induced currents were blocked by the addition of GDP-beta-S [guanosine-5'-O-(2-thiodiphosphate)] or Cs+ to the pipette solution. These findings suggest that dexmedetomidine hyperpolarizes the membrane potentials of SG neurons by G-protein-mediated activation of K+ channels through alpha(2A)- and alpha(2C)-adrenoceptors. This action of dexmedetomidine might contribute, at least in part, to its antinociceptive action in the spinal cord.


Subject(s)
Adrenergic alpha-Agonists/pharmacology , Dexmedetomidine/pharmacology , Posterior Horn Cells/drug effects , Substantia Gelatinosa/cytology , Substantia Gelatinosa/drug effects , Animals , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , GTP-Binding Proteins/metabolism , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Organ Culture Techniques , Patch-Clamp Techniques , Posterior Horn Cells/physiology , Potassium Channels/physiology , Rats , Rats, Wistar , Substantia Gelatinosa/physiology , Synapses/drug effects , Synapses/physiology
5.
Pain ; 134(1-2): 24-31, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17481820

ABSTRACT

The effects of nitrous oxide (N2O) are thought to be mediated by several pharmacological pathways at different levels of the central nervous system. Here, we focus on excitatory glutamatergic transmission in the superficial dorsal horn of the spinal cord with respect to its importance for the nociceptive processing. The effects of 50% N2O on electrically evoked and spontaneous excitatory glutamatergic transmission and on the response to exogenous administration of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid (AMPA) receptor agonists were examined in lamina II neurons of adult rat spinal cord slices using the whole-cell patch-clamp technique. Peak amplitudes of Adelta- and C-fiber evoked monosynaptic NMDA- and AMPA-receptor-mediated excitatory postsynaptic currents (EPSCs) were decreased in the presence of N2O. N2O reduced the peak amplitude and integrated area of exogenous NMDA- and AMPA-induced currents. Moreover N2O changed the distribution of miniature EPSC amplitude, but not frequency distribution in most neurons. N2O inhibits glutamatergic transmission in the superficial dorsal horn by modulating the NMDA- and AMPA-receptors. Our findings raise the possibility that the antinociceptive effect of N2O may be directly mediated at the level of the spinal cord.


Subject(s)
Glutamic Acid/physiology , Neural Inhibition/physiology , Nitrous Oxide/pharmacology , Posterior Horn Cells/drug effects , Posterior Horn Cells/physiology , Synaptic Transmission/drug effects , Animals , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , N-Methylaspartate/pharmacology , Rats , Rats, Wistar , Receptors, AMPA/agonists , Receptors, AMPA/antagonists & inhibitors , Receptors, AMPA/physiology , Synaptic Transmission/physiology
6.
Neuropharmacology ; 50(6): 741-7, 2006 May.
Article in English | MEDLINE | ID: mdl-16427663

ABSTRACT

Although the properties of ketamine appear to be well characterized, there is a lot of ambiguity in the literature regarding its analgesic effects. After careful selection of proper experimental conditions and drug doses, we systematically characterized the effects of systemic ketamine on acute somatic nociception in mice and examined the role of the NMDA receptor epsilon1 subunit in mediating its analgesia. Intraperitoneal administration of ketamine was not analgesic in any of the phasic pain assays (thermal, mechanical, electrical) applied to C57BL/6 (wild-type) and NMDA receptor epsilon1 subunit knockout (mutant) mice. Surprisingly, rather than being analgesic for thermal nociception, ketamine showed pronociceptive properties in case of low-intensity heat stimulation in wild-type mice. In the formalin test (tonic pain), ketamine significantly reduced phase 2 nociceptive behavior in both wild-type and mutant mice. These data indicate that in wild-type mice ketamine has no analgesic effect on phasic pain in normal somatic tissues, but alleviates tonic pain after inflammation. Such analgesic spectrum of ketamine can be fully explained by its NMDA receptor antagonist properties. The results for the mutant mice suggest that the epsilon1 subunit of the NMDA receptor does not mediate the analgesic effects of ketamine in tonic pain.


Subject(s)
Excitatory Amino Acid Antagonists/administration & dosage , Ketamine/administration & dosage , Nociceptors/drug effects , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Behavior, Animal , Dose-Response Relationship, Drug , Drug Interactions , Formaldehyde/pharmacology , Hot Temperature , Hyperalgesia/drug therapy , Mice , Mice, Inbred C57BL , Mice, Knockout , Morphine/administration & dosage , Pain/psychology , Pain Measurement/methods , Receptors, N-Methyl-D-Aspartate/deficiency
7.
Anesthesiology ; 104(2): 338-43, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16436854

ABSTRACT

BACKGROUND: Although intrathecal administration of midazolam, a water-soluble imidazobenzodiazepine derivative, has been found to produce analgesia, how it exerts this effect at the neuronal level in the spinal cord is not fully understood. METHODS: The effects of midazolam on electrically evoked and spontaneous excitatory transmission were examined in lamina II neurons of adult rat spinal cord slices using the whole cell patch clamp technique. RESULTS: Bath-applied midazolam (1 microm) diminished Adelta- and C-fiber evoked polysynaptic excitatory postsynaptic currents in both amplitude and integrated area. However, it affected neither Adelta- and C-fiber evoked monosynaptic excitatory postsynaptic currents in amplitude nor miniature excitatory postsynaptic currents in amplitude, frequency, and decay time constant. In the presence of a benzodiazepine receptor antagonist, flumazenil (5 microm), midazolam (1 microm) did not diminish Adelta-fiber evoked polysynaptic excitatory postsynaptic currents, suggesting that midazolam modulate the gamma-aminobutyric acid interneurons in the dorsal horn. CONCLUSIONS: Midazolam reduced excitatory synaptic transmission by acting on the gamma-aminobutyric acid type A/benzodiazepine receptor in interneurons, leading to a decrease in the excitability of spinal dorsal horn neurons. This may be a possible mechanism for the antinociception by midazolam in the spinal cord.


Subject(s)
Adjuvants, Anesthesia/pharmacology , Hypnotics and Sedatives/pharmacology , Midazolam/pharmacology , Neurons/drug effects , Spinal Cord/drug effects , Synaptic Transmission/drug effects , Animals , Bicuculline/pharmacology , Electric Stimulation , Electrophysiology , Excitatory Amino Acid Agonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , GABA Antagonists/pharmacology , Glutamic Acid/physiology , In Vitro Techniques , Nerve Fibers, Myelinated/drug effects , Nerve Fibers, Unmyelinated/drug effects , Patch-Clamp Techniques , Rats , Spinal Cord/cytology , Spinal Nerve Roots/cytology , Spinal Nerve Roots/drug effects , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
8.
Anesth Analg ; 102(1): 124-8, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16368816

ABSTRACT

Volatile inhaled anesthetics and nitrous oxide (N2O) are often used together in clinical practice to produce analgesia. Because the analgesic effect of N2O is, at least in part, mediated by norepinephrine (NE) release in the spinal cord, we examined the interaction between isoflurane (ISO) and NE in the adult rat spinal cord with respect to central nociceptive information processing. The effects of clinically relevant concentrations of ISO (1 MAC) and NE (20 microM) on spontaneous inhibitory transmission in substantia gelatinosa (SG) neurons were examined using the blind whole-cell patch-clamp method. ISO prolonged the decay time and increased the total charge transfer of spontaneous inhibitory postsynaptic currents. NE increased the frequency and mean amplitude of inhibitory postsynaptic currents and the charge transfer as well. Coapplication of both drugs led to an additive increase of the charge transfer and frequent temporal summation of inhibitory postsynaptic currents. We conclude that both ISO and NE enhance the inhibitory synaptic transmission in the rat SG neurons and their interaction is additive, suggesting that ISO may add to the analgesic action of N2O at the spinal cord dorsal horn level.


Subject(s)
Isoflurane/pharmacology , Neural Inhibition/drug effects , Norepinephrine/pharmacology , Substantia Gelatinosa/drug effects , Synaptic Transmission/drug effects , Action Potentials/drug effects , Action Potentials/physiology , Animals , In Vitro Techniques , Male , Neural Inhibition/physiology , Rats , Rats, Wistar , Substantia Gelatinosa/physiology , Synaptic Transmission/physiology
10.
Anesth Analg ; 101(5): 1381-1388, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16243998

ABSTRACT

A wide range of physiological effects are mediated by alpha2-adrenoceptors (ARs) through their association with G protein-coupled inwardly rectifying potassium (GIRK) channels. Although alpha2-ARs are divided into three subtypes (alpha2A-C), a pharmacological distinction among the subtypes is difficult to establish because of the lack of a selective agonist and antagonist; therefore, little is known about the effects of anesthetics on the alpha2-AR subtypes. We expressed each subtype together with GIRK1/GIRK2 subunits in Xenopus oocytes and observed alpha2-AR-mediated GIRK1/GIRK2 currents to test the effects of ethanol, halothane, and several IV anesthetics at clinical concentrations. UK 14,304, a selective alpha2-AR agonist, evoked GIRK1/GIRK2 currents in every subtype. None of the IV anesthetics, which included pentobarbital, propofol, ketamine, and alphaxalone, influenced UK 14,304-evoked potassium currents in any of the receptor subtypes. Ethanol enhanced the UK 14,304-evoked potassium currents, whereas halothane inhibited the currents. However, these effects were not significantly different from those on the baseline-GIRK1/GIRK2 current, suggesting that neither ethanol nor halothane acts directly on the alpha2-AR subtypes. Although none of the drugs examined had any effect on the alpha2-ARs, the physiological actions of the alpha2-ARs mediated by the GIRK1/GIRK2 channels may be affected by ethanol and halothane.


Subject(s)
Anesthetics/pharmacology , Ethanol/pharmacology , Receptors, Adrenergic, alpha-2/drug effects , Animals , Brimonidine Tartrate , Female , Quinoxalines/pharmacology , Receptors, Adrenergic, alpha-2/classification , Xenopus laevis
11.
Neurosci Res ; 52(4): 387-92, 2005 Aug.
Article in English | MEDLINE | ID: mdl-15982768

ABSTRACT

Endogenous polyamines like spermine are known to have four distinct effects on recombinant N-methyl-d-aspartate (NMDA) receptor channels: voltage-dependent inhibition, glycine-dependent stimulation, glycine-independent stimulation and decreased affinity to the agonist (l-glutamate). These effects are highly dependent on the constituting epsilon subunits (epsilon1-epsilon4) of the recombinant NMDA receptor channels. Agmatine reportedly inhibits native NMDA receptor channels in cultured hippocampal neurons. In the present investigation, the effects of agmatine on the epsilon/zeta heteromeric NMDA receptor channels expressed in Xenopus laevis oocytes were examined using the two-electrode voltage clamp method. Agmatine inhibited the four epsilon/zeta (epsilon1/zeta1, epsilon2/zeta1, epsilon3/zeta1 and epsilon4/zeta1) channels with similar sensitivity (an IC50 value of about 300microM at -70mV). This effect was dependent on the membrane potential and was more pronounced at hyperpolarized membrane potentials (voltage-dependent inhibition). Agmatine did not exhibit other stimulatory (glycine-dependent and -independent effects) or inhibitory (decreased affinity to l-glutamate) effects. These properties are similar to the pharmacological profile of well-characterized NMDA receptor channel blockers like phencyclidine and ketamine. Thus, regarding the effects on the NMDA receptor channels, agmatine is not like other endogenous polyamines rather it acts as a channel blocker.


Subject(s)
Agmatine/pharmacology , Membrane Potentials/drug effects , Receptors, N-Methyl-D-Aspartate/chemistry , Receptors, N-Methyl-D-Aspartate/drug effects , Aldehydes/pharmacology , Animals , Cloning, Molecular , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Drug Interactions , Electric Stimulation/methods , Epoxy Compounds/pharmacology , Glutamic Acid/pharmacology , Inhibitory Concentration 50 , Membrane Potentials/genetics , Membrane Potentials/physiology , Microinjections/methods , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques/methods , Receptors, N-Methyl-D-Aspartate/genetics , Recombinant Proteins/drug effects , Xenopus laevis
12.
Anesth Analg ; 100(6): 1687-1692, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15920196

ABSTRACT

The N-methyl-D-aspartate (NMDA) receptor NR3B subunit co-assembles with NR1 and NR2 subunits to form a receptor complex with distinct channel properties. In the present study, we investigated the effects of co-expression of the NR3B subunit on the anesthetic sensitivities of NMDA receptors for NR1/NR2 channels expressed in Xenopus oocytes. Although the NR3B subunit prominently reduced the current amplitude of NR1/NR2A-B channels, the sensitivities of NR1/NR2A-B channels to Mg2+, ketamine, isoflurane, nitrous oxide, and ethanol were not altered by coexpression of the NR3B subunit. These results suggest that the anesthetic sensitivities of NMDA receptors do not depend on the presence or absence of the NR3 subunit. Mutations of two amino acid residues in the NR3B subunit at positions homologous to the N and N + 1 sites in the NR1 and NR2 subunits, which constitute the blocking sites for Mg2+ and ketamine, did not affect the sensitivities of NR1/NR2B/NR3B channels to Mg2+, ketamine and isoflurane. Thus, the amino acid residues at the N and N + 1 sites in NR3 subunits are unlikely to be involved in the formation of channel blocking sites in NR1/NR2/NR3 channels.


Subject(s)
Anesthetics/pharmacology , Receptors, N-Methyl-D-Aspartate/drug effects , Amino Acid Sequence , Anesthetics, Dissociative/pharmacology , Anesthetics, Inhalation/pharmacology , Animals , Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Glutamic Acid/pharmacology , Glycine/pharmacology , Ketamine/pharmacology , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Nitrous Oxide/pharmacology , Oocytes/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, N-Methyl-D-Aspartate/agonists , Recombinant Proteins/pharmacology , Xenopus
13.
Anesthesiology ; 102(2): 379-86, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15681954

ABSTRACT

BACKGROUND: Although isoflurane, a volatile anesthetic, can block the motor response to noxious stimulation (immobility and analgesia) and suppress autonomic responsiveness, how it exerts these effects at the neuronal level in the spinal cord is not fully understood. METHODS: The effects of a clinically relevant concentration (1 rat minimum alveolar concentration [MAC]) of isoflurane on electrically evoked and spontaneous excitatory/inhibitory transmission and on the response to exogenous administration of the gamma-aminobutyric acid type A receptor agonist muscimol were examined in lamina II neurons of adult rat spinal cord slices using the whole cell patch clamp technique. The effect of isoflurane on the action potential-generating membrane property was also examined. RESULTS: Bath-applied isoflurane (1.5%, 1 rat MAC) diminished dorsal root-evoked polysynaptic but not monosynaptic excitatory postsynaptic currents. Glutamatergic miniature excitatory postsynaptic currents were also unaffected by isoflurane. In contrast, isoflurane prolonged the decay phase of evoked and miniature gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents and increased the amplitude of the muscimol-induced current. Isoflurane had little effect on action potential discharge activity. CONCLUSIONS: Isoflurane augments gamma-aminobutyric acid-mediated inhibitory transmission, leading to a decrease in the excitability of spinal dorsal horn neurons. This may be a possible mechanism for the antinociceptive effect of isoflurane in the spinal cord.


Subject(s)
Isoflurane/pharmacology , Neurons/drug effects , Spinal Cord/drug effects , Substantia Gelatinosa/drug effects , Animals , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Glutamates/physiology , In Vitro Techniques , Neurons/physiology , Rats , Spinal Cord/physiology , Spinal Nerve Roots/drug effects , Spinal Nerve Roots/physiology , Substantia Gelatinosa/physiology , Synapses/drug effects , Synapses/physiology , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , gamma-Aminobutyric Acid/physiology
14.
Anesth Analg ; 99(4): 1136-1140, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15385364

ABSTRACT

Ketamine is an IV anesthetic with N-methyl-d-aspartate receptor (NMDAR)-blocking properties. However, it is still unclear whether ketamine's general anesthetic actions are mediated primarily via blockade of NMDAR. Functional NMDARs are composed by the assembly of a GluRzeta1 (NR1) subunit with GluRepsilon (GluRepsilon1-4; NR2A-D) subunits, which confer unique properties on native NMDARs. We hypothesized that animals deficient in GluRepsilon1, an abundant and ubiquitously postnatally expressed NMDAR subunit, might be resistant to the effects of ketamine. Here, we evaluated a righting reflex to determine the general anesthetic/hypnotic potency of ketamine administered intraperitoneally to GluRepsilon1 knockout mice and compared these results with those for wild-type mice. Mutant mice were more resistant to ketamine than control mice. Unexpectedly, mutant mice were also more resistant to pentobarbital, which is thought not to interact with NMDAR at clinically relevant concentrations. Although these data in no way eliminate the possibility of the involvement of the NMDAR GluRepsilon1 subunit in mediation of ketamine anesthesia/hypnosis, they suggest the difficulties with interpretation of altered anesthetic sensitivity in knockout animal models.


Subject(s)
Anesthetics, Dissociative/pharmacology , Hypnotics and Sedatives/pharmacology , Ketamine/pharmacology , Pentobarbital/pharmacology , Receptors, N-Methyl-D-Aspartate/genetics , Anesthetics, Dissociative/pharmacokinetics , Animals , Biotransformation , Brain/metabolism , Hypnotics and Sedatives/pharmacokinetics , Injections, Intraperitoneal , Ketamine/pharmacokinetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation/genetics , Mutation/physiology , Pentobarbital/pharmacokinetics , Reflex/drug effects
16.
Anesth Analg ; 97(4): 1108-1116, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14500166

ABSTRACT

There is accumulating evidence to implicate the importance of N-methyl-D-aspartate (NMDA) receptors to the induction and maintenance of central sensitization during pain states. However, NMDA receptors may also mediate peripheral sensitization and visceral pain. NMDA receptors are composed of NR1, NR2 (A, B, C, and D), and NR3 (A and B) subunits, which determine the functional properties of native NMDA receptors. Among NMDA receptor subtypes, the NR2B subunit-containing receptors appear particularly important for nociception, thus leading to the possibility that NR2B-selective antagonists may be useful in the treatment of chronic pain.


Subject(s)
Pain/physiopathology , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Central Nervous System/drug effects , Chronic Disease , Excitatory Amino Acid Agonists/administration & dosage , Excitatory Amino Acid Agonists/pharmacology , Humans , Peripheral Nervous System/drug effects , Receptors, N-Methyl-D-Aspartate/drug effects , Receptors, N-Methyl-D-Aspartate/metabolism
17.
Spine (Phila Pa 1976) ; 28(17): 2006-12, 2003 Sep 01.
Article in English | MEDLINE | ID: mdl-12973149

ABSTRACT

STUDY DESIGN: Spinal epidural and subarachnoid spaces were observed with the newly developed fine flexible fiberscopes in 55 patients with chronic pain. OBJECTIVES: To evaluate the fiberscopes as diagnostic tools for spinal canal disease. SUMMARY OF BACKGROUND DATA: Fine flexible fiberscopes make it possible to visualize the entire length of the spinal subarachnoid space without major complications, and they may be of value for the diagnosis of certain spinal canal diseases. METHODS: The epidural and subarachnoid spaces were accessed by fine flexible fiberscopes (Purely Fine [PF] types) in the initial 45 patients and by those equipped with a tip-steering function and a working channel (Medical Science [MS] types) in the later 10 patients, respectively. The procedures were based on those of continuous epidural or subarachnoid block. RESULTS: Normal and abnormal subarachnoid spaces were clearly observed. When the MS types were used, the intended sites of the spinal structures could be more easily approached. In 12 patients, new diagnoses were made (chronic arachnoiditis 9, subarachnoid cyst 2, old subdural hematoma 1) that could not be found by magnetic resonance imaging or computed tomography. Additionally, chronic arachnoiditis was found in 2 patients with spinal trauma. Pathologic changes were confirmed by fiberscopic examination in 16 patients (arachnoiditis 11, spinal trauma 2, arteriovenous malformation 2, subarachnoid cyst 1). No pathologic changes could be detected in 27 patients with spinal canal stenosis, disc herniation, reflex sympathetic dystrophy, or posttraumatic pain syndrome. There were no significant differences in incidence of new diagnoses between the PF and MS types of fiberscopes. There were no major complications. There were 2 cases of light fever in the initial 10 patients and 7 cases of headache in the initial 14 patients. Only 4 cases of headache were observed in the subsequent 41 patients, in whom 20 mL of saline was injected into the epidural space. CONCLUSION: These fine flexible fiberscopes may provide new diagnostic and interventional tools for spinal canal diseases, provided skilled techniques are applied.


Subject(s)
Endoscopy/methods , Pain/etiology , Spinal Diseases/diagnosis , Adult , Aged , Arachnoid Cysts/pathology , Cauda Equina/pathology , Cervical Vertebrae/pathology , Chronic Disease , Epidural Space/pathology , Female , Fiber Optic Technology , Hematoma, Subdural/pathology , Humans , Lumbar Vertebrae/pathology , Male , Middle Aged , Spinal Canal/pathology , Spinal Diseases/complications , Spinal Diseases/pathology , Subarachnoid Space/pathology , Thoracic Vertebrae/pathology
18.
Anesth Analg ; 97(2): 436-441, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12873931

ABSTRACT

UNLABELLED: Spinal dorsal column stimulation (DCS) modulates sensory transmission, including pain, at the dorsal horn of the cord. However, the mechanisms of DCS modulatory actions and the effects of anesthetics on these mechanisms remain to be investigated. We studied the effects of isoflurane (1.0% and 2.0%) on conditioned inhibition, the amplitude decrease of the spinal cord potentials (SCPs) after a conditioning volley (DCS), in the ketamine-anesthetized rat by recording the sharp negative (N) and slow positive (P) waves of the SCPs evoked by conditioning dorsal column (DC) and testing segmental stimulations. The N wave is believed to be the synchronized activity of the dorsal horn neurons, and the P wave, primary afferent depolarization (PAD), reflecting presynaptic inhibition. The P potentials evoked by either DC or segmental stimulation were depressed by isoflurane, whereas the N waves remained unchanged, indicating that the pharmacological characteristics of these N and P waves are similar between DC-evoked and segmentally evoked SCPs. The conditioned inhibition of segmental N and P waves by DC stimulation was almost completely suppressed by 2.0% isoflurane. The conditioned inhibition of the segmental N wave was not changed by spinal cord transection, whereas the conditioned inhibition of the segmental P wave was decreased. The results indicate that isoflurane depresses presynaptic inhibition without affecting the synchronized activity of dorsal horn neurons and, most profoundly, depresses the conditioned inhibition by DC stimulation of the dorsal horn neurons and PAD. Further, the results indicate that conditioned inhibition by DC stimulation of PAD receives a facilitatory influence from the supraspinal structures, whereas that of the synchronized activity of the dorsal horn neurons does not. IMPLICATIONS: To investigate how anesthetics affect supraspinal modulation of sensory transmission in the spinal cord, the spinal cord potential (SCP) evoked by dorsal cord stimulation (DCS) and segmentally evoked SCP conditioned by DCS were recorded in intact and spinal cord-transected rats during isoflurane anesthesia.


Subject(s)
Anesthetics, Inhalation/pharmacology , Isoflurane/pharmacology , Neural Inhibition/drug effects , Spinal Cord/physiology , Animals , Electric Stimulation/methods , Evoked Potentials/drug effects , Male , Rats , Rats, Sprague-Dawley , Spinal Cord/drug effects
19.
Neurosci Res ; 46(2): 199-204, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12767483

ABSTRACT

Noxious afferent input following tissue damage and inflammation triggers a state of neuronal hyperexcitability-a phenomenon of central sensitization-which manifests behaviorally as allodynia and hyperalgesia. At the molecular level, maintenance of central sensitization is largely dependent on the N-methyl-D-aspartate receptor (NMDAR) activation. NMDARs are composed of GluRzeta1 (NR1) and one of four GluRepsilon (NR2) subunits, which determine the functional properties of native NMDARs. Although there is accumulating evidence to implicate GluRepsilon 2-containing NMDARs in pain mechanisms, the functional significance of GluRepsilon 1-containing NMDARs in this setting has not been examined in detail. Here, we used hind paw injection of formalin, complete Freund's adjuvant and a nerve injury model to investigate the effects of GluRepsilon 1 subunit gene deletion on pain-related behavior in mice. In all of the models tested, GluRepsilon 1-deficient mice exhibited responses similar to wild-type controls. These results suggest that GluRepsilon 1 disruption does not result in altered nociceptive behavior in mice. Although the contribution of other nociceptive pathways cannot be ruled out, we speculate that the preserved function of GluRepsilon 2-containing NMDARs could explain unaltered nociceptive behavior in mutant mice.


Subject(s)
Behavior, Animal/physiology , Pain/genetics , Pain/metabolism , Receptors, N-Methyl-D-Aspartate/deficiency , Animals , Axotomy , Blotting, Western , Formaldehyde/pharmacology , Freund's Adjuvant/pharmacology , Hindlimb/drug effects , Hindlimb/innervation , Hindlimb/physiology , Irritants/pharmacology , Male , Mice , Mice, Knockout , Nociceptors/metabolism , Pain Measurement , Pain Threshold/physiology , Physical Stimulation , Reaction Time/genetics , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/metabolism
20.
Anesthesiology ; 97(4): 896-901, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12357156

ABSTRACT

BACKGROUND: Preconditioning to ischemia is a phenomenon whereby a brief episode of sublethal ischemia and other nonlethal stressors produce protection against a subsequent detrimental ischemic insult. As mitochondrial dysfunction is related to necrotic and apoptotic neuronal death after cerebral ischemia, the authors examined if ischemic preconditioning is capable of inducing mitochondrial tolerance. METHODS: Forebrain ischemia was induced by bilateral common carotid artery occlusion with simultaneous hypotension for 8 min in Wistar rats (275-300 g). A 3-min ischemic episode performed 48 h before the 8-min ischemia was used for preconditioning. The extents of hippocampal CA1 neuronal damage were evaluated 7 days after reperfusion by neuro-specific nuclear protein immunostaining. Brain mitochondria were isolated 48 h after animals were subjected to the sham operation or the 3-min conditioning ischemia. Loss of cytochrome c from mitochondria after cerebral ischemia in vivo and after exposure of brain mitochondria to calcium in vitro was used as an indication of mitochondrial dysfunction. RESULTS: Results showed that ischemic preconditioning induced by a 3-min ischemic episode dramatically reduced the loss of hippocampal CA1 neurons resulting from a subsequent 8-min ischemia 7 days after reperfusion, and this protection was associated with a preservation of mitochondrial cytochrome c as examined after early reperfusion. Exposure of isolated brain mitochondria to calcium produced a dose-dependent increase in cytochrome c release either at 30 degrees C or at 37 degrees C. Compared with those animals receiving only sham operation, cytochrome c release caused by 100 microm calcium was significantly reduced in conditioned animals. CONCLUSION: Regarding the importance of mitochondrial dysfunction in mediating ischemic neuronal death, the above results indicate that mitochondria may serve as end-effecting organelles to ischemic preconditioning.


Subject(s)
Brain/physiology , Ischemic Preconditioning , Mitochondria/physiology , Animals , Blotting, Western , Brain/enzymology , Cell Count , Cell Nucleus/metabolism , Cerebrovascular Circulation/physiology , Cytochrome c Group/metabolism , Fluorescent Antibody Technique , Male , Microscopy, Confocal , Mitochondria/enzymology , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Neurons/ultrastructure , Prosencephalon/blood supply , Prosencephalon/physiology , Rats , Reperfusion
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