scholarly journals Enflurane Actions on Spinal Cords from Mice That Lack the β3Subunit of the GABAAReceptor

2001 ◽  
Vol 95 (1) ◽  
pp. 154-164 ◽  
Author(s):  
Shirley M. E. Wong ◽  
Gong Cheng ◽  
Gregg E. Homanics ◽  
Joan J. Kendig
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Dominant Role ◽  
Glycine Receptor ◽  
Excitatory Postsynaptic Potential ◽  
Evoked Responses ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Root Potential ◽  
Beta3 Subunit

Background Gamma-aminobutyric acid type A (GABA(A)) receptors are considered important in mediating anesthetic actions. Mice lacking the beta3 subunit of this receptor (beta3-/-) have a higher enflurane minimum alveolar concentration (MAC) than wild types (+/+). MAC is predominantly determined in spinal cord. Methods The authors measured three population-evoked responses in whole spinal cords, namely, the excitatory postsynaptic potential (pEPSP), the slow ventral root potential (sVRP), and the dorsal root potential. Synaptic and glutamate-evoked currents from motor neurons in spinal cord slices were also measured. Results Sensitivity of evoked responses to enflurane did not differ between +/+ and -/- cords. The GABA(A) receptor antagonist bicuculline significantly (P < 0.05) attenuated the depressant effects of enflurane on pEPSP, sVRP and glutamate-evoked currents in +/+ but not -/- cords. The glycine antagonist strychnine elevated the pEPSP to a significantly greater extent in -/- than in +/+ cords, but the interactions between strychnine and enflurane did not differ between -/- and +/+ cords. Conclusions Similar enflurane sensitivity in spinal cords from -/- and +/+ mice was coupled with a decreased role for GABA(A) receptors in mediating the actions of enflurane in the former. This finding implies that other anesthetic targets substitute for GABA(A) receptors. Increase in glycine receptor-mediated inhibition was found in -/- cords, but the glycine receptor does not appear to be a substitute anesthetic target. This mutation thus led to a quantitative change in the molecular basis for anesthetic depression of spinal neurotransmission in a fashion not predicted by the mutation itself. The results argue against an immutable dominant role for GABA(A) receptors in mediating spinal contributions to MAC.

Antagonism of the Antinocifensive Action of Halothane by Intrathecal Administration of GABA-A Receptor Antagonists

1996 ◽  
Vol 84 (5) ◽  
pp. 1205-1214 ◽  
Author(s):  
Peggy Mason ◽  
Casey A. Owens ◽  
Donna L. Hammond
Keyword(s):  
Spinal Cord ◽  
Receptor Antagonist ◽  
Gabaa Receptor ◽  
Glycine Receptor ◽  
Intrathecal Administration ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Receptor Antagonists ◽  
Response Latencies ◽  
Halothane Concentration

Background The hind brain and the spinal cord, regions that contain high concentrations of gamma-aminobutyric acid (GABA) and GABA receptors, have been implicated as sites of action of inhalational anesthetics. Previous studies have established that general anesthetics potentiate the effects of gamma-aminobutyric acid at the GABAA receptor. It was therefore hypothesized that the suppression of nocifensive movements during anesthesia is due to an enhancement of GABAA receptor-mediated transmission within the spinal cord. Methods Rats in which an intrathecal catheter had been implanted 1 week earlier were anesthetized with halothane. Core temperature was maintained at a steady level. After MAC determination, the concentration of halothane was adjusted to that at which the rats last moved in response to tail clamping. Saline, a GABAA, a GABAB, or glycine receptor antagonist was then injected intrathecally. The latency to move in response to application of the tail clamp was redetermined 5 min later, after which the halothane concentration was increased by 0.2%. Response latencies to application of the noxious stimulus were measured at 7-min intervals during the subsequent 35 min. To determine whether these antagonists altered baseline response latencies by themselves, another experiment was conducted in which the concentration of halothane was not increased after intrathecal administration of GABAA receptor antagonists. Results Intrathecal administration of the GABAA receptor antagonists bicuculline (0.3 micrograms) or picrotoxin (0.3, 1.0 micrograms) antagonized the suppression of nocifensive movement produced by the small increase in halothane concentration. In contrast, the antinocifensive effect of the increase in halothane concentration was not attenuated by the GABAB receptor antagonist CGP 35348 or the glycine receptor antagonist strychnine. By themselves, the GABAA receptor antagonists did not alter response latency in rats anesthetized with sub-MAC concentrations of halothane. Conclusions Intrathecal administration of bicuculline or picrotoxin, at doses that do not change the latency to pinch-evoked movement when administered alone, antagonized the suppression of noxious-evoked movement produced by halothane concentrations equal to or greater than MAC. These results suggest that enhancement of GABAA receptor-mediated transmission within the spinal cord contributes to halothane's ability to suppress nocifensive movements.

Halothane Suppression of Spinal Sensory Neuronal Responses to Noxious Peripheral Stimuli Is Mediated, in Part, by Both GABAAand Glycine Receptor Systems

2002 ◽  
Vol 97 (2) ◽  
pp. 412-417 ◽  
Author(s):  
Masanori Yamauchi ◽  
Hiroshi Sekiyama ◽  
Steven G. Shimada ◽  
J. G. Collins
Keyword(s):  
Dynamic Range ◽  
Glycine Receptor ◽  
Gamma Aminobutyric Acid ◽  
Neuronal Responses ◽  
General Anesthetic ◽  
Gaba A ◽  
Low Threshold ◽  
Noxious Stimuli ◽  
Evoked Activity ◽  
Wdr Neurons

Background A major effect of general anesthesia is lack of response in the presence of a noxious stimulus. Anesthetic depression of spinal sensory neuronal responses to noxious stimuli is likely to contribute to that essential general anesthetic action. The authors tested the hypothesis that gamma-aminobutyric acid receptor type A (GABA(A)) and strychnine-sensitive glycine receptor systems mediate halothane depression of spinal sensory neuronal responses to noxious stimuli. Methods Extracellular activity of single spinal dorsal horn wide dynamic range (WDR) neurons was recorded in decerebrate, spinal cord transected rats. Neuronal responses to noxious (thermal and mechanical) and nonnoxious stimuli were examined in the drug-free state. Subsequently, cumulative doses (0.1-2.0 mg/kg) of bicuculline (GABA(A) antagonist) or strychnine (glycine antagonist) were administered intravenously in the absence or presence of 1 minimum alveolar concentration (MAC) of halothane. Results Halothane, 1.1%, depressed the response of WDR neurons to both forms of noxious stimuli. Antagonists, by themselves, had no effect on noxiously evoked activity. However, bicuculline and strychnine (maximum cumulative dose, 2.0 mg/kg) partially but significantly reversed the halothane depression of noxiously evoked activity. Similar results were seen with most, but not all, forms of nonnoxiously evoked activity. In the absence of halothane, strychnine significantly increased neuronal responses to low threshold receptive field brushing. Conclusion Halothane depression of spinal WDR neuronal responses to noxious and most nonnoxious stimuli is mediated, in part, by GABA(A) and strychnine-sensitive glycine systems. A spinal source of glycine tonically inhibits some forms of low threshold input to WDR neurons.

scholarly journals Developmental Formation of the GABAergic and Glycinergic Networks in the Mouse Spinal Cord

2022 ◽  
Vol 23 (2) ◽  
pp. 834
Author(s):  
Chigusa Shimizu-Okabe ◽  
Shiori Kobayashi ◽  
Jeongtae Kim ◽  
Yoshinori Kosaka ◽  
Masanobu Sunagawa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Radial Glia ◽  
Ventricular Zone ◽  
Glycine Receptor ◽  
Ventral Horn ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Gamma Aminobutyric Acid ◽  
Mouse Spinal Cord ◽  
Mature Mouse

Gamma-aminobutyric acid (GABA) and glycine act as inhibitory neurotransmitters. Three types of inhibitory neurons and terminals, GABAergic, GABA/glycine coreleasing, and glycinergic, are orchestrated in the spinal cord neural circuits and play critical roles in regulating pain, locomotive movement, and respiratory rhythms. In this study, we first describe GABAergic and glycinergic transmission and inhibitory networks, consisting of three types of terminals in the mature mouse spinal cord. Second, we describe the developmental formation of GABAergic and glycinergic networks, with a specific focus on the differentiation of neurons, formation of synapses, maturation of removal systems, and changes in their action. GABAergic and glycinergic neurons are derived from the same domains of the ventricular zone. Initially, GABAergic neurons are differentiated, and their axons form synapses. Some of these neurons remain GABAergic in lamina I and II. Many GABAergic neurons convert to a coreleasing state. The coreleasing neurons and terminals remain in the dorsal horn, whereas many ultimately become glycinergic in the ventral horn. During the development of terminals and the transformation from radial glia to astrocytes, GABA and glycine receptor subunit compositions markedly change, removal systems mature, and GABAergic and glycinergic action shifts from excitatory to inhibitory.

GABAergic Interneurons at Supraspinal and Spinal Levels Differentially Modulate the Antinociceptive Effect of Nitrous Oxide in Fischer Rats

2003 ◽  
Vol 98 (5) ◽  
pp. 1223-1230 ◽  
Author(s):  
Ryo Orii ◽  
Yoko Ohashi ◽  
Sunil Halder ◽  
Mariangela Giombini ◽  
Mervyn Maze ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Nitrous Oxide ◽  
Antinociceptive Effect ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Fischer Rats ◽  
The Brain ◽  
Gas Exposure

Background The study hypothesizes that nitrous oxide (N(2)O) releases opioid peptide in the brain stem, which results in inhibition of gamma-aminobutyric acid-mediated (GABAergic) neurons that tonically inhibit the descending noradrenergic inhibitory neurons (DNIN), resulting in activation of DNIN. In the spinal cord, activation of DNIN leads to the release of norepinephrine, which inhibits nociceptive processing through direct activation of alpha2 adrenoceptor and indirect activation of GABAergic neurons through alpha1 adrenoceptor. Arising from this hypothesis, it follows that GABAergic neurons will modulate the antinociceptive effect of N(2)O in diametrically opposite directions at supraspinal and spinal levels. The authors have tested this tenet and further examined the effect of midazolam, a GABA-mimetic agent, on N(2)O-induced antinociceptive effect. Methods Adult male Fischer rats were administered muscimol (GABA(A) receptor agonist) intracerebroventricularly (icv), gabazine (GABA(A) receptor antagonist) intrathecally (intrathecal), or midazolam intraperitoneally (intraperitoneal). Fifteen minutes later, they were exposed to air or 75% N(2)O and were subjected to the plantar test after 30 min of gas exposure. In some animals administered with midazolam, gas exposure was continued for 90 min, and the brain and spinal cord were examined immunohistochemically. Results The N(2)O-induced antinociceptive effect, which was attenuated by icv muscimol, intrathecal gabazine, and intraperitoneal midazolam. Midazolam inhibited N(2)O-induced c-Fos expression (a marker of neuronal activation) in the pontine A7 and spinal cord. Conclusions The GABAergic neurons modulate the antinociceptive effect of N(2)O in opposite directions at supraspinal and spinal levels. The pronociceptive effects of enhancement at the supraspinal GABAergic site predominate in response to systemically administered midazolam.

Enflurane Directly Depresses Glutamate AMPA and NMDA Currents in Mouse Spinal Cord Motor Neurons Independent of Actions on GABAAor Glycine Receptors

2000 ◽  
Vol 93 (4) ◽  
pp. 1075-1084 ◽  
Author(s):  
Gong Cheng ◽  
Joan J. Kendig
Keyword(s):  
Spinal Cord ◽  
Nmda Receptor ◽  
Glutamate Receptors ◽  
Dorsal Horn ◽  
Motor Neurons ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Excitatory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Anesthetic Concentration

Background The spinal cord is an important anatomic site at which volatile agents act to prevent movement in response to a noxious stimulus. This study was designed to test the hypothesis that enflurane acts directly on motor neurons to inhibit excitatory synaptic transmission at glutamate receptors. Methods Whole-cell recordings were made in visually identified motor neurons in spinal cord slices from 1- to 4-day-old mice. Excitatory postsynaptic currents (EPSCs) or potentials (EPSPs) were evoked by electrical stimulation of the dorsal root entry area or dorsal horn. The EPSCs were isolated pharmacologically into glutamate N-methyl-d-aspartate (NMDA) receptor- and non-NMDA receptor-mediated components by using selective antagonists. Currents also were evoked by brief pulse pressure ejection of glutamate under various conditions of pharmacologic blockade. Enflurane was made up as a saturated stock solution and diluted in the superfusate; concentrations were measured using gas chromatography. Results Excitatory postsynaptic currents and EPSPs recorded from motor neurons by stimulation in the dorsal horn were mediated by glutamate receptors of both non-NMDA and NMDA subtypes. Enflurane at a general anesthetic concentration (one minimum alveolar anesthetic concentration) reversibly depressed EPSCs and EPSPs. Enflurane also depressed glutamate-evoked currents in the presence of tetrodotoxin (300 nm), showing that its actions are postsynaptic. Block of inhibitory gamma-aminobutyric acid A and glycine receptors by bicuculline (20 micrometer) or strychnine (2 micrometer) or both did not significantly reduce the effects of enflurane on glutamate-evoked currents. Enflurane also depressed glutamate-evoked currents if the inhibitory receptors were blocked and if either D,L-2-amino-5-phosphonopentanoic acid (50 micrometer) or 6-cyano-7-nitroquinoxaline-2,3-dione disodium (10 micrometer) was applied to block NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-kainate receptors respectively. Conclusions Enflurane exerts direct depressant effects on both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and NMDA glutamate currents in motor neurons. Enhancement of gamma-aminobutyric acid A and glycine inhibition is not needed for this effect. Direct depression of glutamatergic excitatory transmission by a postsynaptic action on motor neurons thus may contribute to general anesthesia as defined by immobility in response to a noxious stimulus.

Mouse spinal cord in cell culture. III. Neuronal chemosensitivity and its relationship to synaptic activity

1977 ◽  
Vol 40 (5) ◽  
pp. 1163-1177 ◽  
Author(s):  
B. R. Ransom ◽  
P. N. Bullock ◽  
P. G. Nelson
Keyword(s):  
Spinal Cord ◽  
Time Course ◽  
Reversal Potential ◽  
Synaptic Activity ◽  
Excitatory Postsynaptic Potential ◽  
Gamma Aminobutyric Acid ◽  
Mouse Spinal Cord ◽  
Ionic Mechanisms ◽  
Inhibitory Transmitter ◽  
Higher Sensitivity

1. Mouse spinal cord (SC) cells in dissociated cell cultures showed strong electrophysiologic responses to glutamate, gamma-aminobutyric acid (GABA), and glycine when these were iontophoretically applied to the neurons. 2. The extrapolated reversal potential for the glutamate response was 20-30 mV negative in contrast to the positive extrapolated reversal potential for the SC-SC excitatory postsynaptic potential. The data are interpreted as indicating different ionic mechanisms for the glutamate response and the EPSP. 3. The reversal potentials for the glycine and GABA responses were similar to one another and to the IPSP reversal potential. The time course of the glycine and GABA responses were quite different from each other, however. 4. While some SC cells showed a relatively uniform sensitivity over their surfaces to iontophoretically applied glutamate, discrete regions of higher sensitivity occurred on most cells. 5. Release of excitatory and inhibitory transmitter could be elicited by focal application of glutamate and, in favorable instances, this could be shown to be due to the sensitivity of presynaptic terminals to the applied glutamate. Considerable spatial resolution of regions from which transmitter release could be elicited was achieved by this technique. Some correspondence between glutamate "hot spots" and such release sites was found.

scholarly journals Neural Mechanisms of Sevoflurane-induced Respiratory Depression in Newborn Rats

2008 ◽  
Vol 109 (2) ◽  
pp. 233-242 ◽  
Author(s):  
Junya Kuribayashi ◽  
Shigeki Sakuraba ◽  
Masanori Kashiwagi ◽  
Eiki Hatori ◽  
Miki Tsujita ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Respiratory Depression ◽  
Motor Neurons ◽  
Type A ◽  
Aminobutyric Acid ◽  
Respiratory Neurons ◽  
Gamma Aminobutyric Acid ◽  
Inspiratory Neurons ◽  
Acid Type ◽  
Bötzinger Complex

Background Sevoflurane-induced respiratory depression has been reported to be due to the action on medullary respiratory and phrenic motor neurons. These results were obtained from extracellular recordings of the neurons. Here, the authors made intracellular recordings of respiratory neurons and analyzed their membrane properties during sevoflurane application. Furthermore, they clarified the role of gamma-aminobutyric acid type A receptors in sevoflurane-induced respiratory depression. Methods In the isolated brainstem-spinal cord of newborn rat, the authors recorded the C4 nerve burst as an index of inspiratory activity. The preparation was superfused with a solution containing sevoflurane alone or sevoflurane plus the gamma-aminobutyric acid type A receptor antagonist picrotoxin or bicuculline. Neuronal activities were also recorded using patch clamp techniques. Results Sevoflurane decreased C4 burst rate and amplitude. Separate perfusion of sevoflurane to the medulla and to the spinal cord decreased C4 burst rate and amplitude, respectively. Both picrotoxin and bicuculline attenuated the reduction of C4 burst rate. Sevoflurane reduced both intraburst firing frequency and membrane resistance of respiratory neurons except for inspiratory neurons. Conclusion Under the influence of sevoflurane, the region containing inspiratory neurons, i.e., the pre-Bötzinger complex, may determine the inspiratory rhythm, because reduced C4 bursts were still synchronized with the bursts of inspiratory neurons within the pre-Bötzinger complex. In contrast, the sevoflurane-induced decrease in C4 burst amplitude is mediated through the inhibition of phrenic motor neurons. gamma-Aminobutyric acid type A receptors may be involved in the sevoflurane-induced respiratory depression within the medulla, but not within the spinal cord.

scholarly journals Developmental Formation of the GABAergic and Glycinergic Networks in the Mouse Spinal Cord

2021 ◽  
Author(s):  
Chigusa Shimizu-Okabe ◽  
Shiori Kobayashi ◽  
Jeongtae Kim ◽  
Yoshinori Kosaka ◽  
Masanobu Sunagawa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Radial Glia ◽  
Ventricular Zone ◽  
Glycine Receptor ◽  
Ventral Horn ◽  
Gabaergic Neurons ◽  
Inhibitory Neurons ◽  
Gamma Aminobutyric Acid ◽  
Mouse Spinal Cord ◽  
Mature Mouse

Gamma-aminobutyric acid (GABA) and glycine act as inhibitory neurotransmitters. Three types of inhibitory neurons and terminals, GABAergic, GABA/glycine co-releasing, and glycinergic, are orchestrated in the spinal cord neural circuits and play key roles in the regulation of pain, locomotive movement, and respiratory rhythms. Herein, we first describe GABAergic and glycinergic transmission and inhibitory networks, which consist of three types of terminals, in the mature mouse spinal cord. Second, we describe the developmental formation of GABAergic and glycinergic networks, with specific focus on the differentiation of neurons, formation of synapses, maturation of removal systems, and changes in their action. GABAergic and glycinergic neurons are derived from the same domains of the ventricular zone. Initially, GABAergic neurons are differentiated and their axons form synapses. Some of these neurons remain GABAergic in lamina I and II. Many of GABAergic neurons convert to co-releasing state. The co-releasing neurons and terminals remain in the dorsal horn, whereas many of co-releasing ones ultimately become glycinergic in the ventral horn. During the development of terminals and the transformation from radial glia to astrocytes, GABA and glycine receptor subunit compositions markedly change, removal systems mature, and GABAergic and glycinergic action shifts from excitatory to inhibitory.

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