scholarly journals Reduced Sensitivity to Anesthetic Agents upon Lesioning the Mesopontine Tegmental Anesthesia Area in Rats Depends on Anesthetic Type

2020 ◽  
Vol 132 (3) ◽  
pp. 535-550 ◽  
Author(s):  
Anne Minert ◽  
Mark Baron ◽  
Marshall Devor
Keyword(s):  
Infusion Pump ◽  
Ibotenic Acid ◽  
Aminobutyric Acid ◽  
Maximal Dose ◽  
Descending Pathways ◽  
Anesthetic Induction ◽  
Anesthetic Agents ◽  
Loss Of Righting Reflex ◽  
Righting Reflex ◽  
Effective Doses

Abstract Background The brainstem mesopontine tegmental anesthesia area is a key node in circuitry responsible for anesthetic induction and maintenance. Microinjecting the γ-aminobutyric acid–mediated (GABAergic) anesthetic pentobarbital in this nucleus rapidly and reversibly induces general anesthesia, whereas lesioning it renders the animal relatively insensitive to pentobarbital administered systemically. This study investigated whether effects of lesioning the mesopontine tegmental anesthesia area generalize to other anesthetic agents. Methods Cell-selective lesions were made using ibotenic acid, and rats were later tested for changes in the dose–response relation to etomidate, propofol, alfaxalone/alfadolone, ketamine, and medetomidine delivered intravenously using a programmable infusion pump. Anesthetic induction for each agent was tracked using five behavioral endpoints: loss of righting reflex, criterion for anesthesia (score of 11 or higher), criterion for surgical anesthesia (score of 14 or higher), antinociception (loss of pinch response), and deep surgical anesthesia (score of 16). Results As reported previously for pentobarbital, on-target mesopontine tegmental anesthesia area lesions reduced sensitivity to the GABAergic anesthetics etomidate and propofol. The dose to achieve a score of 16 increased to 147 ± 50% of baseline in control animals ± SD (P = 0.0007; 7 lesioned rats and 18 controls) and 136 ± 58% of baseline (P = 0.010; 6 lesioned rats and 21 controls), respectively. In contrast, responsiveness to the neurosteroids alfaxalone and alfadolone remained unchanged compared with baseline (94 ± 24%; P = 0.519; 6 lesioned rats and 18 controls) and with ketamine increased slightly (90 ± 11%; P = 0.039; 6 lesioned rats and 19 controls). The non-GABAergic anesthetic medetomidine did not induce criterion anesthesia even at the maximal dose tested. The dose to reach the maximal anesthesia score actually obtained was unaffected by the lesion (112 ± 8%; P = 0.063; 5 lesioned rats and 18 controls). Conclusions Inability to induce anesthesia in lesioned animals using normally effective doses of etomidate, propofol, and pentobarbital suggests that the mesopontine tegmental anesthesia area is the effective target of these, but not necessarily all, GABAergic anesthetics upon systemic administration. Cortical and spinal functions are likely suppressed by recruitment of dedicated ascending and descending pathways rather than by direct, distributed drug action. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Anesthesia Sensitivity in Mice that Lack the β3 Subunit of the γ-Aminobutyric Acid Type A Receptor 

1998 ◽  
Vol 88 (3) ◽  
pp. 775-780 ◽  
Author(s):  
Joseph J. Quinlan ◽  
Gregg E. Homanics ◽  
Leonard L. Firestone
Keyword(s):  
Null Allele ◽  
Volatile Anesthetic ◽  
Aminobutyric Acid ◽  
Wild Type ◽  
Gaba A ◽  
Anesthetic Agents ◽  
Loss Of Righting Reflex ◽  
Acid Type ◽  
Beta3 Subunit ◽  
Righting Reflex

Background The mammalian gamma-aminobutyric acid type A (GABA(A)) receptor, a likely target of anesthetic action, exhibits remarkable subunit heterogeneity. In vitro expression studies suggest that there is subunit specificity to anesthetic responses at the GABA(A) receptor. The authors tested whether genetically engineered mice that lack the beta3 subunit of the GABA(A) receptor differed in their sensitivities to several general anesthetic agents. Methods Median effective concentrations for loss-of-righting reflex and tail clamp/withdrawal for enflurane and halothane were determined in mice with and without the beta3 gene and gene product. Sleep time was measured after intraperitoneal injection of pentobarbital, ethanol, etomidate, and midazolam. Results Null allele mice (beta3 -/-) did not differ from wild-type mice (beta3 +/+) in the obtunding response to enflurane and halothane but were significantly more resistant to enflurane (null allele half-effect concentrations [EC50] of 2.59 +/- 0.10 vs. wild-type EC50 of 2.06 +/- 0.12 atm %, P < 0.001) and halothane (null allele EC50 of 1.73 +/- 0.04 vs. wild-type EC50 of 1.59 +/- 0.05 atm %, P = 0.01) as determined by tail clamp response. Wild-type and null allele mice exhibited divergent responses to other sedative agents active at the GABA(A) receptor. No differences were noted in sleep times after administration of pentobarbital and ethanol, but null allele mice were more resistant to etomidate (null allele EC50 of 17.8 +/- 1.9 min vs. wild-type EC50 of 26.2 +/- 2.4 min, P < 0.02) and midazolam (null allele EC50 of 14.2 +/- 7.8 min vs. wild-type EC50 of 41.3 +/- 10.4 min, P < 0.05). Conclusions The beta3 subunit of the GABA(A) receptor appears to be important in the mediation of the immobilizing (tail clamp) but not obtunding (loss-of-righting reflex) effects of the volatile anesthetic agents enflurane and halothane. These data support the hypotheses that separate components of the anesthetic state are mediated via different central nervous system loci; that the GABA(A) receptor is a likely target for the immobilizing response to volatile anesthetic agents; and that the beta3 subunit plays a direct or indirect role in the mediation of this response. Absence of the beta3 subunit appears to attenuate the obtunding effect of midazolam and etomidate but appears not to alter the obtunding effect of pentobarbital, enflurane, and halothane, suggesting that these anesthetic agents produce hypnosis by different specific molecular mechanisms.

Sleep Deprivation Potentiates the Onset and Duration of Loss of Righting Reflex Induced by Propofol and Isoflurane

2002 ◽  
Vol 97 (4) ◽  
pp. 906-911 ◽  
Author(s):  
Avery Tung ◽  
Martin J. Szafran ◽  
Bryan Bluhm ◽  
Wallace B. Mendelson
Keyword(s):  
Sleep Deprivation ◽  
Neuronal Networks ◽  
Fixed Dose ◽  
Patient Response ◽  
Disk Rotation ◽  
Anesthetic Agents ◽  
Loss Of Righting Reflex ◽  
Separate Control ◽  
Righting Reflex ◽  
Time Required

Background Sleep and anesthesia differ physiologically but produce a similar loss of responsiveness to environmental stimuli. Recent data suggest that neuronal networks active in naturally occurring sleep also play a role in the anesthetized state. Changes in the propensity to sleep may then modify the response to anesthetic agents. The authors tested the hypothesis that sleep-deprived rats would require less anesthetic than rested rats to achieve a similar loss of responsiveness. Methods Rats were subjected to a 24-h period of either sleep deprivation or ad libitum activity. Sleep deprivation was produced by placing rats on a disk that rotated when sleep was detected by electroencephalographic and electromyographic (EEG, EMG) monitoring. A fixed dose of anesthetic agent was then administered, and the time required to induce loss of righting reflex was measured. Anesthetic administration was then stopped, and the time to recovery measured. All rats received both treatments separated by 7 days. Results Sleep deprivation reduced the time to loss of righting reflex by 40% for propofol (P < 0.025) and 55% for isoflurane (P < 0.025) and prolonged the time to recovery. In a separate control experiment, exposure to the deprivation environment but with disk rotation modified to allow adequate sleep did not affect the response to anesthetic administration. Conclusions Sleep deprivation significantly potentiated the ability of inhaled and intravenous anesthetic agents to induce a loss of righting reflex. These results support the hypothesis that neuronal networks active in sleep are also involved in the anesthetized state and suggest that sleep deprivation may partly explain the variability in patient response to anesthesia.

scholarly journals Mutation of α1GT-type Calcium Channels in Mice Does Not Change Anesthetic Requirements for Loss of the Righting Reflex and Minimum Alveolar Concentration but Delays the Onset of Anesthetic Induction

2007 ◽  
Vol 106 (6) ◽  
pp. 1177-1185 ◽  
Author(s):  
Andrey B. Petrenko ◽  
Mika Tsujita ◽  
Tatsuro Kohno ◽  
Kenji Sakimura ◽  
Hiroshi Baba
Keyword(s):  
Calcium Channels ◽  
Minimum Alveolar Concentration ◽  
Volatile Anesthetics ◽  
Effective Concentration ◽  
Mutant Mice ◽  
Neuronal Membrane ◽  
Normal Functioning ◽  
Anesthetic Agents ◽  
Loss Of Righting Reflex ◽  
Righting Reflex

Background T-type calcium channels regulate neuronal membrane excitability and participate in a number of physiologic and pathologic processes in the central nervous system, including sleep and epileptic activity. Volatile anesthetics inhibit native and recombinant T-type calcium channels at concentrations comparable to those required to produce anesthesia. To determine whether T-type calcium channels are involved in the mechanisms of anesthetic action, the authors examined the effects of general anesthetics in mutant mice lacking alpha1G T-type calcium channels. Methods The hypnotic effects of volatile and intravenous anesthetics administered to mutant and C57BL/6 control mice were evaluated using the behavioral endpoint of loss of righting reflex. To investigate the immobilizing effects of volatile anesthetics in mice, the minimum alveolar concentration (MAC) values were determined using the tail-clamp method. Results The 50% effective concentration for loss of righting reflex and MAC values for volatile anesthetics were not altered after alpha1G channel knockout. However, mutant mice required significantly more time to develop anesthesia/hypnosis after exposure to isoflurane, halothane, and sevoflurane and after intraperitoneal administration of pentobarbital. Conclusions The 50% effective concentration for loss of righting reflex and MAC values for the volatile anesthetics were not altered after alpha1G calcium channel knockout, indicating that normal functioning of alpha1G calcium channels is not required for the maintenance of anesthetic hypnosis and immobility. However, the timely induction of anesthesia/hypnosis by volatile anesthetic agents and some intravenous anesthetic agents may require the normal functioning of these channel subunits.

scholarly journals Methoxycarbonyl-etomidate

2009 ◽  
Vol 111 (2) ◽  
pp. 240-249 ◽  
Author(s):  
Joseph F. Cotten ◽  
S Shaukat Husain ◽  
Stuart A. Forman ◽  
Keith W. Miller ◽  
Elizabeth W. Kelly ◽  
...  
Keyword(s):  
Half Life ◽  
Human Liver ◽  
Type A ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Loss Of Righting Reflex ◽  
Acid Type ◽  
Righting Reflex ◽  
S9 Fraction

Background Etomidate is a rapidly acting sedative-hypnotic that provides hemodynamic stability. It causes prolonged suppression of adrenocortical steroid synthesis; therefore, its clinical utility and safety are limited. The authors describe the results of studies to define the pharmacology of (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), the first etomidate analogue designed to be susceptible to ultra-rapid metabolism. Methods The gamma-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared by using electrophysiological techniques in human alpha1beta2gamma2l receptors. MOC-etomidate's hypnotic concentration was determined in tadpoles by using a loss of righting reflex assay. Its in vitro metabolic half-life was measured in human liver S9 fraction, and the resulting metabolite was provisionally identified by using high-performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats. Results MOC-etomidate potently enhanced gamma-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order, with an in vitro half-life of 4.4 min versus more than 40 min for etomidate. MOC-etomidate's only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 min after administration. Conclusions MOC-etomidate is an etomidate analogue that retains etomidate's important favorable pharmacological properties. However, it is rapidly metabolized, ultra-short-acting, and does not produce prolonged adrenocortical suppression after bolus administration.

Increased ??-Aminobutyric Acid Levels in Mouse Brain Induce Loss of Righting Reflex, but Not Immobility, in Response to Noxious Stimulation

2007 ◽  
Vol 104 (6) ◽  
pp. 1422-1429 ◽  
Author(s):  
Sohtaro Katayama ◽  
Masahiro Irifune ◽  
Nobuhito Kikuchi ◽  
Tohru Takarada ◽  
Yoshitaka Shimizu ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Aminobutyric Acid ◽  
Noxious Stimulation ◽  
Loss Of Righting Reflex ◽  
Righting Reflex

Anesthesia for rabbits submitted to experimental surgeries: Report of a series of eight anesthesias

2020 ◽  
pp. 151-158
Author(s):  
Rafael Antonio Caldart Bedin ◽  
Maisa Schultz ◽  
Antonio Bedin
Keyword(s):  
Muscle Relaxation ◽  
Anesthetic Management ◽  
Laboratory Animals ◽  
Average Weight ◽  
Anesthetic Induction ◽  
Anesthetic Agents ◽  
Reasonable Degree ◽  
Bioethical Debate ◽  
Precordial Stethoscope

Anesthesia for laboratory animals is a matter of biomedical concern and one of the most present dilemmas in the current bioethical debate. The use of anesthetic agents in experimental surgery aims at analgesia and restraining the animal, in order to achieve a reasonable degree of muscle relaxation and to produce sufficient analgesia. This practice requires the use of protocols for the administration of safe and efficient doses. Eight New Zealand rabbits were submitted to laparotomies demonstrating the surgical technique discipline of the local medical course. For pre-anesthetic medication, acepromazine 1 mg.kg-1 associated with ketamine 15 mg.kg-1 was used subcutaneously. Anesthesia was maintained with isoflurane and oxygen under a laryngeal mask in a Mapleson D anesthesia system and under spontaneous breathing. Hydration was performed with 10 ml.kg-1 saline every hour. A thermal mattress was used. Precordial stethoscope, pulse oximetry and clinical parameters were used for monitoring. For euthanasia, ketamine 10 mg.kg-1 associated with potassium chloride 19.1% 1 ml.kg-1 was used intravenously. The average weight of the rabbits was 2721.25 ± 275.01 grams and the duration of the anesthetic procedure was 120 ± 87 minutes. Discussion. In long-term anesthesia, such as laparotomies, the use of pre-anesthetic medication and then anesthetic induction by the combination of agents is recommended. However, anesthetic management requires monitoring to prevent insufficient or excessive doses from occurring.

Investigation of Potassium Chloride for Euthanasia of Anesthetized Marine Toads (Rhinella marina)

2021 ◽  
Author(s):  
Meghan M. Louis ◽  
Gregory Scott ◽  
Dustin Smith ◽  
Brigid V. Troan ◽  
Larry J. Minter ◽  
...  
Keyword(s):  
Potassium Chloride ◽  
Potassium Concentration ◽  
Plasma Potassium ◽  
Post Treatment ◽  
Spontaneous Movement ◽  
Limits Of Detection ◽  
Rhinella Marina ◽  
Loss Of Righting Reflex ◽  
Righting Reflex ◽  
Technique Failure

Euthanasia techniques in amphibians are poorly described and sparsely validated. This study investigated potassium chloride (KCl) for euthanasia of anesthetized marine toads ( Rhinella marina ). Twenty three toads were immersed in buffered MS-222 (2 g/L) for five minutes (min) beyond loss of righting reflex, manually removed, and randomly administered KCl (n = 6/group) via one of three routes: intracardiac at 10 mEq/kg (IC), intracoelomic at 100 mEq/kg (ICe), or immersion at 4500 mEq/L (IMS) or no treatment (C) (n = 5/group). Doppler sounds were assessed continuously from prior to treatment until two min post-treatment and every five min thereafter until sound cessation or resumption of spontaneous movement. Plasma potassium concentration (K+) was measured at the time of Doppler sound cessation in ICe and IMS. In IC, ICe, IMS, and C, Doppler sound cessation occurred in 4/6, 6/6, 6/6, and 1/5 toads with median (range) or mean + SD times of 0.23 (0-4.65), 17.5 + 9.0, 40.6 + 10.9, and >420 min, respectively. Nonsuccess in 2/6 toads in IC was suspected due to technique failure. Plasma K+ exceeded the limits of detection (>9 mmol/L) in 12/12 toads in ICe and IMS. Five of six toads in C resumed spontaneous movement at median (range) times of 327 (300-367) min. KCl delivered via an intracardiac, intracoelomic, or immersion routes resulted in Doppler sound cessation in 16 of 18 toads and may be appropriate for euthanasia of anesthetized marine toads.

Stereoselective Loss of Righting Reflex in Rats by Isoflurane

2000 ◽  
Vol 93 (3) ◽  
pp. 837-843 ◽  
Author(s):  
Robert Dickinson ◽  
Ian White ◽  
William R. Lieb ◽  
Nicholas P. Franks
Keyword(s):  
Molecular Targets ◽  
Maximal Effect ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Response Curves ◽  
Loss Of Righting Reflex ◽  
Large Numbers ◽  
Righting Reflex ◽  
Volatile Agents

Background Although it is accepted widely that optically active intravenous general anesthetics produce stereoselective effects in animals, the situation regarding volatile agents is confused. Conventional studies with scarce isoflurane enantiomers have been limited to small numbers of animals and produced conflicting results. By injecting these volatile enantiomers intravenously, however, it is possible to study large numbers of animals and obtain reliable results that can help to identify the molecular targets for isoflurane. Methods Pure isoflurane enantiomers were administered intravenously to rats after solubilization in a lipid emulsion. The ability of each enantiomer to produce a loss of righting reflex was determined as a function of dose, and quantal dose-response curves were constructed. In addition, sleep times were recorded with each enantiomer. Chiral gas chromatography was used to measure relative enantiomer concentrations in the brains of rats injected with racemic isoflurane. Results The S(+)-enantiomer was 40 +/- 8% more potent than the R(-)-enantiomer at producing a loss of righting reflex. The S(+)-enantiomer induced longer sleep times (by about 50%) than did the R(-)-enantiomer. Rats anesthetized by a dose of racemic isoflurane sufficient to achieve a half-maximal effect had essentially identical brain concentrations of the two enantiomers. Conclusions The S(+)-enantiomer of the general anesthetic isoflurane is significantly (P < 0.001) more potent than the R(-)-enantiomer at causing a loss of righting reflex in rats. This confirms the view that isoflurane acts by binding to chiral sites. The observed degree of stereoselectivity provides a useful guide for ascertaining from in vitro experiments which molecular targets are most likely to play major roles in the loss of righting reflex caused by isoflurane.

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