Immobilizing Doses of Halothane, Isoflurane or Propofol, Do Not Preferentially Depress Noxious Heat-Evoked Responses of Rat Lumbar Dorsal Horn Neurons with Ascending Projections

Barter, Linda S; Mark, Laurie O.; Jinks, Steven L.; Carstens, Earl; Antognini, Joseph F.

doi:10.1213/ane.0b013e318163f8f3

Cited by 16 publications

(11 citation statements)

References 21 publications

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“…Although immobility results from anesthetic action in the spinal cord (Antognini and Schwartz, 1993;Rampil et al, 1993), and ␣2 is highly expressed in the dorsal horn of the spinal cord (Bohlhalter et al, 1996), this negative result is consistent with the conclusions of previous studies with GABA A -R mutant mice and pharmacologic perturbations that GABA A -Rs have at most a limited role in mediating inhaled anesthetic-induced immobility (Eger et al, 2008). Furthermore, immobility is caused by actions of inhaled anesthetics on the ventral horn of the spinal cord (Barter et al, 2008;Jinks et al, 2008).…”

Section: Discussionsupporting

confidence: 90%

Inhaled Anesthetic Responses of Recombinant Receptors and Knockin Mice Harboring α2(S270H/L277A) GABAA Receptor Subunits That Are Resistant to Isoflurane

Werner¹,

Swihart²,

Rau³

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

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The mechanism by which the inhaled anesthetic isoflurane produces amnesia and immobility is not understood. Isoflurane modulates GABA A receptors (GABA A -Rs) in a manner that makes them plausible targets. We asked whether GABA A -R ␣2 subunits contribute to a site of anesthetic action in vivo. Previous studies demonstrated that Ser270 in the second transmembrane domain is involved in the modulation of GABA A -Rs by volatile anesthetics and alcohol, either as a binding site or a critical allosteric residue. We engineered GABA A -Rs with two mutations in the ␣2 subunit, changing Ser270 to His and Leu277 to Ala. Recombinant receptors with these mutations demonstrated normal affinity for GABA, but substantially reduced responses to isoflurane. We then produced mutant (knockin) mice in which this mutated subunit replaced the wildtype ␣2 subunit. The adult mutant mice were overtly normal, although there was evidence of enhanced neonatal mortality and fear conditioning. Electrophysiological recordings from dentate granule neurons in brain slices confirmed the decreased actions of isoflurane on mutant receptors contributing to inhibitory synaptic currents. The loss of righting reflex EC 50 for isoflurane did not differ between genotypes, but time to regain the righting reflex was increased in N 2 generation knockins. This effect was not observed at the N 4 generation. Isoflurane produced immobility (as measured by tail clamp) and amnesia (as measured by fear conditioning) in both wild-type and mutant mice, and potencies (EC 50 ) did not differ between the strains for these actions of isoflurane. Thus, immobility or amnesia does not require isoflurane potentiation of the ␣2 subunit.

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Section: Discussionsupporting

confidence: 90%

Inhaled Anesthetic Responses of Recombinant Receptors and Knockin Mice Harboring α2(S270H/L277A) GABAA Receptor Subunits That Are Resistant to Isoflurane

Werner¹,

Swihart²,

Rau³

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

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“…Immobility and analgesia are not necessary for loss of consciousness but occur due to drug activity at widespread sites (Antognini et al, 2005). Similarly, analgesia is produced to varying degrees by different anesthetic agents and by nonanesthetic drugs, but is neither necessary nor sufficient for anesthesia (Sukhotinsky et al, 2007;Barter et al, 2008). Understanding the transition from awake to "unresponsive," and how various networks may be sequentially affected during this transition is key to dissecting this multidimensional phenomenon.…”

Section: Discussionmentioning

confidence: 99%

Cortical and Subcortical Connectivity Changes during Decreasing Levels of Consciousness in Humans: A Functional Magnetic Resonance Imaging Study using Propofol

Mhuircheartaigh¹,

Rosenorn-Lanng²,

Wise³

et al. 2010

Journal of Neuroscience

199

144

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. We investigated the effects of propofol, widely used for anesthesia and sedation, on spontaneous and evoked cerebral activity using functional magnetic resonance imaging (fMRI). A series of auditory and noxious stimuli was presented to eight healthy volunteers at three behavioral states: awake, "sedated" and "unresponsive." Performance in a verbal task and the absence of a response to verbal stimulation, rather than propofol concentrations, were used to define these states clinically. Analysis of stimulus-related blood oxygenation level-dependent signal changes identified reductions in cortical and subcortical responses to auditory and noxious stimuli in sedated and unresponsive states. A specific reduction in activity within the putamen was noted and further investigated with functional connectivity analysis. Progressive failure to perceive or respond to auditory or noxious stimuli was associated with a reduction in the functional connectivity between the putamen and other brain regions, while thalamo-cortical connectivity was relatively preserved. This result has not been previously described and suggests that disruption of subcortical thalamo-regulatory systems may occur before, or even precipitate, failure of thalamo-cortical transmission with the induction of unconsciousness.

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“…Sensory-evoked potentials in humans can be recorded at concentrations well in excess of MAC 9. Transmission of impulses through the dorsal horn of rats continues during halothane, isoflurane and propofol anesthesia,10,11 and propofol anesthesia does not prevent spinal cord c-fos expression in mice subjected to an intraplantar injection of formalin 12. Similarly, immobility is not a consequence of paralysis, nor does it necessarily result from the inability of motor nerves in the anterior horn to respond to impulses from the brain.…”

Section: Introductionmentioning

confidence: 96%

Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility?

Eger

Raines

Shafer³

et al. 2008

Anesthesia &Amp; Analgesia

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A paradox arises from present information concerning the mechanism(s) by which inhaled anesthetics produce immobility in the face of noxious stimulation. Several findings, such as additivity, suggest a common site at which inhaled anesthetics act to produce immobility. However, two decades of focused investigation have not identified a ligand- or voltage-gated channel that alone is sufficient to mediate immobility. Indeed, most putative targets provide minimal or no mediation. For example, opioid, 5-HT3, gamma-aminobutyric acid type A and glutamate receptors, and potassium and calcium channels appear to be irrelevant or play only minor roles. Furthermore, no combination of actions on ligand- or voltage-gated channels seems sufficient. A few plausible targets (e.g., sodium channels) merit further study, but there remains the possibility that immobilization results from a nonspecific mechanism.

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Immobilizing Doses of Halothane, Isoflurane or Propofol, Do Not Preferentially Depress Noxious Heat-Evoked Responses of Rat Lumbar Dorsal Horn Neurons with Ascending Projections

Cited by 16 publications

References 21 publications

Inhaled Anesthetic Responses of Recombinant Receptors and Knockin Mice Harboring α2(S270H/L277A) GABAA Receptor Subunits That Are Resistant to Isoflurane

Inhaled Anesthetic Responses of Recombinant Receptors and Knockin Mice Harboring α2(S270H/L277A) GABAA Receptor Subunits That Are Resistant to Isoflurane

Cortical and Subcortical Connectivity Changes during Decreasing Levels of Consciousness in Humans: A Functional Magnetic Resonance Imaging Study using Propofol

Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility?

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