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A pressure-reversible cellular mechanism of general anesthetics capable of altering a possible mechanism for consciousness.

Vadakkan KI - Springerplus (2015)

Bottom Line: Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines.The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia.The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Department of Medicine, University of Toronto, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room A4-08, Toronto, ON M4N 3M5 Canada.

ABSTRACT
Different anesthetics are known to modulate different types of membrane-bound receptors. Their common mechanism of action is expected to alter the mechanism for consciousness. Consciousness is hypothesized as the integral of all the units of internal sensations induced by reactivation of inter-postsynaptic membrane functional LINKs during mechanisms that lead to oscillating potentials. The thermodynamics of the spontaneous lateral curvature of lipid membranes induced by lipophilic anesthetics can lead to the formation of non-specific inter-postsynaptic membrane functional LINKs by different mechanisms. These include direct membrane contact by excluding the inter-membrane hydrophilic region and readily reversible partial membrane hemifusion. The constant reorganization of the lipid membranes at the lateral edges of the postsynaptic terminals (dendritic spines) resulting from AMPA receptor-subunit vesicle exocytosis and endocytosis can favor the effect of anesthetic molecules on lipid membranes at this location. Induction of a large number of non-specific LINKs can alter the conformation of the integral of the units of internal sensations that maintain consciousness. Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines. Externally applied pressure can transduce from the middle ear through the perilymph, cerebrospinal fluid, and the recently discovered glymphatic pathway to the extracellular matrix space, and finally to the paravenular space. The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia. Changes in membrane composition and the conversion of membrane hemifusion to fusion due to defects in the checkpoint mechanisms can lead to cytoplasmic content mixing between neurons and cause neurodegenerative changes. The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics.

No MeSH data available.


Related in: MedlinePlus

Reactivation of an inter-postsynaptic functional LINK that induces the formation of units of internal sensation. An action potential arriving at presynaptic terminal A activates synapse A–B and reactivates inter-postsynaptic functional LINK between postsynapses B and D. When postsynapse D is activated in the absence of arrival of activity from its presynapse (not shown), a semblance of arrival of activity from its presynapse occurs. The sensory equivalent of the semblance (sensory hallucinations) can be extrapolated from examining the packets of minimum sensory stimuli capable of stimulating postsynapse D. The sensory identity of the semblance of activity occurring at postsynapse D consists of inputs from neuron Y. Neuron Y is normally activated by inputs from a set of lower order neurons {X}. Continuing this extrapolation towards the sensory level identifies a set of sensory receptors {SR}. {a}, {b} and {c} are subsets of {SR} and are capable of independently activating postsynapse D. Hypothetical packets of sensory stimuli activating sensory receptor sets {a}, {b} and {c} are called semblions 1, 2 and 3 respectively. Activation of postsynapse D through inter-postsynaptic functional LINK B–D by the cue stimulus can lead to the virtual internal sensation of semblions either 1, or 2, or 3 or their integral or their overlapping region. Cue stimulus-induced activation of postsynapse D reaches the soma of its neuron Z. If neuron Z already receives baseline summated EPSP short of one EPSP to trigger an action potential, then the additional EPSP arriving through inter-postsynaptic functional LINK B–D and through postsynapse D can add to the sub-threshold EPSP and fire neuron Z, resulting in latter’s concurrent activation during the formation of internal sensation (Figure modified from Vadakkan 2010)
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Fig2: Reactivation of an inter-postsynaptic functional LINK that induces the formation of units of internal sensation. An action potential arriving at presynaptic terminal A activates synapse A–B and reactivates inter-postsynaptic functional LINK between postsynapses B and D. When postsynapse D is activated in the absence of arrival of activity from its presynapse (not shown), a semblance of arrival of activity from its presynapse occurs. The sensory equivalent of the semblance (sensory hallucinations) can be extrapolated from examining the packets of minimum sensory stimuli capable of stimulating postsynapse D. The sensory identity of the semblance of activity occurring at postsynapse D consists of inputs from neuron Y. Neuron Y is normally activated by inputs from a set of lower order neurons {X}. Continuing this extrapolation towards the sensory level identifies a set of sensory receptors {SR}. {a}, {b} and {c} are subsets of {SR} and are capable of independently activating postsynapse D. Hypothetical packets of sensory stimuli activating sensory receptor sets {a}, {b} and {c} are called semblions 1, 2 and 3 respectively. Activation of postsynapse D through inter-postsynaptic functional LINK B–D by the cue stimulus can lead to the virtual internal sensation of semblions either 1, or 2, or 3 or their integral or their overlapping region. Cue stimulus-induced activation of postsynapse D reaches the soma of its neuron Z. If neuron Z already receives baseline summated EPSP short of one EPSP to trigger an action potential, then the additional EPSP arriving through inter-postsynaptic functional LINK B–D and through postsynapse D can add to the sub-threshold EPSP and fire neuron Z, resulting in latter’s concurrent activation during the formation of internal sensation (Figure modified from Vadakkan 2010)

Mentions: Potentials arriving at the postsynaptic terminal through a LINK (the word “link” is highlighted to emphasize its importance) from the neighboring postsynaptic terminal can evoke units of internal sensations eliciting the semblance of the arrival of activity from the presynaptic terminal. An inter-postsynaptic functional LINK is expected to form between the abutted postsynaptic locations as a function of the simultaneous arrival of activity from two different sensory inputs during associative learning between two stimuli (Fig. 1a). The reactivation of the LINK occurs as a function of the arrival of activity from the one of the associatively learned stimuli through the inter-postsynaptic functional LINK to the inter-LINKed postsynaptic terminal (Fig. 1b). Since lipid bilayers of different postsynaptic terminals (Fig. 1c) abut each other with a negligible extracellular matrix volume, as visualized in electron microscopic pictures, an interaction between their outer layers is expected to occur (Fig. 1d). The sensory identity of the semblance of the second stimulus formed at a postsynaptic terminal by the reactivation of the inter-postsynaptic functional LINK by the arrival of activity from the first stimulus and how it can be derived are explained in Fig. 2.Fig. 1


A pressure-reversible cellular mechanism of general anesthetics capable of altering a possible mechanism for consciousness.

Vadakkan KI - Springerplus (2015)

Reactivation of an inter-postsynaptic functional LINK that induces the formation of units of internal sensation. An action potential arriving at presynaptic terminal A activates synapse A–B and reactivates inter-postsynaptic functional LINK between postsynapses B and D. When postsynapse D is activated in the absence of arrival of activity from its presynapse (not shown), a semblance of arrival of activity from its presynapse occurs. The sensory equivalent of the semblance (sensory hallucinations) can be extrapolated from examining the packets of minimum sensory stimuli capable of stimulating postsynapse D. The sensory identity of the semblance of activity occurring at postsynapse D consists of inputs from neuron Y. Neuron Y is normally activated by inputs from a set of lower order neurons {X}. Continuing this extrapolation towards the sensory level identifies a set of sensory receptors {SR}. {a}, {b} and {c} are subsets of {SR} and are capable of independently activating postsynapse D. Hypothetical packets of sensory stimuli activating sensory receptor sets {a}, {b} and {c} are called semblions 1, 2 and 3 respectively. Activation of postsynapse D through inter-postsynaptic functional LINK B–D by the cue stimulus can lead to the virtual internal sensation of semblions either 1, or 2, or 3 or their integral or their overlapping region. Cue stimulus-induced activation of postsynapse D reaches the soma of its neuron Z. If neuron Z already receives baseline summated EPSP short of one EPSP to trigger an action potential, then the additional EPSP arriving through inter-postsynaptic functional LINK B–D and through postsynapse D can add to the sub-threshold EPSP and fire neuron Z, resulting in latter’s concurrent activation during the formation of internal sensation (Figure modified from Vadakkan 2010)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561946&req=5

Fig2: Reactivation of an inter-postsynaptic functional LINK that induces the formation of units of internal sensation. An action potential arriving at presynaptic terminal A activates synapse A–B and reactivates inter-postsynaptic functional LINK between postsynapses B and D. When postsynapse D is activated in the absence of arrival of activity from its presynapse (not shown), a semblance of arrival of activity from its presynapse occurs. The sensory equivalent of the semblance (sensory hallucinations) can be extrapolated from examining the packets of minimum sensory stimuli capable of stimulating postsynapse D. The sensory identity of the semblance of activity occurring at postsynapse D consists of inputs from neuron Y. Neuron Y is normally activated by inputs from a set of lower order neurons {X}. Continuing this extrapolation towards the sensory level identifies a set of sensory receptors {SR}. {a}, {b} and {c} are subsets of {SR} and are capable of independently activating postsynapse D. Hypothetical packets of sensory stimuli activating sensory receptor sets {a}, {b} and {c} are called semblions 1, 2 and 3 respectively. Activation of postsynapse D through inter-postsynaptic functional LINK B–D by the cue stimulus can lead to the virtual internal sensation of semblions either 1, or 2, or 3 or their integral or their overlapping region. Cue stimulus-induced activation of postsynapse D reaches the soma of its neuron Z. If neuron Z already receives baseline summated EPSP short of one EPSP to trigger an action potential, then the additional EPSP arriving through inter-postsynaptic functional LINK B–D and through postsynapse D can add to the sub-threshold EPSP and fire neuron Z, resulting in latter’s concurrent activation during the formation of internal sensation (Figure modified from Vadakkan 2010)
Mentions: Potentials arriving at the postsynaptic terminal through a LINK (the word “link” is highlighted to emphasize its importance) from the neighboring postsynaptic terminal can evoke units of internal sensations eliciting the semblance of the arrival of activity from the presynaptic terminal. An inter-postsynaptic functional LINK is expected to form between the abutted postsynaptic locations as a function of the simultaneous arrival of activity from two different sensory inputs during associative learning between two stimuli (Fig. 1a). The reactivation of the LINK occurs as a function of the arrival of activity from the one of the associatively learned stimuli through the inter-postsynaptic functional LINK to the inter-LINKed postsynaptic terminal (Fig. 1b). Since lipid bilayers of different postsynaptic terminals (Fig. 1c) abut each other with a negligible extracellular matrix volume, as visualized in electron microscopic pictures, an interaction between their outer layers is expected to occur (Fig. 1d). The sensory identity of the semblance of the second stimulus formed at a postsynaptic terminal by the reactivation of the inter-postsynaptic functional LINK by the arrival of activity from the first stimulus and how it can be derived are explained in Fig. 2.Fig. 1

Bottom Line: Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines.The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia.The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Department of Medicine, University of Toronto, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room A4-08, Toronto, ON M4N 3M5 Canada.

ABSTRACT
Different anesthetics are known to modulate different types of membrane-bound receptors. Their common mechanism of action is expected to alter the mechanism for consciousness. Consciousness is hypothesized as the integral of all the units of internal sensations induced by reactivation of inter-postsynaptic membrane functional LINKs during mechanisms that lead to oscillating potentials. The thermodynamics of the spontaneous lateral curvature of lipid membranes induced by lipophilic anesthetics can lead to the formation of non-specific inter-postsynaptic membrane functional LINKs by different mechanisms. These include direct membrane contact by excluding the inter-membrane hydrophilic region and readily reversible partial membrane hemifusion. The constant reorganization of the lipid membranes at the lateral edges of the postsynaptic terminals (dendritic spines) resulting from AMPA receptor-subunit vesicle exocytosis and endocytosis can favor the effect of anesthetic molecules on lipid membranes at this location. Induction of a large number of non-specific LINKs can alter the conformation of the integral of the units of internal sensations that maintain consciousness. Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines. Externally applied pressure can transduce from the middle ear through the perilymph, cerebrospinal fluid, and the recently discovered glymphatic pathway to the extracellular matrix space, and finally to the paravenular space. The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia. Changes in membrane composition and the conversion of membrane hemifusion to fusion due to defects in the checkpoint mechanisms can lead to cytoplasmic content mixing between neurons and cause neurodegenerative changes. The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics.

No MeSH data available.


Related in: MedlinePlus