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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

Route through which the externally applied pressure is transduced for the pressure reversal of anesthesia. Externally applied pressure get transduced to the cerebrospinal fluid (CSF) through the perilymph and cochlear aqueduct. This pressure gradient from CSF reaches the extracellular matrix (ECM) space through the glymphatic system (paravascular space). The pressure gradient gets transduced through the extracellular matrix space and result in displacement of the anesthetic molecules from the lipid membranes to the ECM and finally to the paravenular space and to the venous system. Both the close inter-postsynaptic membrane contacts and the reversible membrane hemifusions established in the presence of the anesthetics reverse back to the ground state. As the anesthetics get displaced, non-specific semblances induced through non-specific inter-postsynaptic functional LINKs will get proportionately reduced. This will bring back the normal conformation to the C-semblance as demonstrated in Fig. 4. Top right On the left side are two synapses with abutted postsynaptic membranes (dendritic spines) B and D in the presence of anesthetics forming an inter-postsynaptic functional LINK. Note the red color of the region of inter-postsynaptic functional LINK. On the right side is the state after pressure reversal of the inter-postsynaptic functional LINK. Inter-postsynaptic hydrophilic region forms again when anesthetic molecules are removed
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Fig7: Route through which the externally applied pressure is transduced for the pressure reversal of anesthesia. Externally applied pressure get transduced to the cerebrospinal fluid (CSF) through the perilymph and cochlear aqueduct. This pressure gradient from CSF reaches the extracellular matrix (ECM) space through the glymphatic system (paravascular space). The pressure gradient gets transduced through the extracellular matrix space and result in displacement of the anesthetic molecules from the lipid membranes to the ECM and finally to the paravenular space and to the venous system. Both the close inter-postsynaptic membrane contacts and the reversible membrane hemifusions established in the presence of the anesthetics reverse back to the ground state. As the anesthetics get displaced, non-specific semblances induced through non-specific inter-postsynaptic functional LINKs will get proportionately reduced. This will bring back the normal conformation to the C-semblance as demonstrated in Fig. 4. Top right On the left side are two synapses with abutted postsynaptic membranes (dendritic spines) B and D in the presence of anesthetics forming an inter-postsynaptic functional LINK. Note the red color of the region of inter-postsynaptic functional LINK. On the right side is the state after pressure reversal of the inter-postsynaptic functional LINK. Inter-postsynaptic hydrophilic region forms again when anesthetic molecules are removed

Mentions: How does the pressure gradient arriving at the ECM reverse the anesthetic-induced inter-postsynaptic functional LINKs? Based on Le Chatelier’s principle, when the pressure on a system at equilibrium is disturbed, the equilibrium position will shift in the direction necessary to reduce the pressure. One of the effects of increased pressure is the extrusion of anesthetic molecules from the lipid membranes to the ECM volume, and then these molecules get displaced through the paravenular space into the venous system. This in turn will reintroduce the hydrophilic region between the postsynaptic membranes, reversing the inter-postsynaptic functional LINKs induced by anesthetics (Fig. 7). Reversal of all the non-specific, inter-postsynaptic functional LINKs changing the C-semblance back into its normal conformation can explain the reversal of the unconscious state back to normal consciousness. In non-mammalian species such as freshwater shrimp (Simon et al. 1983) and nematodes (Eckenhoff and Yang 1994), pressure reversal of general anesthetics is not efficient, possibly due to the absence of the glymphatic pathway or due to some other structural variations.Fig. 7


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

Vadakkan KI - Springerplus (2015)

Route through which the externally applied pressure is transduced for the pressure reversal of anesthesia. Externally applied pressure get transduced to the cerebrospinal fluid (CSF) through the perilymph and cochlear aqueduct. This pressure gradient from CSF reaches the extracellular matrix (ECM) space through the glymphatic system (paravascular space). The pressure gradient gets transduced through the extracellular matrix space and result in displacement of the anesthetic molecules from the lipid membranes to the ECM and finally to the paravenular space and to the venous system. Both the close inter-postsynaptic membrane contacts and the reversible membrane hemifusions established in the presence of the anesthetics reverse back to the ground state. As the anesthetics get displaced, non-specific semblances induced through non-specific inter-postsynaptic functional LINKs will get proportionately reduced. This will bring back the normal conformation to the C-semblance as demonstrated in Fig. 4. Top right On the left side are two synapses with abutted postsynaptic membranes (dendritic spines) B and D in the presence of anesthetics forming an inter-postsynaptic functional LINK. Note the red color of the region of inter-postsynaptic functional LINK. On the right side is the state after pressure reversal of the inter-postsynaptic functional LINK. Inter-postsynaptic hydrophilic region forms again when anesthetic molecules are removed
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig7: Route through which the externally applied pressure is transduced for the pressure reversal of anesthesia. Externally applied pressure get transduced to the cerebrospinal fluid (CSF) through the perilymph and cochlear aqueduct. This pressure gradient from CSF reaches the extracellular matrix (ECM) space through the glymphatic system (paravascular space). The pressure gradient gets transduced through the extracellular matrix space and result in displacement of the anesthetic molecules from the lipid membranes to the ECM and finally to the paravenular space and to the venous system. Both the close inter-postsynaptic membrane contacts and the reversible membrane hemifusions established in the presence of the anesthetics reverse back to the ground state. As the anesthetics get displaced, non-specific semblances induced through non-specific inter-postsynaptic functional LINKs will get proportionately reduced. This will bring back the normal conformation to the C-semblance as demonstrated in Fig. 4. Top right On the left side are two synapses with abutted postsynaptic membranes (dendritic spines) B and D in the presence of anesthetics forming an inter-postsynaptic functional LINK. Note the red color of the region of inter-postsynaptic functional LINK. On the right side is the state after pressure reversal of the inter-postsynaptic functional LINK. Inter-postsynaptic hydrophilic region forms again when anesthetic molecules are removed
Mentions: How does the pressure gradient arriving at the ECM reverse the anesthetic-induced inter-postsynaptic functional LINKs? Based on Le Chatelier’s principle, when the pressure on a system at equilibrium is disturbed, the equilibrium position will shift in the direction necessary to reduce the pressure. One of the effects of increased pressure is the extrusion of anesthetic molecules from the lipid membranes to the ECM volume, and then these molecules get displaced through the paravenular space into the venous system. This in turn will reintroduce the hydrophilic region between the postsynaptic membranes, reversing the inter-postsynaptic functional LINKs induced by anesthetics (Fig. 7). Reversal of all the non-specific, inter-postsynaptic functional LINKs changing the C-semblance back into its normal conformation can explain the reversal of the unconscious state back to normal consciousness. In non-mammalian species such as freshwater shrimp (Simon et al. 1983) and nematodes (Eckenhoff and Yang 1994), pressure reversal of general anesthetics is not efficient, possibly due to the absence of the glymphatic pathway or due to some other structural variations.Fig. 7

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