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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

Increasing number of inter-LINKed postsynapses increases the horizontal component and reduces the frequency of oscillating potentials. a Graph showing the vector component of the oscillations. Four different states are marked. 1 Baseline state represented by equal vertical (synaptic) and horizontal (inter-postsynaptic functional LINKs) components. 2 As the horizontal component increases with increasing number of inter-LINKs between the islets of inter-LINKed postsynapses during the initial stage of anesthesia, more subthreshold neurons get activated increasing further vertical component. 3 Gradual increase in the number of inter-postsynaptic functional LINKs lead to increase in the horizontal component leading to gradual decrease in the frequency of oscillating potentials. 4 Represents phase 2 vegetative state in anesthesia where the frequency of oscillating potentials decreases further due to further increase in the horizontal component. b Oscillation of potentials during state 1 in the graph a, which is the normal baseline. Diagram showing islets of inter-LINKed postsynapses viewed as a cross-sectional view from above. For simplicity, the size of all the islets are drawn same. Spontaneous activity spreads across all the hemifused spines within that islet inducing semblances. N represents cortico-thalamic-cortical pathways and recurrent collaterals that contribute to the oscillating potentials. The frequency of oscillating potentials is determined by the horizontal component that depends on the inter-LINKs between the postsynapses horizontally. c Oscillation of potentials during state 4 in the graph a. Anesthetic molecules increase the number of inter-LINKed postsynapses and will inter-LINK several of the islets of already inter-LINKed postsynapses, increasing the magnitude of the horizontal component of the oscillating potentials. This reduces the measured frequency of these oscillations as shown by the wave form changes
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Fig6: Increasing number of inter-LINKed postsynapses increases the horizontal component and reduces the frequency of oscillating potentials. a Graph showing the vector component of the oscillations. Four different states are marked. 1 Baseline state represented by equal vertical (synaptic) and horizontal (inter-postsynaptic functional LINKs) components. 2 As the horizontal component increases with increasing number of inter-LINKs between the islets of inter-LINKed postsynapses during the initial stage of anesthesia, more subthreshold neurons get activated increasing further vertical component. 3 Gradual increase in the number of inter-postsynaptic functional LINKs lead to increase in the horizontal component leading to gradual decrease in the frequency of oscillating potentials. 4 Represents phase 2 vegetative state in anesthesia where the frequency of oscillating potentials decreases further due to further increase in the horizontal component. b Oscillation of potentials during state 1 in the graph a, which is the normal baseline. Diagram showing islets of inter-LINKed postsynapses viewed as a cross-sectional view from above. For simplicity, the size of all the islets are drawn same. Spontaneous activity spreads across all the hemifused spines within that islet inducing semblances. N represents cortico-thalamic-cortical pathways and recurrent collaterals that contribute to the oscillating potentials. The frequency of oscillating potentials is determined by the horizontal component that depends on the inter-LINKs between the postsynapses horizontally. c Oscillation of potentials during state 4 in the graph a. Anesthetic molecules increase the number of inter-LINKed postsynapses and will inter-LINK several of the islets of already inter-LINKed postsynapses, increasing the magnitude of the horizontal component of the oscillating potentials. This reduces the measured frequency of these oscillations as shown by the wave form changes

Mentions: The lipophilic anesthetic molecules are more likely to get partitioned inside the hydrophobic lipid phase in the regions of membrane reorganization at the postsynaptic membranes. The net result is the dehydration of the inter-membrane environment, which causes the abutted membranes to come into physical contact with each other (Fig. 5c). The spontaneous curvature induced by anesthetics arriving from the outside aqueous phase can contribute to asymmetry between the outer and inner leaflets of the lipid bilayer (Lipowsky 2014). The direct contact between the membranes that excludes the inter-membrane hydrophilic region is expected to be sufficient for the excitatory postsynaptic potential (EPSP) to spread from one postsynaptic membrane to the other. In this manner, anesthetics can induce a large number of non-specific inter-postsynaptic functional LINKs. It is observed that only reduced amounts of anesthetic agents are required for anesthesia in the presence of levodopa (Segal et al. 1990). Levodopa, known to cause the enlargement of dendritic spines (Meredith et al. 1995; Lee et al. 2006), supports the effect of dendritic spine enlargement in achieving direct contact between the spines as proposed by the present work. When islets of inter-LINKed postsynapses are inter-LINKed non-specifically, it will lead to alterations in the frequency of oscillating waveforms (Fig. 6) and conformation of C-semblance, resulting in changes in consciousness. The inter-postsynaptic functional LINKs induced by anesthetics can be readily reversed by removing the anesthetic agent.Fig. 6


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

Vadakkan KI - Springerplus (2015)

Increasing number of inter-LINKed postsynapses increases the horizontal component and reduces the frequency of oscillating potentials. a Graph showing the vector component of the oscillations. Four different states are marked. 1 Baseline state represented by equal vertical (synaptic) and horizontal (inter-postsynaptic functional LINKs) components. 2 As the horizontal component increases with increasing number of inter-LINKs between the islets of inter-LINKed postsynapses during the initial stage of anesthesia, more subthreshold neurons get activated increasing further vertical component. 3 Gradual increase in the number of inter-postsynaptic functional LINKs lead to increase in the horizontal component leading to gradual decrease in the frequency of oscillating potentials. 4 Represents phase 2 vegetative state in anesthesia where the frequency of oscillating potentials decreases further due to further increase in the horizontal component. b Oscillation of potentials during state 1 in the graph a, which is the normal baseline. Diagram showing islets of inter-LINKed postsynapses viewed as a cross-sectional view from above. For simplicity, the size of all the islets are drawn same. Spontaneous activity spreads across all the hemifused spines within that islet inducing semblances. N represents cortico-thalamic-cortical pathways and recurrent collaterals that contribute to the oscillating potentials. The frequency of oscillating potentials is determined by the horizontal component that depends on the inter-LINKs between the postsynapses horizontally. c Oscillation of potentials during state 4 in the graph a. Anesthetic molecules increase the number of inter-LINKed postsynapses and will inter-LINK several of the islets of already inter-LINKed postsynapses, increasing the magnitude of the horizontal component of the oscillating potentials. This reduces the measured frequency of these oscillations as shown by the wave form changes
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
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Fig6: Increasing number of inter-LINKed postsynapses increases the horizontal component and reduces the frequency of oscillating potentials. a Graph showing the vector component of the oscillations. Four different states are marked. 1 Baseline state represented by equal vertical (synaptic) and horizontal (inter-postsynaptic functional LINKs) components. 2 As the horizontal component increases with increasing number of inter-LINKs between the islets of inter-LINKed postsynapses during the initial stage of anesthesia, more subthreshold neurons get activated increasing further vertical component. 3 Gradual increase in the number of inter-postsynaptic functional LINKs lead to increase in the horizontal component leading to gradual decrease in the frequency of oscillating potentials. 4 Represents phase 2 vegetative state in anesthesia where the frequency of oscillating potentials decreases further due to further increase in the horizontal component. b Oscillation of potentials during state 1 in the graph a, which is the normal baseline. Diagram showing islets of inter-LINKed postsynapses viewed as a cross-sectional view from above. For simplicity, the size of all the islets are drawn same. Spontaneous activity spreads across all the hemifused spines within that islet inducing semblances. N represents cortico-thalamic-cortical pathways and recurrent collaterals that contribute to the oscillating potentials. The frequency of oscillating potentials is determined by the horizontal component that depends on the inter-LINKs between the postsynapses horizontally. c Oscillation of potentials during state 4 in the graph a. Anesthetic molecules increase the number of inter-LINKed postsynapses and will inter-LINK several of the islets of already inter-LINKed postsynapses, increasing the magnitude of the horizontal component of the oscillating potentials. This reduces the measured frequency of these oscillations as shown by the wave form changes
Mentions: The lipophilic anesthetic molecules are more likely to get partitioned inside the hydrophobic lipid phase in the regions of membrane reorganization at the postsynaptic membranes. The net result is the dehydration of the inter-membrane environment, which causes the abutted membranes to come into physical contact with each other (Fig. 5c). The spontaneous curvature induced by anesthetics arriving from the outside aqueous phase can contribute to asymmetry between the outer and inner leaflets of the lipid bilayer (Lipowsky 2014). The direct contact between the membranes that excludes the inter-membrane hydrophilic region is expected to be sufficient for the excitatory postsynaptic potential (EPSP) to spread from one postsynaptic membrane to the other. In this manner, anesthetics can induce a large number of non-specific inter-postsynaptic functional LINKs. It is observed that only reduced amounts of anesthetic agents are required for anesthesia in the presence of levodopa (Segal et al. 1990). Levodopa, known to cause the enlargement of dendritic spines (Meredith et al. 1995; Lee et al. 2006), supports the effect of dendritic spine enlargement in achieving direct contact between the spines as proposed by the present work. When islets of inter-LINKed postsynapses are inter-LINKed non-specifically, it will lead to alterations in the frequency of oscillating waveforms (Fig. 6) and conformation of C-semblance, resulting in changes in consciousness. The inter-postsynaptic functional LINKs induced by anesthetics can be readily reversed by removing the anesthetic agent.Fig. 6

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