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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

Sources of potentials that contribute to the horizontal and vertical components of the oscillating potentials. Upper left side A cortical pyramidal neuron with different locations of spike generation. The source of surface-recorded electro-encephalogram (EEG) waveforms is likely to have significant contributions from the NMDA spikes from the apical tufts since their magnitude is higher than that of the somatic spikes (neuronal firing) and they occur close to the pial surface. Upper right side Five islets of inter-LINKed postsynaptic terminals (IILPS) are shown that represent the abundance of dendritic spines in this area that permits several postsynapses to get inter-LINKed both by innate and acquired mechanisms. The islets are expected to be connected with each other through recurrent collaterals, layer 1 cortical neurons and cortico-thalamo-cortical pathways. This pattern of arrangement will provide a mechanism for long-range synchronization that is being recorded as EEG waveforms. Bottom The role of both thalamus and brain stem inputs in maintaining the frequency of oscillations in the cortex. Various nuclei in the brain stem that provide inputs to both thalamus and cortex are shown (neurotransmitters are given in brackets). Cortico-thalamo-cortical pathway maintains a significant role in controlling the oscillating potentials in the cortex. Pontine reticular activating system sends glutamatergic inputs to the thalamus potentially regulating the oscillating potentials in the cortex. RC recurrent collateral, C-T cortico-thalamic pathway, T-C thalamo-cortical pathway, L1 layer 1 cortical neuron, IILPS islet of inter-LINKed postsynapses, Glu glutamate, ACh acetyl choline, 5HT 5-hydroxy tryptamine (serotonin), NE nor-epinephrine
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Fig3: Sources of potentials that contribute to the horizontal and vertical components of the oscillating potentials. Upper left side A cortical pyramidal neuron with different locations of spike generation. The source of surface-recorded electro-encephalogram (EEG) waveforms is likely to have significant contributions from the NMDA spikes from the apical tufts since their magnitude is higher than that of the somatic spikes (neuronal firing) and they occur close to the pial surface. Upper right side Five islets of inter-LINKed postsynaptic terminals (IILPS) are shown that represent the abundance of dendritic spines in this area that permits several postsynapses to get inter-LINKed both by innate and acquired mechanisms. The islets are expected to be connected with each other through recurrent collaterals, layer 1 cortical neurons and cortico-thalamo-cortical pathways. This pattern of arrangement will provide a mechanism for long-range synchronization that is being recorded as EEG waveforms. Bottom The role of both thalamus and brain stem inputs in maintaining the frequency of oscillations in the cortex. Various nuclei in the brain stem that provide inputs to both thalamus and cortex are shown (neurotransmitters are given in brackets). Cortico-thalamo-cortical pathway maintains a significant role in controlling the oscillating potentials in the cortex. Pontine reticular activating system sends glutamatergic inputs to the thalamus potentially regulating the oscillating potentials in the cortex. RC recurrent collateral, C-T cortico-thalamic pathway, T-C thalamo-cortical pathway, L1 layer 1 cortical neuron, IILPS islet of inter-LINKed postsynapses, Glu glutamate, ACh acetyl choline, 5HT 5-hydroxy tryptamine (serotonin), NE nor-epinephrine

Mentions: The dendritic spikes indicate that potentials are spontaneously generated at several postsynaptic terminals. The resistive properties of the long thin spine necks result in large potentials at the spine heads (postsynaptic terminal). There are two findings that need a matching explanation. First, the postsynaptic terminals are abutted to each other at the apical tuft area. The second one is the presence of surface or extracellular recorded oscillatory potentials. Since the oscillating potentials require a mechanism for their horizontal components, an innate mechanism whereby several postsynaptic terminals form islets of inter-LINKed postsynapses (Fig. 3) is expected to occur at areas of the cortex where postsynaptic terminals of different neurons abut each other. The changes in the horizontal component can then be examined for the observed changes in the frequency of oscillations during various conditions.Fig. 3


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

Vadakkan KI - Springerplus (2015)

Sources of potentials that contribute to the horizontal and vertical components of the oscillating potentials. Upper left side A cortical pyramidal neuron with different locations of spike generation. The source of surface-recorded electro-encephalogram (EEG) waveforms is likely to have significant contributions from the NMDA spikes from the apical tufts since their magnitude is higher than that of the somatic spikes (neuronal firing) and they occur close to the pial surface. Upper right side Five islets of inter-LINKed postsynaptic terminals (IILPS) are shown that represent the abundance of dendritic spines in this area that permits several postsynapses to get inter-LINKed both by innate and acquired mechanisms. The islets are expected to be connected with each other through recurrent collaterals, layer 1 cortical neurons and cortico-thalamo-cortical pathways. This pattern of arrangement will provide a mechanism for long-range synchronization that is being recorded as EEG waveforms. Bottom The role of both thalamus and brain stem inputs in maintaining the frequency of oscillations in the cortex. Various nuclei in the brain stem that provide inputs to both thalamus and cortex are shown (neurotransmitters are given in brackets). Cortico-thalamo-cortical pathway maintains a significant role in controlling the oscillating potentials in the cortex. Pontine reticular activating system sends glutamatergic inputs to the thalamus potentially regulating the oscillating potentials in the cortex. RC recurrent collateral, C-T cortico-thalamic pathway, T-C thalamo-cortical pathway, L1 layer 1 cortical neuron, IILPS islet of inter-LINKed postsynapses, Glu glutamate, ACh acetyl choline, 5HT 5-hydroxy tryptamine (serotonin), NE nor-epinephrine
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Fig3: Sources of potentials that contribute to the horizontal and vertical components of the oscillating potentials. Upper left side A cortical pyramidal neuron with different locations of spike generation. The source of surface-recorded electro-encephalogram (EEG) waveforms is likely to have significant contributions from the NMDA spikes from the apical tufts since their magnitude is higher than that of the somatic spikes (neuronal firing) and they occur close to the pial surface. Upper right side Five islets of inter-LINKed postsynaptic terminals (IILPS) are shown that represent the abundance of dendritic spines in this area that permits several postsynapses to get inter-LINKed both by innate and acquired mechanisms. The islets are expected to be connected with each other through recurrent collaterals, layer 1 cortical neurons and cortico-thalamo-cortical pathways. This pattern of arrangement will provide a mechanism for long-range synchronization that is being recorded as EEG waveforms. Bottom The role of both thalamus and brain stem inputs in maintaining the frequency of oscillations in the cortex. Various nuclei in the brain stem that provide inputs to both thalamus and cortex are shown (neurotransmitters are given in brackets). Cortico-thalamo-cortical pathway maintains a significant role in controlling the oscillating potentials in the cortex. Pontine reticular activating system sends glutamatergic inputs to the thalamus potentially regulating the oscillating potentials in the cortex. RC recurrent collateral, C-T cortico-thalamic pathway, T-C thalamo-cortical pathway, L1 layer 1 cortical neuron, IILPS islet of inter-LINKed postsynapses, Glu glutamate, ACh acetyl choline, 5HT 5-hydroxy tryptamine (serotonin), NE nor-epinephrine
Mentions: The dendritic spikes indicate that potentials are spontaneously generated at several postsynaptic terminals. The resistive properties of the long thin spine necks result in large potentials at the spine heads (postsynaptic terminal). There are two findings that need a matching explanation. First, the postsynaptic terminals are abutted to each other at the apical tuft area. The second one is the presence of surface or extracellular recorded oscillatory potentials. Since the oscillating potentials require a mechanism for their horizontal components, an innate mechanism whereby several postsynaptic terminals form islets of inter-LINKed postsynapses (Fig. 3) is expected to occur at areas of the cortex where postsynaptic terminals of different neurons abut each other. The changes in the horizontal component can then be examined for the observed changes in the frequency of oscillations during various conditions.Fig. 3

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