anatomy and physiology of the neuron(1)
TRANSCRIPT
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Physiologyof the
Neuron
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Generalities
In order to understand the effects of drugs on the CNS,
the structure and function of the neuron (the nerve
cell) is essential
The neuron is the basic component of the CNS
Neurons have special characteristics that distinguish
them from other cells
A Can conduct electrical impulses over long
distances
B Carry out specific input and output relations
with other cells and other tissues of the body
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Generalities
These input/output connections determine the
functions of a particular neuron and therefore the
behavioral response that neuronal activity may elicit
The typical neuron consists of:
Soma (the cell body)
Dendrites (zillions of branched extensions)
Axon (an elongated nerve bundle)
**Synapse (the microspace between neurons)
** Not considered to be a structure
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Introduction
Research regarding the electrical activity of the neuron
was originally conducted using the giant axon of the
squid
The axon of the squid measures up to a millimeter in
diameter and is 100 times larger than the axon of human
nerve cells
The squids axon is used to contract muscles that squirtwater out of the squids body, thereby propelling it
through the body
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Resting Potential
Neurons have a charge across their membranes
(electrical)
If the charge is measured by an oscilloscope and the
charge is left undisturbed, this charge will remain
relatively constant at about -70 millivolts (mV)
This charge is called the RESTING POTENTIAL
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The Resting Potential
0
-70
-Time (milliseconds)
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Resting Potential
Salt is NaCl
Na is positively charged, therefore calledNa+
Cl is negatively charged, therefore called Cl-
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Resting Potential
If you put salt into a glass of water it would dissolve into
Na+ and Cl-
Inequalities in the concentration of the ions in different
places would cause the ions to flow down theirconcentration gradientuntil they are equally distributed
Inequalities in the charges would cause the the ions to
flow down theirelectrostatic gradient
Therefore, the concentrationAND the charge of sodium
and chloride will be equal everywhere and so will the
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Cell Membrane
Intracellular compartment is inside
Extracellular compartment is outside
Ions present:An- - Negatively charged organic compounds
Cl- - Negatively charged Clorine
K+ - Positively charged Potassium
Na+ - Positively charged Sodium
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Depolarization
When the transmembrane voltage decreases toward 0 mV,
the membrane is said to have become depolarized
Depolarization is thought to be due to increased inwardmovement of Na+ ions
The NA+ gates open when the membrane is depolarized
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Hyperpolarization
When the transmembrane voltage increases, the
membrane is said to have become hyperpolarized
Hyperpolarization is thought to be due to increased
outward movement of K+ ions or an increased inward
movement of Cl- ions
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Cell Membrane
The four charged ions would be present in equal amountson both sides of the membrane if it did not act as a
barrier to their passage
The membranes act as a barrier in three ways:
An- - Too large to pass through the membrane -
therefore retained in the intracellular fluid
The membrane is semipermeable to Na+, K+, and
Cl- ; each of these has its own channel throughwhich it passes
The membrane contains a pumping system - also
called the sodium-potassium pump, which
exchanges intracellular Na+ for extracellular K+
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Action PotentialThe neurons membrane undergoes a dramatic change if
stimulation is intense enough to cause the transmembrane
voltage to depolarize to about -50 mV
At the voltage of -50 mV the membrane becomes
completely permeable to Na+
Na+ rushes into the cell until the voltage across the
membrane falls to 0 mV
The Na+ channel then closes
At the same time the membrane also becomes permeable
to K+ ions which flow outside the cell to balance the
inward flow of Na+
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The Nerve Impulse
When an action potential occurs, it opens up the voltage-
sensitive Na+ channels
The action potential that occurs at one end of an axon willtravel along the length of that axon - these usually occur
at the cell body and travel away from it
The traveling of this action potential is termed the nerveimpulse
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The Nerve Impulse
The nerve impulse speed increases as the resistance to the
impulse decreases (daaaahhh!!!)
Large axons conduct at a faster rate than the small ones
Glial cells are used to speed impulse propagation
Shwann cells in the peripheral nervous system andoligodendroglia cells in the CNS wrap around some
axons, forming a myelin sheath (myelin in Greek means
marrow)
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The Nerve Impulse
Gaps in the myelin (between glial cells) are calledNodes
of Ranvier
Impulses, therefore, jump along the axon from node to
node called saltatory conduction
Saltatory conduction is an extremely efficient way of
speeding the impulse because a small myelinated axon
can conduct an impulse as rapidly as an unmyelinatedaxon 30 times as large
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Axon
Electrical impulses:
Originate in the dendrite
Integrated in the soma
Transmitted down the axon to the synapse
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Electrical Impulse
Electrical impulses:
From the soma
Down the axon
To a specialized structure that together withthe dendrites from another neuron, form a
complex microstructure called a synapse
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Synapse
Small space between the presynaptic membrane (on
the axon terminal) of one neuron and the postsynaptic
membrane (usually found on the dendrite)
The presynaptic terminal contains numerous structuralelements, the most important of which are small
synaptic vesicles
These vesicles store several thousands of molecules ofneurotransmitter chemicals
These vesicles, therefore, store the transmitter which
is available for release
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Synapse
Exocytosis- The process of exocytosis is wheremolecules of neurotransmitter are released into the
synaptic cleft
The transmitter substance diffuses across the synaptic
cleft and attaches to receptors on the dendrite of the
next neuron
The process of transmitting information across the
synaptic cleft, from one neuron to another, is one of achemical nature
Because neurons do not touch each other, synaptic
transmission is a chemical rather than an electr ical
process
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The Neuron
Usually only one axon arises from the soma
The projections from the soma give rise to many side
branches
These side branches send impulses to hundreds or
thousands of other neurons
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The Neuron
Remember that the dendrite partly consists of the post-
synaptic terminal membrane
These side branches send impulses to hundreds orthousands of other neurons - this is known as
divergence of information
The dendrites branch profusely and receive severalthousand contacts from other cells - this results in
what is called convergence of information
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The Neuron
The dendrites then process the information and
passively transmit electrical activity to the soma
The soma actively transmit the impulses down theaxon to as many as 10,000 other neurons
Thus, thousands of neurons converge on a single
neuron, which, in turn, spreads its own impulses tothousands of other neurons
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The Neuron
Neurons tend to group together and form circuits
The areas in the brain where cell bodies congregate
are called nuclei
Bundles of axons that project from one group of
neurons to another are calledfiber tracts
In the peripheral nervous system, these fiber tracts are
called nerves
The sciatic nerve is actually a bundle of axons, the
somas of which are located in the spinal cord (motor
neurons), the dorsal root ganglia (sensory neurons), orautonomic an lia
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The Neuron
In the brain, nuclei tend to congregate to form yet
larger structures
Thalamus
Hypothalamus
Amygdala
Hyppocampus
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Review: The neuron consists of three basic elements
Dendrites
Soma
Axon
Electrical impulses (review):
Originate in the dendrites
Are integrated in the soma
Are transmitted down the axon to the synapse
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The Axon
The axon is specialized solely for the reliableconduction of electrical activity
All action potentials are conducted down a given axon
rapidly and without alteration
The only way to change content of informationrelayed by an axon is to alter the number of action
potentials that are conducted each second
The axon is not a site of action for psychoactive drugs The axon is the site of action for local anesthetics
The local anesthetic blocks the propagation of
impulses down the axon - synaptic processes are not
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The Dendrite
The distal terminals of the axon align themselves atthe synapse with one or more of the dendrites or the
soma of the next neuron
Dendrites contain receptors that are sensitive to
transmitter released from other neurons
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The Dendrite Order of steps in the transmission of a nerve impulse
(this is general - specific will come later)
An impulse is conducted down an axon of a neuron
A chemical transmitter is released into the synapse
The receptors on the dendrite of the postsynaptic
neuron exhibit an electrical charge
The magnitude of the electrical charge that
crosses the synapse is proportional to the
amount of the chemical transmitter that is
released(implications for drug therapy)
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The Soma
The dendrites and soma receive input from other
neurons through synapses
These dendrites and soma respond by becoming either
depolarized or hyperpolarized
The effect of the depolarization or hyperpolarization is
reflected in the excitability of the soma
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The Soma
If the influence of the excitatory synapses is greaterthan the influence of the inhibitory synapses, the soma
responds by producing an action potential that is
propagated through its axon and conducted to the next
synapse
If the influence of the inhibitory synapses is greater
than the influence of the excitatory synapses, the soma
hyperpolarizes and the neuron becomes less excitable
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Steps in Synaptic Transmission
There are about a dozensteps in the synaptic
transmission process - each
one constitutes a possible
site of drug action
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Acetylcholine Acetylcholine is a neurotransmitter found in large
amounts in the brain
H3C C S CoA
O Acetyl-CoA
+ H3C N+ CH2 CH2 OH
CH3
CH3
CholineCholine
Acetylase
H3C N+ CH2 CH2 O
CH3
CH3 Acetylcholine
C CH3
O
+ HS CoA
Coenzyme A
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Acetylcholine
After acetylcholine is synthesized, it is stored in thenerve terminal within synaptic vesicles
It is released into the synaptic cleft when an action
potential arrives from the axon
AcH then diffuses across the cleft and attaches itself to
postsynaptic receptors
Note: Scopolamine is a psychedelic drug that blockspostsynaptic receptors for AcH - this causes impulses
to continue across the cleft and the effects of a
psychedelic drug
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Acetylcholine
There are two types of AcH receptors on thepostsynaptic dendritic membrane
A nicotinic receptor (a ligand-gated ion channel)
A muscarinic receptor (is part of a seven helix
family)
At the postsynaptic receptor (on the dendrite) the
action of AcH is terminated when the enzyme
acetylcholine esterase (AChE) destroys it
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Acetylcholine
The enzyme reaction that destroys AcH is important as
there are many drugs that inhibit this enzyme called
AChE inhibitors
This results in continuing passing of impulses acrosssynapses
These drugs, AChE inhibitors, are used in agriculture
as insecticides
Also used in the military as lethal nerve gasses
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Acetylcholine
AcH postsynaptic dendritic receptors are largely
absent in patients with Alzheimer's disease - therefore
the tremor which is the results of persisting impulses
across neural clefts that are not opposed byAcetylcholine Esterase
These drugs, AChE inhibitors, are used in agriculture
as insecticides
Also used in the military as lethal nerve gasses
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Acetylcholine
Acetylcholine secreting neurons are located in the
hyppocampus and cerebral cortex and may participate
in:
Learning
Memory function
Retrieval of memory
Mood
Behavioral arousal
Attention
Energy conservation
REM activity
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Norepinephrine and Dopamine
The term catecholamine refers to three chemically
related compounds
Epinephrine
Norepinephrine
Dopamine
Epinephrine (adrenaline) is found mainly in the
peripheralnervous system and works to maintain
blood pressure and heart rate - not commonly found in
the brain
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Norepinephrine and Dopamine
Norepinephrine and dopamine are the primary
catecholamine neurotransmitters in the brain
Many drugs that profoundly affect brain function and
behavior exert their effects by altering the synaptic
action of norepinephrine and dopamine in the brain
Drugs that alter behavior probably produce their
effects because they alter the chemical transmission
between neurons
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Norepinephrine and Dopamine
Note: Patients with Parkinsons disease exhibit a level
of dopamine in the caudate nucleus that is lower than
the amount normally present
Administration of dopamine does not work asdopamine does not cross the blood-brain barrier
The administration of Dopa, the precursor to
dopamine, does cross the blood brain barrier, where itis converted to dopamine
Therefore, the chemical synthesis of a transmitter may
be used for clinical benefit
i h d l
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HO CH2 CH NH2
COOH
Tyrosine Tyrosine hydrolase
HO CH2 CH NH2
HO Dopa dopa decarboxylase
COOH
HO CH2 CH NH2
HODopamine dopamine b-hydroxylase
HO CH2 CH NH2
HONorepinephrine
COO
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Norepinephrine and Dopamine
Metabolic fate of norepinephrine and dopamine
A transmitter is synthesized (produced), stored (in
vesicles), exerts its postsynaptic effect, and then
inactivated
Inactivation occurs by either of two processes
Enzymatic destruction of the transmitter within the
synaptic cleft
Active reuptake of the transmitter from the synaptic
cleft back into the presynaptic nerve terminal
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Norepinephrine and Dopamine
Catecholamines are inactivated by two enzymesMonoamine oxidase (MAO)
Catechol O-methyltransferase (COMT)
Monoamine oxidase (MAO)
Catechol O-methyltransferase (COMT)
This inactivation process by these two enzymes is
slow and does not account for rapid termination of
either norepinephrine or dopamine
The postsynaptic effects of these two transmitters are
terminated primarily by an active process (thatrequires energy) of reuptake across the presynaptic
nerve membrane back into the nerve endings
This way, these two transmitters are stored again in the
synaptic vesicles and reused later
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Norepinephrine and Dopamine
The principle of reuptake into the nerve terminal andthen into the storage vesicles is critically important
because certain drugs may block:
The active uptake process into the nerve terminal(thus prolonging the synaptic action of the
transmitter)
The uptake of the transmitter from the intracellularfluid in the nerve terminal back into the synaptic
vesicles (this decreasing the amount of the stored
transmitter available for release)
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Norepinephrine and Dopamine
Cocaine - blocks presynaptic reuptake of dopaminefrom the synaptic cleft into the nerve terminal
resulting in prolonged synaptic action or stimulation
(therefore not allowing the dopamine to re-enter the
intracellular fluid then go back into the vesicle)
Tricyclic antidepressants are drugs that block
presynaptic reuptake into the nerve terminals of
norepinephrine Reserpine blocks the uptake of the transmitter back
into the vesicle (resulting in depression, mood swings,
etc)
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Norepinephrine and Dopamine
The dynamics of dopamine and norepinephrine
resemble those of other CNS transmitters - those
previously described
The Norepinephrine synapse is very similar to the
acetylcholine terminal
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Norepinephrine and Dopamine
The presynaptic terminal contains mitochondria andsmall vesicles that contain stored transmitter
The vesicles contain chemicals that are different from
the acetylcholine terminal
They contain the amino acid tyrosine (from food)
Tyrosine is taken up into the presynaptic terminal,
where it is transformed into dopa, dopamine, and then
norepinephrine In the terminals where the enzyme beta-hydroxylase is
not present, dopamine isnt converted into
norepinephrine, and dopamine serves as the
transmitter
Tyrosine Tyrosine hydrolase
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HO CH2 CH NH2
COOH
Tyrosine Tyrosine hydrolase
HO CH2 CH NH2
HO Dopa dopa decarboxylase
COOH
HO CH2 CH NH2
HODopamine
dopamine b-hydroxylase
HO CH2 CH NH2
HONorepinephrine
COOH
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Norepinephrine and Dopamine After synthesis (after the transmitter is produced or
manufactured) it is stored in the presynaptic vesicles
An action potential arrives
There is a brief influx of calcium
The transmitter is released by exocytosis from the
vesicles
The transmitter enters the synaptic cleft
Transmitter diffuses across the cleft and attaches to the
postsynaptic receptors
Process terminates with reuptake of the transmitter
into the nerve (presynaptic) terminal
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Norepinephrine Pathways
The cell bodies of the norepinephrine neurons arelocated in the brain stem
From the brain stem the axons project into the nerve
terminals of:
The cerebral cortex
The limbic system
The hypothalamus
And the cerebellum
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Norepinephrine Pathways
The release of norepinephrine produces:Mood altering
Focusing
Orienting (fight/flight/fright response)
Positive feeling of reward
Analgesia
Hunger
Thirst Emotion
Sex
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Messengers
Remember this:
F irst Messenger- this is the neurotransmitter
Second Messenger- this is the post-syanpticmembrane substance
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Dopamine Pathways
Large amounts of dopamine are found in the basalganglia, frontal cortex, and limbic system
The originating cell bodies of these nerve terminals
are found in the substantia nigra
Examples of dopamine function involve schizophrenia
and parkinsonism
Schizophrenics show increase dopamine synthesis in
the frontal cortex - therefore this disease is treated
with dopamine blocking agents
Parkinson's - no dopamine receptors (receptor
agonists) found in the substantia nigra
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Dopamine Pathways
Phenothiazine drugs, as an expression of toxicity, and
show Parkinson-like signs; due to blockade of
dopamine receptors in the frontal cortex
Parkinsonism is treated with drugs that stimulate the
production of dopamine
The behavioral stimulant and reinforcing properties ofcocaine and amphetamine reflect activation of
dopamine receptors
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Serotonin
Is a neurotransmitter
Is an inhibitor of activity and behavior
Functions in
Sleep
Wakefulness
Mood Temperature regulation
Feeding
Sexual activity
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Amino Acids
In order to understand how the CNS depressants work,it is necessary to understand how the transmission of
impulses across nerve ending occur
Four amino acids function as neuronal transmitters
Glutamic acid
Aspartic acidExcite neuronal transmission
GABA
Glycine
Inhibit neuronal
transmission
**GABA = gamma-aminobutyric acid
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Amino Acids
GABA is the majorinhibitorof neurotransmission in
the brain
When GABA receptors are stimulated by the presenceof GABA, they typically inhibit the post-synaptic
neuron from firing
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Amino Acids
Many classes of drugs can bind to various sites on the
GABA receptor, enhancing GABA-mediated
inhibition
Benzodiazepines
Barbiturates
Anesthetics
Steroids
Alcohol
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Amino Acids
Probably all neurons of the CNS have GABAreceptors embedded in their cell bodies, dendrites, and
axon endings
Many classes of drugs can bind to various sites on the
GABA receptor, enhancing GABA-mediated
inhibition
Benzodiazepines
BarbituratesAnesthetics
Steroids
Alcohol
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Amino Acids
Virtually every neuron in the CNS is responsive toGABA
When GABA receptors are activated, chloride
permeability increases, thus hyperpolarizing the
affected membrane
When the receptor becomes hyperpolarized resulting
an increase in Cl- permeability, this is termed a
GABAA receptor
A second type of GABA receptor is one whose
activation opens channels to K+ or Ca+ = GABAB
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Amino Acids
GABAA receptors are ligand-gated ion channels withmultiple binding sites
GABAB receptors are G-protein-coupled receptors
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GABA GABA comes from (is synthesized by) the amino
acid glutamate via the enzyme glutamic acid
decarboxylase
C OH
O
CH2
CH2
C
O
OH
H C NH2
glutamic aciddecarboxylase
H
CH2
CH2
C
O
OH
H C NH2
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GABA
After GABA is synthesized (remember GABA is a
neurosynaptic transmitter) it is stored for release
After GABA is released it acts on both the presynapticand postsynaptic GABAA and GABAB receptors
The action of GABA is terminated by reuptake from
the synaptic cleft
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GABA
REMEMBER and DONT FORGET- GABA is the
majorinhibitorof neurotransmission in the brain
Drugs that facilitate GABAergic (promoters)
neurotransmission produce results that demonstrate
the inhibitory effect of this neurotransmitter
Sedation
Reduced vigilance
Sleep
Reduced emotional reactivity
Amnesia
Muscle relaxation
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Opioid Receptors
In the 1960s it was proposed that chemicals exist in
the brain that provide analgesia (relief of pain) by
acting on specific receptors and that opioid narcotics
might mimic these natural analgesic substances bybinding the same receptors
In 1973 opioid receptors were identified in the CNS
In 1976 four types of opioid receptors were identifiedMu Kappa
Delta Sigma
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Opioid Receptors
The question was whether there were substances in the
brain that acted like opioids
Crude extracts were taken from the brain thatdemonstrated an ability to stop intestinal peristalsis (a
morphine like action)- which, get this, could be
blocked by naloxone (a drug used to stop opiate
action)
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Opioid Receptors
Two proteins were isolated from these extracts called:Met-enkephalin Leu-enkephalin
Later, a protein was identified in the pituitary gland
Beta-lipotran
This pituitary protein contained met-enkephalin