Anatomy and Physiology of the Neuron(1)

7/28/2019 Anatomy and Physiology of the Neuron(1)

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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 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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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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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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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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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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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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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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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



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HO CH2 CH NH2

COOH


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

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Anatomy and Physiology of the Neuron(1)