Download 9/7/2012 1 Receptors and Neurotransmitters: It Sounds Greek to Me

9/7/2012
Receptors and
Neurotransmitters: It Sounds
Greek to Me
Cathy Carlson, PhD, RN
Northern Illinois University
Agenda
• We will be going through this lecture
on basic pain physiology using
analogies, mnemonics, cartoons,
rhymes, songs, games, and
visualizations to:
– learn and
– learn to teach pain physiology
What We Know About Pain
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Anatomy of a Neuron
Structural Classes of Neurons
Unipolar Sensory Neurons and
Ganglia
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Pain & Sensory Receptors
Primary Afferent Sensory Nerve
Fibers
• A-alpha (Aα)
– Carry information related
to proprioception (muscle
sense)
• A-beta (A-β)
– Carry information related
to touch
• A-delta(A-δ)
– Carry information related
to pain and temperature
• C-nerve fibers
– Carry information related
to pain, temperature, and
itch
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Neural Steps in the
Processing of Pain Signals
1. Transduction - noxious stimuli are converted
to electrical signals in sensory nerve endings.
2. Transmission - neural events which relay the
information from the periphery to the cortex.
3. Modulation - the nervous system can
selectively inhibit the transmission of pain
signals.
4. Perception - subjective interpretation by the
cortex of the noxious stimulus.
a. Sensory component (intensity, location)
b. Affective component (psychological)
Transduction
Transduction
• Begins in periphery
• All cellular damage caused by thermal,
mechanical, or chemical stimuli result in
the release of pain producing excitatory
mediators
• Mediators surround the pain fibers in the
extracellular fluid, spreading the pain
message through excitation
(depolarization) of the free nerve endings
(nociceptors) of the pain fibers
– Also causes the inflammatory response
• This is called nociception
• “Nocire” means to suffer
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Peripheral Excitatory Mediators
Substance
Receptor
Mechanism
Substance P
(SP)
NK1
 neuronal excitability,
edema
Prostaglandin
(PG)
?
Sensitize nociceptors,
inflammation, edema
Bradykinin
Sensitize nociceptors
B2 (normal)
B1 (inflammation)  PG production
Histamine
H1
C-fiber activation, edema,
vasodilation
Serotonin
5-HT3
C-fiber activation, release
SP
Norepinephrine
(NE)
1
Sensitize nociceptors
Activate nociceptors
Threshold
Threshold
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Depolarization
• Sodium/potassium
pump polarizes
neuron
– At resting state:
• K+ intracellular
• Na++ Extracellular
• More negative
intracellular
• Stimulus begins wave
of depolarization as
Na++ ion channels
open and Na++ rushes
in
• Wave of
repolarization follows
close behind
Opening of the Ion Channels
• Touch-pressure:
– Mechanical tension opens ion channels
• Rapidly adapting mechanoreceptors: vibration, touch, mov
ement
• Slowly adapting mechanoreceptors: pressure
• Sense of posture and movement:
– Muscle stretch opens ion channels
• Muscle spindle stretch receptor:
– Responsible for the senses of posture and kinesthesia (sense
of movement at a joint)
– Sense organs of balance: vision, vestibular organs, muscle
spindles
• Temperature: Heat and cold
– Changes in temperature opens ion channels
• Pain:
– Tissue damage release chemical mediators
that open ion channels
Transmission
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Transmission
• The transmission process occurs
in three stages
• The pain impulse is transmitted:
1. From the site of transduction
along the peripheral afferent
neuron (first order neuron) to the
dorsal horn in the spinal cord
2. From the spinal cord to the brain
stem (second order neuron)
3. Through connections between
the thalamus, cortex and higher
levels of the brain (third order
neuron)
Transmission
Characteristics and Functions
of C fibers and A-δ Fibers
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A δ and C Fiber Pain
C‐fiber
First
pain
A fiber
Second
pain
Pain
intensity
Time
Transmission
• C fibers and A-δ fibers terminate in the dorsal horn
of the spinal cord
• A synapse exists
• A synapse contains three elements:
1.
Presynaptic neuron
a.
2.
3.
Presynaptic terminal
Synaptic cleft
Postsynaptic neuron
a.
Receptive membrane
• For the action potential to be transmitted
across the synaptic cleft to the postsynaptic
neuron, excitatory neurotransmitters are
released, which bind to specific receptors
on the postsynaptic neuron
Release and Reuptake of
Neurotransmitters
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Major Excitatory Neurotransmitters of
Pain in Spinal Cord
Synapse in the Dorsal Horn of
Spinal Cord
Central Nervous System
Ascending Pathways
• Spinothalamic Tract
– Two subdivisions:
• Neospinothalamic
tract (lateral
spinothalamic tract)
– Acute pain
• Paleospinothalamic
Tract (anterior
spinothalamic tract)
– Dull/burning pain
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Second Order Neurons in Spinal
Cord
• Types
– Wide Dynamic range
• Receive impulses from A-beta, A-delta, & C
– Nociceptive specific
• Receive impulses from A-delta & C
– Interneurons
• May be inhibitory
or excitatory
Second Order Cells in the Spinal Dorsal Horn
A
A
C
Polymodal
A
C
Polymodal
Wide Dynamic Range (WDR)
+
Dorsal Horn
Lamina V
-
Dorsal Horn
Lamina I, V
Wide Dynamic Range Neuron
To Brain
Nociceptive Specific Neuron
To Brain
Nociception Pathways
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Perception
Perception
• Point at which person is aware of pain
• Fast pain stimuli are transmitted up
spinal cord to via the neospinothalamic
tract with some fibers to the thalamus
and the majority of fibers to the
somatosensory cortex
– Identifies location
& intensity of pain
Perception
• Slow pain stimuli are transmitted up
spinal cord to via the
palespinothalamic tract to the
midbrain and thalamus limbic system
• Limbic system-controls emotion,
anxiety, & emotional reaction to pain
• Responses to pain can be
physiological
and behavioral
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Modulation
Modulation of Pain
• Involves changing or inhibiting
transmission of pain impulses in the
spinal cord.
• Multiple, complex pathways involved in
the modulation of pain
• Increases the transmission of pain
impulses (excitatory) or decreases
transmission (inhibition)
Modulation of Pain at the Spinal
Cord Level
• Gate Control Theory of Pain
– Pain impulses can be regulated or even
blocked by “gating” mechanism along CNS
– Theory suggests that pain impulses pass
when gate is open and blocked when gate
is closed
– Closing the gate is basis for pain relief
interventions
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Gate Control Theory of Pain, Cont.
• Involves the addition of mechanoreceptors
(A-β neurons), which releases inhibiting
neurotransmitter (Serotonin)
• If dominant input is from A-β fibers, gating
mechanism will close, pain reduced, due to
release of Serotonin
• If dominant input from A-δ fiber, gate will be
open and pain perceived
• Release of endorphins also close gate
Descending Modulatory Pain
Pathways (DMPP)
• Transmit impulses from the
brain (corticospinal tract in
the cortex) to the spinal cord
(lamina)
– Periaquaductal Gray Area
(PGA) – releases enkephalins
– Nucleus Raphe Magnus (NRM)
– releases serotonin
– The release of these
neurotransmitters inhibit
ascending neurons
• Stimulation of the PGA in the
midbrain & NRM in the pons
& medulla causes analgesia.
Descending Modulatory Pain
Pathways (DMPP)
• Afferent stimulation of
periaqueductal gray
(PAG) area stimulates
efferent neurons
– Periaquaductal Gray Area
(PGA) – releases enkephalins
and secretes serotonin
– Rostral pons secretes
norepinephrine
– Nucleus Raphe Magnus (NRM)
– releases serotonin
• Efferent neurons
synapse in medulla
• Impulse travels to
dorsal horn to block
afferent sensory fibers
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Inhibitory Neurotransmitters of Pain
• Inhibitory neurotransmitters involved with the
modulation of pain include:
1. Endogenous opioids
• Endorphins, enkephalins, dynorphins, and
endormorphins
2. Gamma-aminobutyric acid (GABA)
• Widespread in brain and spinal cord
Amygdala
• Inhibitory GABA receptors on WDR
neurons inhibit excitatory neurotransmitter release
3. Neurotensin
• Highest levels in hypothalamus, amygdala, and
nucleus accumbens
• Causes analgesia and is also involved in regulation of
dopamine pathways
4. Acetylcholine
• Increased release of spinal acetylcholine is
associated with an elevated pain threshold
Inhibitory Neurotransmitters of
Pain
5. Oxytocin
• Released by receptors in the PGA
• Believed to play an antinociceptive role
• Binds to μ and κ opioid receptors
6. Norepinephrine
PGA
• Different effects in different parts of body
• In descending pathways causes inhibition of transmitter release
from peripheral afferent neuron
Cingulate Cortex
7. Serotonin (5-HT)
• Inhibits pain in pons and medulla
• Transmitter in descending inhibitory pathways
• Inhibits substance P transmission in
dorsal horn (mechanism uncertain)
8. Dopamine
• Inhibits processing of pain in multiple levels of the central nervous
system including the spinal cord, periaqueductal gray (PAG),
thalamus, basal ganglia, insular cortex, and cingulate cortex
Endogenous Opioids
•
•
Endorphin receptors are found in periphery, ascending, and descending
pathways
4 Types
1.
Endorphins
•
•
•
2.
Enkephalins
•
•
•
3.
•
Bind with the κ receptor
Located in the hypothalamus, the brainstem, PAG, rostral ventromedial medulla (PAG-RVM)
system, and the spine
Most powerful
Endomorphins
•
•
•
•
•
Located in neurons of brain, spinal cord
Bind with the δ receptor
Found concentrated in the hypothalamus, the PAG matter, the nucleus raphe magnus of the
medulla, and the dorsal horns of the spine
Dynorphins
•
•
4.
Located in hypothalamus and pituitary
Bind to both μ and δ receptors with comparable affinity
Produce a sense of exhilaration, or “high”
Located in the brain and the spinal cord and PNS
Show the highest affinity and selectivity for the μ receptor
Thought to assist in adaptation to pain and stress and enhancement of reward perceptions
Release of endorphins can raise an individual’s pain threshold
Release is increased by
–
Stress, excessive physical exertion, acupuncture, intercourse, and other factors
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Opioid Receptors
• Important opioid
receptors:
– mu (), kappa (),
delta ()
– Activation of opioid
receptors by
endogenous opioids
inhibits the release
of excitatory
neurotransmitters
such as substance P
in the brain, spinal
cord, and peripheral
nervous system
Opioid Receptors
Questions?
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