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Receptors and Neurotransmitters: It Sounds

Greek to MeCathy 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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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)

Neural Steps in the Processing of Pain Signals

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 B2 (normal)

B1 (inflammation)

Sensitize nociceptors PG production

Histamine H1 C-fiber activation, edema,vasodilation

Serotonin 5-HT3 C-fiber activation, release SP

Norepinephrine(NE)

1Sensitize nociceptorsActivate 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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Firstpain Second

pain

Time

Painintensity

C‐fiber

A fiber

A δ and C Fiber Pain

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 neurona. Presynaptic terminal

2. Synaptic cleft3. 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

• PaleospinothalamicTract (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

To Brain To Brain

-+

Dorsal HornLamina V

Wide Dynamic Range Neuron

Dorsal HornLamina I, V

Nociceptive Specific Neuron

A ACPolymodal

CPolymodalA

Second Order Cells in the Spinal Dorsal Horn

Wide Dynamic Range (WDR)

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 neospinothalamictract 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 enkephalinsand 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

endormorphins2. Gamma-aminobutyric acid (GABA)

• Widespread in brain and spinal cord• Inhibitory GABA receptors on WDR

neurons inhibit excitatory neurotransmitter release3. 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

Amygdala

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• Different effects in different parts of body• In descending pathways causes inhibition of transmitter release

from peripheral afferent neuron7. 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

PGA

Cingulate Cortex

Endogenous Opioids• Endorphin receptors are found in periphery, ascending, and descending

pathways

• 4 Types1. Endorphins

• Located in hypothalamus and pituitary• Bind to both μ and δ receptors with comparable affinity• Produce a sense of exhilaration, or “high”

2. Enkephalins• 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

3. Dynorphins• Bind with the κ receptor• Located in the hypothalamus, the brainstem, PAG, rostral ventromedial medulla (PAG-RVM)

system, and the spine• Most powerful

4. Endomorphins• 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?