Lecture 18: Pain (peripheral nervous system pain) Flashcards
What is conduction velocity in an axon enhanced by?
Myelination
What does myelination do?
Enhances conduction velocity in an axon
What are axons in the CNS mylinated by?
Oligodendrocytes
What do oligodendrocytes mylinate?
Axons in the CNS
What myelinates axons in the PNS?
Schwann cells
What do Schwann cells do?
Myelinate axons in the PNS
What happens during the myelination process?
An axon is ensheathed by a glial cell which extrudes its cytoplasm. The cytoplasm has adhesive properties which hold to the phospholipid bilayers tightly
What is Guillain-Barre Syndrome?
The demyelinating disease in the PNS
What is the demyelinating disease in the PNS?
Guillain-Barre Syndrome
What does the increased lipid content of the myelin sheath do?
Provides insulation for the underlying axon
What is myelin important for?
Allowing saltatory conduction of action potentials. Ensures conduction is not lost across the membrane
Which types of axons are always myelinated?
Motor axons
What would happen without myelin?
The sodium would dissipate laterally
How are unmyelinated axons in the PNS affected by myelin?
Unmyelinated axons in the PNS are encased by Schwann cell cell cytoplasm but no wrapped coating of myelin
What are Remak Bundles?
Unmyelinated axons in the PNS that are encased by Schwann cell cytoplasm but don’t have the wrapped coating of myelin
What is the ratio for Schwann cell myelination and axons?
One Schwann cell can ensheath multiple axons, but myelinates only one axon segment
How are small diameter nerve fibers affected by myelin?
Small diameter nerve fibres are non-myelinated
What are the three types of connective tissue layers found in nerves?
Endoneurium
Perineurium
Epineurium
What does endoneurium do?
Surrounds axons
What does perineurium do?
Surrounds axon fascicles
What does epineurium do?
Surrounds the entire nerve
What surrounds axons?
Endoneurium
What surrounds axon fascicles?
Perineurium
What surrounds an entire nerve?
Epineurium
Why do peripheral nerves have elastin?
Because they need to be able to stretch and move the same way the body does
Which neuron layer sits around the myelin sheath?
The endoneurium
What are the two types of ganglia?
Spinal Ganglia and Autonomic Ganglia
What are the two types of spinal ganglia?
Dorsal root and cranial ganglia
What are the dorsal root ganglia associated with?
Spinal nerves
What are the cranial ganglia associated with?
Cranial nerves
Does a synapse happen in ganglia?
No
What do spinal ganglia contain?
Large sensory neurons and abundant small glial cells called satellite cells
What are Satellite cells?
Cell bodies around sensory nerves
What kind of neurons are sensory neurons?
Pseudounipolar
What are autonomic ganglia?
The cell bodies of second-order neurons out in the peripheral nervous system
What are autonomic ganglia associated with?
Sympathetic and parasympathetic nervous systems
Does a synapse occur in autonomic ganglia?
Yes
Which ganglia does a synapse occur and what ganglia does a synapse not occur?
Spinal ganglia - no synapse
Autonomic ganglia - synapse
What kind of neurons are in autonomic ganglia?
Multipolar neurons
What is the difference in the type of neurons in the two ganglia?
Spinal ganglia - Pseudounipolar
Autonomic ganglia - Multipolar
What are sympathetic ganglion cells?
Multipolar neurons that reside entirely within the PNS in sympathetic ganglia and preaortic ganglia
Where do sympathetic ganglion cells reside?
In the PNS in the sympathetic chain ganglia
What are sensory receptors classified based on?
Source of stimulus
What are the three types of sensory receptors?
- Exteroreceptors
- Interoceptors/Visceroreceptors
- Proprioceptors
What do Exteroreceptors respond to?
External stimuli (touch, temperature, pressure, sight, smell, taste, hearing)
What do Interoceptors/Visceroreceptors response to?
Stimuli within the body (respiration, cardiovascular, digestion, reproductive, urinary)
What do Proprioceptors respond to?
Interoceptors of muscle stretch and movement (tendons, ligament, joints, skeletal muscles, connective tissue covering the bones and muscles)
What are the four types of nerve fibers?
- Aα
- Aβ
- Aδ
- C
What are the largest diameter axons?
Aα
How is diameter correlated with myelination?
The larger the diameter, the more myelination the faster the axon
What do Aα fibers sense?
Proprioception
Which nerve fibers sense propriception?
Aα fibers
What are the fastest neurons in the body?
Aα neurons that sense proprioception
What are the most heavily myelinated axons?
Aα neurons
What do Aβ fibers sense?
Mechanoreceptors of skin (texture, touch, temperature)
Which fibers are mechanoreceptors of skin (touch receptors)?
Aβ fibers
What are the two pain-sensing afferents in the body?
Aδ and C fibers
What do Aδ and C fibers sense?
Pain
Which pain fibers are myelinated?
Aδ fibers
Which pain fibers are unmyelinated?
C
What kind of pain does Aδ fibers sense?
Sharp immediate pain
What kind of pain do C fibers sense?
Dull achy pain
Which fibers carry pain fastet?
Aδ fibers
Which pain fibers sense sharp pain?
Aδ pain
Which pain fibers sense dull pain?
C fibers
Which laminae of the spinal cord do Aδ fibers go to?
I or V
Which laminae of the spinal cord do C fibers go to?
II - substantia gelatinosa
Which pain fibers go to I or V?
Aδ fibers
Which pain fibers go to II?
C
Where in the periphery are Aβ, Aδ and C nerve fibers?
In the skin
What provides sensory information to muscles and tendons?
Aα
What other nerve fibers do motor nerves contain?
A𝛼 𝑎𝑛𝑑 𝐴𝛾
Why is it important for touch and proprioception fibers to be faster than pain?
Because we require touch information move ourselves from pain
What are the two main layers of the skin?
The epidermis and dermis
What is the basal layer of skin?
The stem cell layer
What do stem cell layers of skin make?
Keratinocytes
What happens as new keratinocyte is made?
They are pushed up away from their blood supply and release their nucleus, produce keratin and die
What is the purpose of keratin?
Keeps us from dehydrating and is a huge immune organ
What free nerve endings are in the skin?
C and Aδ fibers
What nerve fibers have free nerve endings?
C and Aδ fibers
What are the most superficial nerve endings?
Pain fibers
What are free nerve endings?
Nerve endings with nothing special at their termini, once there is a chemical release, they will initiate an action potential. (whereas mechanoreceptors require a certain stimulus)
Where do Merkel’s disks sit?
At the stem cell layer of the skin
What are Merkel’s disks?
Aβ receptors
What do Meissner’s corpuscles sense?
Mechanoreception
What are the mechanoreceptors in the skin?
- Merkel’s disks
- Meissner’s corpuscles
- Pacinian corpuscles
- Ruffini endings
What are arrector pili innervated by?
The autonomic nervous system
What are receptors in the skin classified based on?
Modality
What are nociceptors classified base on?
Conduction velocity and noxious stimuli
What are the five classes of receptors?
- Nociceptor
- Chemoreceptors
- Photoreceptors
- Thermoreceptors
- Mechanoreceptors
What are mechanoreceptors classified based on?
Location and physical properties and rate of adaptation
What are nociceptors involved in?
Perception of pain
Which pain fibres are responsible for extremely sharp pain?
Aδ
Which pain fibers are responsible for prolonged slightly intense and diffused pain?
C-fibers
What are Aδ responsible for?
First phasic (initial) extremely sharp pain
What are C-fibers responsible for?
second phasic, prolonged slightly intense and diffused pain as result of acute damage to the skin
What are the different types of noxious stimuli?
Thermal
Mechanical
Chemical
Polymodal
What do thermal noxious receptors respond to?
Respond to noxious heat and cold (>45°C or <5°C)
What do mechanical noxious receptors respond to?
Excessive pressure
What do chemical noxious receptors respond to?
respond to chemical substances (inflammatory mediators) from the surrounding damages tissue (histamine)
What do Polymodal noxious receptors respond to?
High-intensity and prolonged stimuli such as thermal, mechanical and chemical stimuli
When are silent or sleeping nociceptors activated?
Only at extreme intensity of mechanical stimulation or inflammation in the surrounding tissue
What do Chemoreceptors detect?
Chemical stimuli
What are examples of chemoreceptors?
- Stimuli in the olfactory system
- Stimuli in taste buds and aortic bodies (for sensing oxygen)
What do photoreceptors respond to?
Light for vision
What are Cones and Rods and ganglion cells receptive to?
Cones (color: red/yellow, green, blue)
Rods (sensitive to light intensity)
Ganglion cells (sympathetic response in adrenal medulla and retina)
What do thermoreceptors respond to?
Innocuous temperature stimuli
Which fibers do thermoreceptors work vis?
Group A and C fibers
What to things are mechanoreceptors comprised of?
Exteroreceptors and proprioceptors
What do mechanoreceptors receptors respond to?
Respond to touch, pressure, stretch, muscles, tendons, ligaments and joint capsules
What do Merkel’s discs sense?
Touch
Where are Merkel’s discs located?
Between dermis and epidermis
What do Meissner Corpuscles sense?
Light touch
Where are meissner’s corpuscles in the skin?
In the dermis near the epidermis
What do Pacinian corpuscles sense?
Pressure
Where are Pacinian corpuscles located?
In the subcutaneous fat of the dermis
What do Ruffini’s endings sense?
Pressure and temperature
What in the skin senses touch?
Merkel’s discs
What in the skin sense light touch?
Meissners corpuscles
What in the skin senses pressure?
Pacinian corpuscles
What in the skin senses pressure and temperature?
Ruffini’s endings
Which mechanoreceptors have a large receptive field?
Those that detect pressure
What are the three rates of adaptation of mechanoreceptos?
Slow Adapting (SA)
Moderate Adapting (MA)
Rapidly Adapting (RA)
What is a receptive field?
An area which when stimulated elicits a neuronal response
What are the slow adapting mechanoreceptors?
Merkel’s discs and Ruffini’s endings
What are the characteristics of slow adapting mechanoreceptors?
They are on and fire as long as a stimulus is present
What fibers are moderate adapting?
Free nerve endings and D-hari (HFA)
What is an example of something moderate adapting fibers may sense?
Insects on the skin
What are examples of rapidly adapting fibers?
Meissner’s corpuscles and Pacinian corpuscles
What are the characteristics of rapidly adapting fibers?
They respond to stimulation with a burst of firing in the beginning and end of stimulation
What do Merkel receptors best respond to?
Steady pressure from small objects
What do Meissner corpuscles best respond to?
Rubbing against the skin or skin movement across a surface
What do Ruffini’s cylinders best respond to?
Steady pressure and stretching of the skin (e.g. joint movement)
What do Pacinian corpuscle best respond to?
Changing stimulation
What is Pain?
An unpleasant sensory and emotional experience associated with actual or potential damaged
What best responds to steady pressure from small objects?
Merkel receptors
What best responds to rubbing against the skin or skin or movement across a surface?
Meissner’s corpuscles
What best responds to steady pressure and stretching of the skin (e.g. joint movement)?
Ruffini cylinders
What best responds to changing stimulation?
Pacinian corpuscles
What is nociceptive pain?
Pain arising from tissue damage (activation of nociceptors)
What is inflammatory pain?
Pain arising by inflammation initiated by autoimmune response
What is neuropathic pain?
Pain arising from nerve damage/somatosensory system
What is Nociplastic pain?
Pain arising with no clear evidence of tissue damage
What are examples of nociceptive pain?
Burns, fractures, lacerations
What are examples of inflammatory pain?
Gout, rheumatoid arthritis
What are examples of neuropathic pain?
Diabetic neuropathy, carpal tunnel syndrome, complex regional pain syndrome
What are examples of nociplastic pain?
Fibromyalgia, chronic lower back pain, irritable bowel syndrome
What are the nociceptors?
Predominantly free nerve ending of Aδ and C afferents
What do nociceptors respond to?
Extremes of:
- Temperature stimuli - raising temperature >45º or <0º C
- Mechanical stimuli - excessive pressure/tension
- Chemical stimuli - endogenous (histamine, prostaglandin) or exogenous
What extremes do Aδ respond to?
Mechanosensitive and thermal stimuli
What extremes do C fibers respond to?
Mechanical, thermal, chemical stimuli
Where are nociceptors found?
In all tissues of the body except the brain
What nociceptive fibers are myelinated?
Aδ are mylinated
What happens if one of the pain fibers is blocked?
The first or second pain (depending on which one is blocked) will still be felt
What are the steps in nociception?
- A stimulus activates a transient receptor potential (TRP) channels on C and Aδ fibers
- This causes a 6 membrane pore to open
- This allows an influx of Na and Ca which generates an action potential which propagates to the spinal cord
Through which types of cells do pain action potentials propogate?
Pseudounipolar
What are two types of clinical pain conditions?
- Congenital Insensitivity to Pain (CIP)
- Paroxysmal Extreme Pain Disorder (PEPD)
What is Congenital Insensitivity to Pain (CIP)?
The inability to perceive pain and anhidrosis (inability to sweat)
What is Paroxysmal Extreme Pain Disorder (PEPD)?
Burning pain in rectum, eyes, mandible but can be diffuse pain
What causes the two pain disorders?
Mutation of SCN9A gene → Nav 1.7 channelopathy
What is Nav 1.7?
Voltage-gated sodium channel on nociceptors for action potential propagation
How are the channels affected in CIP?
channel is nonfunctional → no action potential initiation
How are the channels affected in PEPD?
channel opens at a lesser membrane depolarization or stays open too long → increased pain
What is the sensory part of the spinal cord?
The dorsal horn
Which three pathways enter the dorsal horn of the spinal cord?
- Dorsal column medial lemniscal pathway
- Spinothalamic tract
- Spinocerebellar tract
Through what tract do the the sensory pathways enter the dorsal horn?
Lissauer’s tract
What is Lissauer’s tract?
The entrance of the dorsal roots into the spinal cord
What laminae do C fibers enter the spinal cord?
Laminae 1 and 2 (Substantia Gelatinosa)
What laminae do Aδ fibers enter the spinal cord?
Laminae 1 and 5
Which laminae do the pain fibers enter the spinal cord?
- C fiber afferents: laminae 1 and 2 (substantia gelatinosa)
- Aδ fiber afferents: laminae 1 and 5
Where in the spinothalamic pathway is the decussation in synapsing?
- First order neurons synapse in the spinal cord
- The second order neurons decussate and ascend to the VPL of the thalamus and synapse
- The then go to the primary somatosensory cortex
How many neurons are in the pain pathways?
Three neurons
Which nuclei in the thalamus does the pain pathway synapse?
The VPL nucleus
Where does the second order neuron in the spinothalamic pathway send its axons?
To the VPL nucleus of the thalamus and collateral branches
What are the five pain intiators?
- Glutamate
- Calcitonin gene related peptides (CGRP)
- Substance P
- Bradykinin
- Prostaglandin
What is the pain initiatory for Aδ fibers?
Glutamate
What does substance P do in the pain pathway?
It is released by the first-order neuron onto the second-order neuron in the spinothalamic tract
What are the two inflammatory pain initiators?
Bradykinin and prostaglandin
What are the seven pain inhibitors?
- Serotonin
- Somatostatin
- Endorphins
- Enkephalins
- Dynorphins
- GABA
- Glycine
Where in the brain is Serotonin?
In the raphe nucleus
What are the three endogenous opioids?
- Endorphins
- Enkephalins
- Dynorphins
When does the second-order neuron in the pain pathway send collateral branches?
When it reaches the brainstem
What does VPL stand for?
Ventral posterior lateral nucleus
What is the neuron pathway of the dorsal column medial lemniscal pathway?
- first-order neuron goes from receptor, ascends the dorsal column in the spinal cord to the medulla. It synapses at the medulla
- Second order neuron decussates and goes from the medulla to thalamus
- Third order neuron goes from the thalamus to the somatic sensory cortex
What is Brown Séquard Syndrome?
A lesion to half of the spinal cord so an individual can’t feel pain and temperature on one side and can’t feel touch and proprioception on the other side
In Brown Séquard Syndrome what does injury to the left hemicord cause?
- Loss of pain/temperature on right side below lesion
- Loss of touch, vibration, proprioception on left side below lesion
Aside from the somatosensory cortex, where does the spinothalamic pathway project to?
- Amygdala
- Hypothalamus
- Periaqueductal gray
- Reticular formation
- Superior Colliculus
What does the spinothalamic pathway projecting to the Amygdala affect?
Memory and emotion
What does the spinothalamic pathway projecting to the Hypothalamus affect?
Activation of the autonomic nervous system
What does the spinothalamic pathway projecting to the reticular formation affect?
It controls the raphe nuclei which produces serotonin
What does the spinothalamic pathway projecting to the reticular activating system affect?
Alertness during pain
What does the sensory/discriminative portion of the pain pathway do?
Observes the location, intensity, and quality of pain
What are the two pain suppression systems?
- Gate control hypothesis
- Supraspinal pain suppression
What is the form of spinal pain suppression?
Gate control hypothesis
What is the form of supraspinal pain suppession?
Descending serotonergic and opioid inhibitory system
What idea does gate control theory act on?
Pressure stops pain
How does gate control theory work?
- Both A-beta (touch) and C fibers (pain) enter Lissauer’s tract
- A- beta fibers stimulate inhibitory interneurons. C fibers inhibit inhibitory interneurons
- A-beta fibers inhibit pain pathways and C fibers stimulate pain pathways
Which order neurons does gate control theory act on?
The second order neuron
How does Descending control of pain modulation work?
- Spinothalamic tract sends collateral branches to the spinomesencephalic tract
- The spinomesencephalic tract activates the periaqueductal grey
- This turns on descending inputs to the raphe nucleus
- The raphe nucleus sends serotonergic projections that release endogenous opioids onto the first order neuron in the spinothalamic pathway to prevent it from releasing substance P onto the second order neuron
What is the first step in the descending pain modulation pathway?
The spinothalamic tract activates the spinomesencephalic pathway
What happens after the spinomesencephalic pathway is activated in the descending pain modulation pathway?
It sends descending inputs to the raphe nucleus
What happens after the spinomesencephalic nucleus sends descedning input to the raphe nucleus?
The raphe nucleus sends serotonergic fibers down to release endogenous opioid onto the first order neuron in the spinothalamic pathway to prevent it from releasing substance P onto the second order neurons
What do the endogenous opioids released by the serotonergic neurons of the raphe nucleus do?
They act on mu and kappa opioid receptors on C fibers and A delta fibers preventing them from releasing substance P onto the second order neuron to activate it
What order neuron does the descending pain pathway act on?
The first order neuron
What is chronic pain?
Pain that persists past the normal healing time
What is hyperalgesia?
Increased pain sensation from a normally painful stimulus
What is Hyperestheisa?
Increased sensitivity to stimulation
What is Allodynia?
Perception of pain from non-noxious stimulus
What is Dysesthesia?
Unpleasant abnormal sensation
What are the two mechanisms of sensitization in chronic pain?
Peripheral sensitization and central sensitization
What is peripheral sensitization?
The upregulation of existing receptors or making new receptors that activate C and A-delta fibers caused by cytokines. Makes an individual sensitive to stimuli.
How can peripheral sensitization be reduced?
NSAIDs which reduce COX and with Antihistamines
What is central sensitization?
Either a hypersensitivity or a responsiveness to non-noxious stimuli. An enlarged receptive field
What is a neuroma?
When a transected peripheral nerve attempts to regenerate to establish contact with motor or sensory end organs but instead forms a ball that activates itself causing pain
Why does a neuroma forma a balck?
Because it lacks an epineurium which will guide it on where to go
What are the two ways to manage neuromas?
Targeted motor reinnervation (TMR) and Regenerative Peripheral Nerve Interface (RPNI)
What occurs in Target Motor Reinnervation?
Distal ends of mixed nerves or sensory nerves transferred to motor nerve of a nearby muscle target
What occurs in Regenerative Peripheral Nerve Interface (RPNI)
Implant distal end of nerve into a free skeletal muscle graft
