Module 26 - Neurophysiology of PAIN

Question 1

What are the two types of pain?

Answer 1

• Acute pain
• Chronic

Question 2

What is acute pain and its function?

Answer 2

• Clearly defined stimulus
• Stimulus determines the intensity & duration of pain
• Localized receptors (afferents) are affected
• Function:
  
  • Detect tissue damage or impending damage; initiate avoidance reaction

Question 3

What is chronic pain?

Answer 3

• Persistence of pain, often in absence of obvious stimulus
  
  • Can be in absence of any physiological disruption
• Cause & mechanisms are largely unknown
  
  • Difficult to treat
• Often involves changes in pain pathways (neural plasticity)
• Can result in a multitude of negative consequences

Question 4

What are some pathological examples of chronic pain?

Answer 4

• Deafferentation pain (phantom limb pain)
• Neuropathic pain
• Thalamic pain
• Trigeminal neuralgia

Question 5

What are some similarities between free nerve endings (nociception) and mechanoreceptors (sensation)?

Answer 5

• Transduce a variety of stimuli into receptor potentials → trigger action potentials
• Frequency (rate) coding:
  
  • Increase stimulus intensity = increase depolarization of receptors and increase the firing rate of pain (nociceptive) afferents
  • This means the sensation of pain is increased
• There are no obvious morphological differences between receptors.

Question 6

What are some differences between free nerve endings and mechanoreceptors?

Answer 6

• These nerve endings only respond to painful stimuli = they are specialized for damaging/nociceptive stimulation. → there are different transduction mechanisms that respond to different stimuli
  
  • Channel transduction mechanism on certain nociceptors → Pore is normally closed - in response to the presence of stimuli on the surface of the cell, the pore opens allowing NA+ (and Ca2+) to flow, resulting in an AP
• Information travels much more slowly
  
  • Fast pain vs slow pain
• Localization is relatively poor
  
  • Due to widespread branching of afferents in the skin
• Repeated or prolonged stimulation often leads to a stronger response (sensitization), rather than adaptation
  
  • ***Referred pain
    ***Pain is both mechanical and affective (amygdala for example)

Question 7

There is a wide variety of nociceptors. What are the two types of nociceptors and their corresponding subdivisions?

Answer 7

• Specific to one type of stimulus
  
  • Mechano-nociceptors (intense force)
  • Thermo-nociceptors (distinct from thermoreceptors)
    
    • Heat nociceptors (> 45 degrees)
    • Cold nociceptors (< 5 degrees)
  • Chemo-nociceptors (Bradykinin, Histamine, H+, ATP, prostaglandins)
• Non-specific (response to more than one stimulus)
  
  • Polymodal (poly = several) nociceptors
    
    • force, temperature, and chemicals

Question 8

How does a nociceptor differ in their travel time to respond to different stimuli to regular mechanoreceptors (basic touch)?

Answer 8

• A beta afferent (mechanoreceptors = touch) → heavily myelinated = 35-75 m/s
• FAST (sharp) → A delta → myelinated = 5-30 m/s (compared to touch sensation = slow)
• SLOW (dull, burning) → C fibers → unmyelinated = <2 m/s (compared to touch sensation = slower)
• ***Both of the two types of pain are still slower than the mechanoreceptors for touch

Question 9

What type of receptive field is responsible for nociception?

Answer 9

It is a large receptive field, therefore we can’t give accurate information about where the stimulus is within its field. The “size” of the receptive field depends on how widespread the branching of its terminals are

Question 10

Is painful sensation simply just excessive stimulation of mechano (touch) receptors? Yes or No? Explain.

Answer 10

• The perception of pain (nociception) depends on specifically dedicated receptors and pathways
• NOT excessive stimulation of the same receptors that generate other somatic sensations

Question 11

Describe/draw the route of the spinothalamic pathway.

Answer 11

• Axons enter the spinal cord from the spinal ganglion and travel up or down 1-2 segments within Lissauer’s tract before synapsing with secondary neurons in the substantia gelatinosa of the posterior horn. Secondary neurons then cross over to the contralateral side via the anterior white commissure.
• Caudal medulla = in the caudal medulla, the spinothalamic tract of the anterolateral system lies adjacent to the pyramids, which contain the corticospinal tracts
• Rostral medulla = in the rostral medulla, the spinothalamic tract lies between the inferior olivary nucleus and the nucleus of the spinal tract of the trigeminal nerve.
• Pons = in the pons, the spinothalamic tract lies just lateral to the medial lemniscus of the posterior column-medial lemniscus ascending tract.
• Midbrain = in the midbrain, the spinothalamic tract lies just posterior to (and can appear somewhat continuous with) the remedial lemniscus of the posterior column-medial lemniscus ascending tract.
• Thalamus = the spinothalamic tract terminates in the VPL nucleus of the thalamus.
• From there, fibers project through the internal capsule and corona radiate to terminate in the primary somatosensory cortex.

Question 12

What is the blood supply to the PCML pathway?

Answer 12

The anterior spinal artery supplies the anterior ⅔ of the spinal cord, which includes the anterolateral system.

Question 13

Once the pain stimulus in the dorsal horn, where do the axons give off branches?

Answer 13

• Axons give off branches which synapse with 2nd order neurons
• Lamina I (marginal zone) → A-delta and C fiber input primarily
• Lamina II (substantia gelatinosa) → C fiber input primarily
• Lamina V (base of dorsal horn) → A-delta

Question 14

What is referred pain? Give an example.

Answer 14

Very few neurons in the dorsal horn of the spinal cord are specialized for transmission of visceral (internal) pain (all coming from the skin/ none are specific for the visceral organs) → it comes from lamina V in the dorsal horn.

• We recognize visceral pain, but it is conveyed centrally via dorsal horn nervous that are also concerned with cutaneous pain.
  
  • As a result of this, we know that visceral pain is often felt or referred to the skin, due to overlapping dermatomes.
• Sometimes the disorder or an internal organ is perceived as a cutaneous pain
• Angina (poorly perfused heart muscle) → there will be convergence onto relay pain neuron
• A heart attack pain is often described at a burning pain down the left side of the arm, because the visceral afferent comes into the dorsal horn at the same place as the information from this dermatome. (Rex lamina V!!!!)

Question 15

What are the two aspects of pain and their general concept?

Answer 15

• Sensory discriminative = qualitative aspect of pain = burning, stabbing, dull, ache, etc.
• Affective motivational = Negative feelings, scared, the emotional component of pain, etc.

Question 16

What is the concept of sensory discriminative of pain?

Answer 16

• It is known to be processed in the ventral posterior lateral nucleus of the thalamus
• It is the location, intensity and quality of the pain.

Question 17

What is the concept of the affective motivational part of pain?

Answer 17

• It is the unpleasantness of pain
• The fear and anxiety
• The autonomic activation (fight or flight)

Question 18

What is the gate control theory of pain?

Answer 18

• It is the ascending pain suppression model
• If we activate the mechanoreceptors that are usually used to detect tactile sensation, this can override the information coming from noxious stimuli. They activate interneurons (for example in the substantia gelatinosa) and stops the flow of transmission of the nociceptive endings.
• This is why pain control can work with a TENS machine. The basis of why rubbing and scratching can reduce pain

Question 19

What are the endogenous opioids (descending control) pain control theory? What are the three main types of endogenous opioids?

Answer 19

• The endogenous opioids which are present in the periaqueductal gray (PAG) can descend be effective in the dorsal horn of the spinal cord. A lot of it comes from the Raphe nuclei (look at image on the right for more detail)
• Enkephalins
• Endorphins
• Dynorphins
  
  • Example - enkephalin release in dorsal horn = descending input excites local circuit neuron resulting in the release of enkephalin onto the nociceptive terminal
  • It inhibits the release of neurotransmitter, decrease signal sent to higher centers in the CNS
  • This response is NOT sensory discriminative!!!!!
  • ***It is why morphine is effective for pain relief → it also has an effect on the amygdala = the emotional concept of pain. Often patients will say that they still feel the pain but they simply do not care about it anymore. Therefore, this opioid does not stop the actual sensation of pain, it is just turning off us caring about the pain. It is why it is so highly addictive.

Question 20

True or false: nociceptive fibers are sensory neurons involved in pain, they are pseudounipolar in structure and their cell bodies lie in the dorsal root ganglia.

Answer 20

TRUE

Question 21

True or false: A-beta fibers are thin, myelinated fibers that allow for fast, saltatory conduction of sharp pricking pain from thermal, mechanical, and chemical stimuli.

Answer 21

FALSE → those are A-delta fibers
A-beta fibers are similar but transmit mechanical sensations such as touch and vibration - not pain.

Question 22

What is the main idea of the mechanism of allodynia?

Answer 22

• Malformation in the neurons may lead to non-nociceptive fibers stimulating second-order neurons - causing inappropriate pain sensation known as allodynia
• Both touch (A-beta) and pain (A-delta) fibers carry information to the dorsal horn. → it is the reason why allodynia can occur

Question 23

What is the main neurotransmitter released by A-delta fibers in the dorsal horn?
Substance P
Histamine
Glutamate
Acetylcholine
Serotonin

Answer 23

Answer: Glutamate

Question 24

What is the main neurotransmitter released by C fibers in the dorsal horn?
Substance P
Histamine
Glutamate
Acetylcholine
Serotonin

Answer 24

Answer: mostly - Substance P, but they can also release glutamate

Question 25

What is neuropathic pain?

Answer 25

Injury to peripheral nerve can cause spontaneous pain signaling in the absence of any stimulus - described as constant, stabbing, shock-like pain

Question 26

What are some possible causes of neuropathic pain?

Answer 26

* The disease of neurons - e.g. shingles and multiple sclerosis * Compression or damage to nerve - e.g. sciatica can also cause neuropathic pain

Question 27

What is the gate control theory? 1. A model for ascending pain suppression due to mechanical stimulation inhibiting nociceptive sensation. 2. A model for descending pain suppression due to nociceptive stimulation inhibiting mechanical sensation. 3. A model for ascending pain sensitization due to thermal stimulation inhibiting nociceptive sensation. 4. A model for ascending pain suppression due to thermal stimulation inhibiting nociceptive sensation 5. A model for descending pain suppression due to mechanical stimulation inhibiting mechanical sensation

Answer 27

Answer: 1. A model for ascending pain suppression due to mechanical stimulation inhibiting nociceptive sensation.

Question 28

What are the two types of sensitization?

Answer 28

Peripheral sensitization Central sensitization

Question 29

What is the mechanism of peripheral sensitization?

Answer 29

Interaction of nociceptors with “inflammatory soup” of substances released due to tissue damage The steps: * Nociceptors release peptides and NTs (eg. substance P) * This causes vasodilation, swelling, histamine release * Non-neuronal cells augment the inflammatory process What ends up happening is the site of damage is surrounded with inflammation/swelling/vasodilation → hyperalgesia = the surrounding skin with flare

Question 30

What is the general mechanism of central sensitization?

Answer 30

* Immediate-onset activity-dependent increase in the excitability of neurons in the dorsal horn of the spinal cord following high levels of activity in the nociceptive afferents. * Activity levels in nociceptive afferents that we subthreshold prior to the sensitizing event become sufficient to generate action potentials in dorsal horn neurons, contributing to an increase in pain sensitivity. * Although central sensitization is triggered in dorsal horn neurons by the activity in nociceptors, the effects generalize to other inputs that arise from low-threshold mechanoreceptors. * This idea is from Lamina V = painful sensation and nonpainful stimulation is firing and it is causing a lot of pain

Question 31

Hyperalgesia & allodynia ???

Answer 31

Hyperalgesia & allodynia (painful sensation to non-painful stimuli) outside of zone terminal branching (of nociceptors) - not due to peripheral mechanisms - must be centrally mediated

Question 32

What is the end result of central sensitization?

Answer 32

* Stimuli that, under normal conditions, would be innocuous, activate second-order neurons in the dorsal horn that would typically only respond to nociceptive information. * SENSATION OF PAIN IN RESPONSE TO NON-PAINFUL STIMULI = ALLODYNIA

Question 33

Why does allodynia happen = what are the two main concepts that are involved?

Answer 33

1. Wind-up (no transcription) * Progressive increase in dorsal horn neuron activity in response to continuous discharge of nociceptive afferents * Only happens during the period of stimulation * \*\*\*For example, if you are hitting yourself with a hammer repeatedly, it would feel more and more painful the more and more you hit yourself, even though you are hitting yourself at the same intensity. 2. Transcription * Involve an LTP-like enhancement of post-synaptic potentials * Last longer than the period of stimulation (i.e., nociception) - allodynia

Question 34

What is the synaptic plasticity that happens with allodynia/central sensitization?

Answer 34

Image

Question 35

What is the difference of sensitization with tissue healing and damage to nerve structure themselves?

Answer 35

* With tissue healing - sensitization (peripheral and central) declines * Damage to nerve structures themselves (afferent fibers/central pathways) results in neuropathic pain → when we start to see these transcripted mediated effects * Shingles * Diabetes (peripheral neuropathy) * Stroke * MS * Spinal cord injury * Burning, shock-like sensations or shooting/stabbing pain

Question 36

What is a general definition of sensitization?

Answer 36

Sustained, abnormal input leads to long-lasting changes in the pain pathway.

Question 37

True or false. Nociception is an all or nothing phenomenon.

Answer 37

* False * Nociceptors have a minimum threshold of intensity before an action potential is generated * Increased stimulation causes an increase in the sensation of pain.

Question 38

True or false. Nociceptive fibers can be stimulated by all of the following substances: Prostaglandins Histamine ATO Bradykinin 5-HT H+ ions

Answer 38

Answer: TRUE

Question 39

Which of these molecules is not released by damaged cells to stimulate nociceptive fibers? ATP Bradykinin Capsaicin Histamine Prostaglandins

Question 40

True or false. Hyperalgesia is excess pain sensation from a low stimulus

Answer 40

TRUE

Question 41

What are some of the substance P peripheral actions?

Answer 41

* Stimulates mast cell degranulation * Stimulates vasodilation, assisting immune response * Stimulates further sensitization

Question 42

What does CGRP stand for?

Answer 42

* Calcitonin gene-related peptide * Nociceptive neurons manufacture substance P and CGRP in the dorsal root ganglia and transport them to the periphery (slow peripheral sensitization) * Its action includes acting as a potent vasodilator, allowing leukocyte and immunoglobulin infiltration. This leads to further nociception and sensitization.

Question 43

Which of these is NOT important for “wind up” in central nociceptive neurons? Substance P Plasticity C fibers Repeated stimulation Saltatory conduction

Answer 43

Answer: Saltatory conduction

Question 44

Which of these is **_not_** a key process in central sensitisation? 1. Reduction in threshold of glutamate receptor activation kinetics 2. Mast cell recruitment 3. Increase in cell membrane glutamate receptor number 4. Alterations to axonal ion channels 5. Reductions in GABA and glycine production

Answer 44

Answer: Mast cell recruitment

Question 45

What is the general definition of allodynia and its mechanism?

Answer 45

Abnormal pain sensation due to sprouting A-beta fibers synapse directly onto nociceptive neurons: the activation of the low-threshold mechanoreceptive fibers that normally generate innocuous sensations causes pain sensation called allodynia.

Question 46

**Which of these options best describes enkephalins?** 1. Endogenous opioid receptor antagonists that inhibit the release of vesicles from 1st order neurons and stimulate the depolarisation of the 2nd order neurons at the dorsal horn 2. Exogenous opioid receptor ligands that stimulate the release of vesicles from 1st order neurons and inhibit the depolarisation of the 2nd order neurons at the dorsal horn 3. Endogenous opioid receptor ligands that inhibit the release of vesicles from 1st order neurons and inhibit the depolarisation of the 2nd order neurons at the dorsal horn 4. Exogenous opioid receptor ligands that inhibit the release of vesicles from 1st order neurons and stimulate the depolarisation of the 2nd order neurons at the dorsal horn 5. Endogenous opioid receptor antagonist s that inhibit the release of vesicles from 1st order neurons and inhibit the depolarisation of the 2nd order neurons at the dorsal horn

Answer 46

Answer: Endogenous opioid receptor ligands that inhibit the release of vesicles from 1st order neurons and inhibit the depolarisation of the 2nd order neurons at the dorsal horn #3