L15 - Pain pathway and mechanisms of pain

Question 1

Difference between nociception and pain?

Answer 1

 Nociception = reception of signals in the CNS evoked by activation of nociceptors that provide information about tissue damage.

 Pain= subjective perception of aversive sensation from a specific region of the body. An individual can have distinct responses to the same nociceptive stimulus

 Pain has affective and emotional components

Question 2

Classify types of pain based on site of origin ?

Answer 2

a) Somatic
a) i) Superficial pain&raquo_space; Initial or delayed pain
a) ii) Deep pain

b)Visceral

Question 3

Give examples of Somatic pain and visceral pain?

Answer 3

Somatic:
1) Superficial pain (skin on finger, e.g. pinprick, pinching): Initial pain (fast, sharp); Delayed pain (slow, dull, diffuse)

2) Deep pain (connective tissue, bones, joints, muscles in hip, e.g. muscle cramp, headache)

Visceral (viscera, e.g. gall and kidney stones, ulcers, appendicitis): slow, chronic, dull

Question 4

Structure and modality of nociceptor? Adaptation abilities?

Answer 4

Non-specialized free nerve endings (not encapsulated)

Majority = multimodal (some activated by specific stimuli)

all non-adapting

Question 5

Are nociceptors distributed throughout every tissue of the body?

Answer 5

No

A few tissues lack pain endings e.g. neural tissues of brain

Question 6

Afferent nerve fibers of nociceptors?

Answer 6

Two kinds of afferent nerve fibers

• A-δ fibers and C fibers (slower, thinner fibers)

Question 7

Classify types of nociceptor based on speed of conduction, stimuli and response to stimuli?

Answer 7

1. A-δ:
   - Finely myelinated, thicker = FASTER conduction
   - Intense MECHANICAL or TEMP&raquo_space; Transient Receptor Potential (TRP)&raquo_space; depolarize
   - Localized* sharp pricking; Fast first pain
2. C:
   - Unmyelinated, thinner = SLOWER conduction
   - POLYMODAL (mechanical, temperature, chemicals)
   - In viscera; normally not activated by noxious stimulus, but their firing threshold is largely reduced by inflammation
   - Burning, DIFFUSE*/ Poorly localized
   - Slow, second pain

Question 8

Sequence of pain transduction from nociceptor to spinal cord?

Answer 8

• 1st order neuron enter the spinal cord via the dorsal horn
• Connect to second order neuron in the dorsal horn
• Cross the midline of spinal cord and ascend to the brain on the contralateral side&raquo_space; spinothalamic tract
• Nociceptors: mainly connect to projection neurons in laminae I, V and VII in grey matter

Question 9

Explain why A-δ fibers transduce more localized pain than C fibers?

Answer 9

Two neurotransmitters from C-fibers: glutamate and substance P (A-δ fibers use only glutamate)

Substance P: not well reuptake, can DIFFUSE to other 2nd order neurons for diffuse signaling
» poor localization of pain

Question 10

What pain pathway process occur after injury that helps wound healing?

Answer 10

Pain hypersensitivity&raquo_space; ensuring that contact with the injured tissue is minimized until repair is complete

Question 11

2 types of pain sensitization?

Answer 11

• Allodynia: normally innocuous stimuli may be perceived as pain
• Hyperalgesia: increased painful sensation to noxious stimuli = CENTRAL or PERIPHERAL SENSITIZATION

Question 12

Mechanism of Peripheral sensitization in Hyperalgesia?

Answer 12

• Damaged cells release bradykinin and prostaglandin, which activate and/or sensitize nociceptors (+mast cells)
• Release of substance P and calcitonin gene-related peptide (CGRP) from nociceptor sensory endings; causes plasma extravasation and dilation of blood vessels (neurogenic inflammation)
• Inflammation further sensitizes nociceptors, making them far more sensitive to stimulation (hyperalgesia)

Question 13

Hyperalgesia is only felt at the site of injury. True or False?

Answer 13

False

Can be primary (felt at the site of stimulation) or secondary (spread to a site remote from the original injury)

Inflammatory factors can diffuse away from site of injury

Question 14

Mechanism of central sensitization in hyperalgesia?

Answer 14

1. Inflammation&raquo_space; Peripheral exposure to nerve growth factor (NGF) from Mast cells
2. Retrograde transport of signaling endosomes
3. Increased transcription of brain-derived neurotrophic factor (BDNF)
4. Central release of BDNF&raquo_space; Increased excitability of second order neuron in dorsal horn (enhanced synaptic transmission) , reduce stimulus threshold

Question 15

List all the ascending pathways for pain transduction?

Answer 15

Discriminative aspect of pain: Lateral spinothalamic tract

Affective aspect of pain: Spinoreticular tract/ Spinomesencephalic tract

Question 16

Pathway for discriminative pain?

Answer 16

For localization, discrimination (intensity, quality) of pain

• 1st order neuron at dorsal horn of spinal cord
• 2nd order neuron corsses spinal cord > lateral spinothalamic tract > medulla, pons, thalamus
• Reach ventral posterior nuclei (VPL and VPM) of thalamus
• somatosensory cortex S-I, S-II + Association cortex

Question 17

Pathway for affective pain via Spinoreticular tract?

Answer 17

• To reticular formation (RAS)
• Medial groups of thalamic nuclei,

> > insular cortex and anterior cingulate cortex (limbic system)

Question 18

Difference in function between Spinoreticular tract and Spinomesencephalic tract?

Answer 18

Spinoreticular = autonomic reflex, arousal and emotional aspects of pain

Spinomesencephalic = affective & aversive behavior associated with pain and descending pain modulation

Question 19

Pathway for affective pain via Spinomesencephalic tract?

Answer 19

areas of midbrain including periaqueductal gray (PAG) > amygdala

Question 20

Define neuropathic pain?

Answer 20

• Different from central pain sensitization
• Injuries to the afferent nerves in the peripheral or central pathways&raquo_space; Burning or electrical sensation
• e.g. shingles

Question 21

Cause and result of Thalamic pain syndrome?

Answer 21

• Lesions in the ventral posterior thalamus due to stroke

* resulted in analgesia followed weeks or months later by paraesthesia (burning, pickling pain)

Question 22

Compare the fiber tracts for pain signal from head, face vs from body, limbs to the thalamus.

Answer 22

Head, face = trigeminal nerve&raquo_space; trigeminothalamic system&raquo_space; VPM

Body, limbs = spinothalamic tract&raquo_space; VPL

Question 23

Define pain perception?

Answer 23

interpretation of the characteristics of noxious stimuli in terms of :
• Type of pain (submodalities)
• Where (spatial localization)

> > elicit body reaction to pain

Question 24

What are the 2 descending pathways for pain modulation?

Answer 24

1) Spinomesenphalic tract:
Cerebral cortex&raquo_space; midbrain periaqueductal gray (PAG)&raquo_space; nucleus raphe magus of the medulla&raquo_space; superficial layers of the dorsal horn.

2) Locus ceruleus tract
noradrenergic locus ceruleus neurons (upper pons)&raquo_space; medulla&raquo_space; dorsal horn laminae

Question 25

What neurotransmitters are used in the 2 descending pathways for pain modulation?

Answer 25

1) Spinomesencephalic tract
• Periaqueductal gray (PAG): serotonin, glutamate, opioid neuropeptides
• Nucleus raphe magnus: serotonergic

2) Locus ceruleus tract
• Locus ceruleus: noradrenergic
• Spinal dorsal horn interneurons: enkephalin (opioid)

Question 26

Action of enkephalin released from interneuron in the NE locus cerulus neuron modulatory pathway?

Answer 26

Raphe magnus neuron/ pontine neuron activate spinal dorsal horn interneurons

> > release enkephalin:

1) Inhibits release of glutamate and substance P from the presynaptic afferent nociceptor
2) Hyperpolarize postsynaptic second-order neuron

> > reduce transduction of pain signals to brain

Question 27

Define the gate control theory in pain modulation.

Answer 27

Local control within spinal cord, doesn’t involve the brainstem: filter out low-level pain via interneuron

i.e. skin rubbing
• Activates Aβ non-receptive mechanoreceptor
• Activate interneuron&raquo_space; Inhibits the pain projection neuron in the dorsal horn

Question 28

Define submodality of pain

Answer 28

Different qualities of pain: sharp, pricking, tearing, crushing, burning, dull, soreness… etc

Question 29

How are submodalities of pain classified? What contribute to these submodalities?

Answer 29

2 classes of nociceptive afferents:

• A-δ: sharp, pricking, tearing, crushing
• C: burning, dull, soreness

Contribution by non-nociceptive modalities

• i.e. mechanoreceptive integrate signal with nociceptor
• Psychological factors
• Learning and experience

Question 30

Explain why pain is not well-localized compared to touch?

Answer 30

• Low innervation density, wide receptive field***** (of nociceptors, neurons of ant. cingulate and insular cortex)
• Coarse topographical representation (pain perception cortexes not as well structured as somatosensory cortex)
• Branching & convergent ascending fibers (thalamus medial groups have larger receptive field than lateral group for touch)

Question 31

Diseases that arise from errors in spatial coding of pain/ localization?

Answer 31

Phantom limb

Referred pain

Question 32

Explain the mechanism of phantom limb?

Answer 32

pain from amputated limbs:

• Reorganization of somatosensory cortex***** (i.e. touch face = feel limb)
• Increase in excitability of second order neuron in dorsal horn (central sensitization) = spontaneous firing

(surgical amputation causes excessive stimuli to nociceptors, increase NGF and BDNF = hyperactivity)

Question 33

Define referred pain.

Answer 33

Excitation of visceral nociceptors sensed as originating from superficial sites

Visceral pain referred to cutaneous dermatomes that share the same dorsal root

Question 34

Define convergence- projection in relation to referred pain.

Answer 34

convergence of nociceptive cutaneous and visceral receptors onto same group of second-or third-order neuron

i.e. nociceptors form skin and heart converge at 2nd or 3rd order neuron&raquo_space; misinterpret pain from diff site

Question 35

Function of Transcutaneous electrical nerve stimulation (TENS)?

Answer 35

stimulate Aβ fibers (gate theory)