HNS15 Pain Pathway And Mechanisms Of Pain

Question 1

Definition of pain

Answer 1

Unpleasant sensory and emotional experience associated with actual / potential tissue damage, or described in terms of such damage

Question 2

Nociception vs Pain

Answer 2

Nociception:
Reception of signals in CNS evoked by activation of specialized sensory receptors (nociceptors) that provide information about tissue damage

Pain:
***Subjective perception of an aversive / unpleasant sensation that originates from a specific region of the body
—> an individual can have distinct responses to the same nociceptive stimulus at different times
—> have Affective + Emotional components

Question 3

Types of pain

Answer 3

Classified based on site of origin:

1. Somatic pain
   - Superficial pain: Skin
   —> Initial pain (fast/sharp)
   —> Delayed pain (slow/dull)
   - Deep pain: Connective tissues, bones, joints, muscles
2. Visceral pain: Gall and kidney stones, ulcers, appendicitis etc.

Question 4

Nociceptors

Answer 4

• Non-specialised free nerve endings (NOT encapsulated)
• Widely distributed throughout body
• A few tissues lack pain endings (e.g. neural tissues of brain)
• Most are ***Non-adapting —> as long as pain stimulus present —> continue firing
• Majority: Multimodal (respond to multiple stimuli), some activated by specific stimuli
• 2 kinds of afferent nerve fibres:
  —> Aδ (thinly myelinated, fast) and C (unmyelinated, slow) fibres
  —> double pain sensation: sharp pain followed by dull pain

Question 5

Sharp pain vs Dull pain

Answer 5

Sharp / First pain:

• larger amplitude
• lasts shorter

Dull / Second pain:

• lower amplitude
• lasts longer

Question 6

Aδ fibres vs C fibres

Answer 6

Aδ fibres:
- Thinly myelinated, fast
- Stimuli (respond to ***single type of stimuli):
—> Mechanical
—> Thermal (extreme temperature: <5oC (TRPA1+TRPM8) / >45oC (TRPV3+TRPV1/M3)) (Transient receptor potential channels)

C fibres:
- Unmyelinated, slow
- Stimuli:
—> Polymodal (mechanical, temperature, chemicals e.g. pH, hypoxia, lactic acid, prostaglandins, bradykinin, histamine, electrolytes e.g. K leaking from damaged cells)
—> Silent nociceptors (in Viscera): normally not activated by noxious stimulus, but firing threshold largely ***reduced by inflammation

Question 7

Pain transduction: Nociceptors to spinal cord

Answer 7

Enter spinal cord via dorsal horn (1st order neuron cell body in dorsal root ganglion)
—> synapse with 2nd order neuron in dorsal horn
—> cross the midline in spinal cord
—> ascend to brain on contralateral side

Dorsal horn grey matter:

• divided in 10 laminae (lamina I most lateral)
• Nociceptors: mainly connect to 2nd order neuron (projection neurons) in laminae I, V, VII (i.e. ***Lateral dorsal horn)

Question 8

Neurotransmitter used by pain fibres: Aδ fibres + C fibres

Answer 8

1. Aδ fibres: ***Glutamate
2. C fibres: **Glutamate + **Substance P

—> Glutamate: small clear vesicles
—> Substance P: large dense vesicles (poor reuptake —> ***diffuse to other places to activate other 2nd order neurons —> more diffuse signaling than glutamate —> poor localisation of pain —> dull pain)

Question 9

Pain sensitisation

Answer 9

Pain hypersensitivity after an injury —> helps healing by ensuring that contact with injured tissue is minimised until repair is complete

Allodynia: Normally innocuous (non-noxious) stimuli may be perceived as pain (e.g. sunburn —> skin touch becomes painful)

Hyperalgesia: Increased painful sensation to noxious stimuli

—> Areas not affected / damaged will also become sensitised
—> lower pain threshold

Question 10

***Hyperalgesia due to peripheral sensitisation

Answer 10

1. During inflammation
   - Damaged cells —> **Prostaglandin + Bradykinin
   - Activated mast cells —> **Histamine
   —> Activate + Sensitise Nociceptors (by modulating ion channels)
2. Release of **Substance P + **CGRP (calcitonin gene-related peptide) from Nociceptor sensory endings
   —> causes ***Neurogenic inflammation
   —> plasma extravasation + dilation of blood vessels + swelling
3. Neurogenic inflammation further sensitises nociceptors (Vicious cycle)
   —> making them far more sensitive to stimulation
   —> Hyperalgesia
4. Hyperalgesia can be
   - Primary (felt at site of stimulation)
   - Secondary (cytokines / neuropeptides spread to a site remote from original injury)

Question 11

***Hyperalgesia due to central sensitisation

Answer 11

Increased excitability of ***2nd order neuron in dorsal horn

Mast cells
—> release neurotrophic factors **NGF (nerve growth factor)
—> carried by nociceptor nerve endings
—> transported to cell body of 1st order neuron (retrograde transport)
—> increased transcription of **BDNF (brain-derived neurotrophic factor)
—> central release of BDNF to 2nd order neuron
—> central sensitisation (reduced threshold)

Question 12

***3 major Ascending pain pathways

Answer 12

Anterolateral system:
3 major ascending pain pathways:

1. Spinothalamic tract —> **Localisation + Discrimination (intensity, quality) of pain
   - 2nd order neuron
   —> **VPL, VPM nucleus
   —> 3rd order neuron
   —> project to ***Somatosensory cortex S-I, S-II (with well somatotopic organisation)
2. Spinoreticular tract —> **Emotion (Limbic system), **Autonomic reflex, Arousal
   - 2nd order neuron
   —> **Reticular formation
   —> **Medial nuclei of Thalamus (3rd order neuron)
   —> **Insula cortex + **Anterior cingulate cortex + ***Hypothalamus (autonomic response e.g. ↑HR) + (Somatosensory cortex)
3. Spinomesencephalic tract —> **Affective and Aversive behaviour associated with pain + **Descending pain modulation
   - 2nd order neuron
   —> **Midbrain (Periaqueductal gray, Reticular formation, Superior colliculus) + **Amygdala

Question 13

Neuropathic pain

Answer 13

• Different from central pain sensitisation
• Injuries to afferent nerves in peripheral (e.g. nociceptors nerve endings) / central pathways
• Pain without stimulus
• Burning / Electrical sensation
• e.g. shingles

Question 14

Thalamic pain syndrome (Dejerine-Roussy syndrome)

Answer 14

• Lesion in VP nucleus of thalamus due to stroke

—> Analgesia followed weeks/months later by Paraesthesia (burning/pickling pain)

Question 15

Pain modulatory pathways

Answer 15

1. Descending pain modulatory pathway

2. Gate control theory

Question 16

***Descending pain modulatory pathway

Answer 16

Structures involved:

1. Periaqueductal gray: Serotonin, Glutamate, Opioid neuropeptides
2. Nucleus raphe magus: Serotonin
3. Locus ceruleus: Norepinephrine
4. Dorsal horn **interneuron: **Enkephalin

2 pathways:
1. Periaqueductal gray (midbrain) —(synapse)—> Nucleus raphe magus (medulla) —> Dorsal horn (interneuron)

2. Noradrenergic locus ceruleus neurons (upper pons) —(through medulla)—> Dorsal horn (interneuron)

• Enkephalin:
  1. Bind to **Opioid receptor on **presynaptic **afferent nociceptor —> **inhibit release of **Glutamate + **Substance P from presynaptic afferent nociceptor

2. Bind to **Opioid receptor on **postsynaptic **2nd order neuron —> **hyperpolarisation —> less likely to fire action potential

—> Overall effect: reduce transduction of pain signals to brain

Question 17

Gate control theory

Answer 17

Occur locally in spinal cord

E.g. Bump knee into table leg —> Skin rubbing
- Activates Aβ mechanoreceptor (non-nociceptive mechanoreceptor)
—> activate interneuron (inhibitory neuron) in dorsal horn
—> inhibits 2nd order pain projection neuron in dorsal horn

(Aβ mechanoreceptor as a gate to close transmission of pain signals from nociceptor to 2nd order neuron)

Question 18

Pain perception

Answer 18

Subjective interpretation of characteristics of noxious stimuli

• in terms of:
  1. What (submodalities)
  2. Where (spatial localisation)
• Body reactions to pain

Question 19

Submodalities of pain

Answer 19

• Sharp, pricking, tearing, crushing, burning, dull, soreness etc.

Basis of submodalities:

1. ***2 classes of nociceptive afferents (Aδ fibres: sharp pain; C fibres: dull pain)
2. Contribution by ***non-nociceptive modalities (needle hit skin activate mechanoreceptor as well —> feeling combination of pain + touch —> give varieties of pain perception)
3. ***Psychological factors
4. ***Learning and experience

Question 20

Spatial coding of pain

Answer 20

• Localisation of pain depends on Topographical organisation + Projection
• **Pain is poorly localised compared to touch due to:
  1. **Low innervation density
  2. **Wide receptive field of nociceptors / neurons in medial thalamic nucleus / anterior cingulate cortex / insula cortex (compared to neurons in somatosensory cortex)
  3. **Coarse topographical representation of brain areas receiving pain signals (e.g. anterior cingulate cortex / insula cortex)
  4. ***Branching and convergent ascending fibres (e.g. converging on same 2nd order from different nociceptors)
• However, localisation can still be aided by contribution from non-nociceptive modalities (e.g. mechanoreception which is sharper)
• Errors in localisation:
  —> Phantom limb
  —> Referred pain

Question 21

Phantom limb and Phantom pain

Answer 21

Phantom limb:
Sensation from amputated limb
—> due to ***Reorganisation of somatosensory cortex
—> regions originally receive input from amputated limb also becomes activated when other areas are stimulated

Phantom pain:
Pain from amputated limb
—> possible cause: **Increase in excitability of 2nd order neuron in dorsal horn (due to inflammation of amputated area) —> fire **spontaneously

Question 22

Referred pain

Answer 22

• Excitation of visceral nociceptors sensed as originating from superficial sites
• Visceral pain referred to cutaneous dermatomes that share ***same dorsal root (e.g. MI, angina, acute appendicitis, gallstone colic, renal and ureteric colic)
• Cause:
  Convergence-Projection:
  1. Convergence of nociceptive **cutaneous and **visceral receptors onto ***same pool of 2nd / higher order neurons
  2. Projection according to “learned” experience (經常刺激皮膚, 到heart attack都以為係皮膚痛)

Question 23

Pain control

Answer 23

1. Oral analgesics
   - inhibition of production of pain-inducing substances e.g. Prostaglandins (sensitise nociceptors, increase excitability of 2nd order neuron)
   - by inhibition of COX e.g. paracetamol, NSAID
2. Local / regional anaesthesia
   - LA: lignocaine, xylocaine —> blockage of Na channel —> prevent axons from conducting action potential
3. Opioids / morphine-like drugs
   - activate opioid receptor (in spinal cord, midbrain etc.) —> activate descending modulatory pathway for pain
   - adverse effects: addictive
4. General anaesthesia
   - loss of consciousness in addition to loss of sensation
5. Surgical treatment (anterolateral cordotomy)
6. Transcutaneous electrical nerve stimulation (TENS)
   - stimulation of Aβ fibres (gate control theory)
7. Acupuncture (possible modulate pain pathway)