sensory processing and pain

Question 1

where does sensory innervation to the head come from?

Answer 1

from the trigeminal ganglion that is adjacent to the pons

Question 2

describe anatomy of the peripheral sensory nervous system

draw and label

Answer 2

Question 3

where are pain sensing neurons found?

Answer 3

in the dorsal root ganglion

Question 4

what are the three major sub-classes of adult DRG neurons?

what is their % of DRG neurons?

Answer 4

• proprioceptive neurons
• nociceptive neurons (60-65%)
• low threshold mechano-receptive (LTM) neurons (25-30%)

Question 5

describe proprioceptive neurons

Answer 5

• large-diameter soma
• large calibre, thickly myelinated axons
• their central projections terminate in intermediate zone and ventral horn of the spinal cord
• they innervate skeletal muscle spindles & golgi tendon organs to provide spatial awareness of the limbs

Question 6

describe LTM neurons

Answer 6

low threshold mechano-receptive neurons - 25-30% of DRG neurons

• large to medium diameter cell bodies
• thickly myelinated axons
• their central projections branch and project up dorsal columns and go to deep dorsal horn
• innervate specialised receptor organs in skin dermis, epidermis and deeper tissue layers
• detect light touch, gentle tissue deformation, allow discrimination between different textures etc.

Question 7

describe nociceptive neurons

Answer 7

60-65% of DRG neurons

• small to medium diameter cell bodies
• small calibre axons
• thinly myelinated or non-myelinated
• their central projections terminate in superficial dorsal horn
• most peripheral fibres end as naked terminal arbors in skin or viscera
• transmit information on painful stimuli, physiological temperatures and itch.

Question 8

where are nociceptive neuron fibre tracts carrying nociceptive information found?

Answer 8

found in the anterolateral region of the spinal cord

Question 9

what are the pathways of ascending fibre tracts carrying nociceptive information called?

how are they classified?

Answer 9

Direct anterolateral pathway:

• spinothamalamic tract
  
  • From spinal cord to thalamus

Indirect anterolateral pathways:

• spinoreticular tract
  
  • To reticular formation in hind brain
• spinomesencephalic tract
  
  • To midbrain

Question 10

describe the spinothalamic tract

Answer 10

Dorsal horn projection neurons

• Projection neurons in lamina I are nociceptive specific
• Projection neurons in lamina III to VI are WDR (noxious and non-noxious stimuli)
  
  • Wide dynamic range neurons

Long axons that cross midline and travel up to thalamus

• Thalamus is somatotopically mapped
  
  • Pain is localised

sharp, precisely localised pain

Question 11

describ the spinoreticular tract

Answer 11

aka paleospinothalamic tract

• Makes connections with areas of hindbrain
• Long axon crosses midline
  
  • Synaptic connection with nuclei of reticular formation
  • Project to thalamus
  • Not somatotopically mapped
    
    • Pain is poorly localised
  • Neurons project to PSC - pain is rationalised
    
    • Perception of pain
• C-fibre nociceptors input to the spinoreticular tract predominantly via excitatory lamina II interneurons

dull, persistent, poorly localised pain and arousal response to nociceptive input

Question 12

describe the spinomesencephalic tract

Answer 12

• Long axon passes midline
  
  • Synaptic connection with neurons in parabrachial nucleus
    
    • Remember in pic
  • PAG
• C-fibre nociceptors input to dorsal horn projection neurons via excitatory lamina II interneurons

ANS response to painful stimuli

emotional response to painful stimuli

input to centres controlling descending modulation of pain

Question 13

what are the benefits of pain?

Answer 13

protective mechanism to minimise tissue damage

Question 14

what can prolonged hyperalgesia lead to?

what is it caused by?

Answer 14

• results from central sensitisation of second order interneuron and/or peripheral sensitisation of primary nociceptor
• results in debilitating persistant pain
  • ​osteoarthritis
  • interstitial cystitis
  • pancreatitis

Question 15

describe the spinal pain reflex

draw diagram and label

Answer 15

removal from source of danger

1. innervated by a heat pain
   * responsive nociceptive neuron
2. Excitatory interneuron projects axon to motor neuron in ventral horn
   * green
3. Motor neuron innervates hand and arm muscle
   * Minimise damage to skin

• A-delta myelinated fibre is the nociceptor involved
  
  • Faster than c-fibre
• Nociceptor branches in the dorsal horn to also synapse with a projection interneuron that carries the pain signal to the brain
  
  • Orange

Question 16

how does temperature perception occur?

Answer 16

Molecules allow us to perceive temperature

Physiological and noxious temperatures are detected by ion channels in temperature responsive and nociceptive neurons

These ion channels change conformation and open when the temperature changes allowing Na+ and Ca2+ to pass through them

• -> membrane depolarisation

Individual neurons only express one type of temperature responsive ion channel

Question 17

what are the hot detecting ion channels?

Answer 17

TrpV1 can also be activated by capsaicin (active ingredient in chilli)

Question 18

what are the cold detecting ion channels?

Answer 18

Expressed by dorsal root ganglion neurons

TrpM8 can also be activated by menthol

Question 19

how does tissue damage activate nociceptiors?

Answer 19

Tissue damage produces chemical that activate and sensitise nociceptors

• skin damage
  
  • detected by nociceptive DRG neuron - as it terminates in superficial layers of dorsal horn

1. skin cut
2. dying cells release K+ ATP and H ions

• K+ ions directly depolarise nociceptor terminals
• ATP binds to P2X3 ion channels - opens & causes depolarisation
• H+ activates ASICS - depolarises nociceptors

3. tissue damage also releases enzymes that contribute to hyperalgesia

• cyclo-oxygenase enzymes
  
  • make PGE2 - increase sensitivity of nociceptors
• bradykinin
  
  • binds to GPCR - depolarises
  • sensitises TrpV channels to open at lower temperature

NSAIDS reduce pain by inhibiting cox

Question 20

what is substance P and what its function?

Answer 20

• Released by depolarised nociceptors
• Can bind to receptors on capillaries
  
  • Makes leaky
  • Local swelling
• Binds to receptors on mast cells
  
  • Causes degranulate
    
    • Empty contents into skin
      
      • Histamine
        
        • Binds
        • Makes capillaries leaky - swelling
      • PGE
      • ATP
      • Bradykinin
• Sensitises nociceptors to be activates by lower intensities of noxious stimuli

Question 21

what is the role of nerve growth factor (NGF)?

Answer 21

• Major role in inducing chronic hyperalgesia
  
  • Normally produced in skin
  • Role in maintaining function and health of nociceptor and sensory neurons
• If tissue is damaged
  
  • Level of NGF in target fields of sensory neurons rapidly increases

Question 22

what are the early effects of NGF in peripheral nociceptor sensitisation?

Answer 22

• NGF is rapidly up-regulated in target fields of nociceptive neurons after tissue trauma
• NGF rapidly phosphorylates the heat channel TrpV1 lowering its threshold for activation
  
  • Activates at body temperature - painful
• NGF facilitates mast cell degranulation

Question 23

what are the late effects of NGF in peripheral nociceptor sensitisation?

Answer 23

• NGF increases the expression of many peptides and ion channels in nociceptive neurons including
  
  • Substance P
  • Heat responsive channels
    
    • TrpV1
    • TrpA1
    • TrpM8
  • Acid sensing ion channels (ASICS)
  • TTX-resistant voltage-gated sodium channels
    
    • Nav1.8
    • Nav1.9

= enhanced sensitivity of nociceptive neurons to noxious stimuli

Question 24

what are the effects of NGF in central sensitisation (sensitisation of the second order interneuron)?

Answer 24

• NGF up-regulated substance P is released at the central terminals of nociceptive neurons (dorsal horn)
• NGF promotes the synthesis of brain derived neurotrophic factor (BDNF) in nociceptive neurons and promotes BDNF release from their terminals in the dorsal horn

->

• Centrally released SubP and BDNF promote increased excitability of second order interneurons that project to the thalamus in the spinothalamic tract Long term potentiation
  
  • Increased synaptic efficiency
• = projection interneurons are more sensitive to nociceptive input from DRG neuron terminals

Question 25

what are the bodies in built mechanisms for modulating the intensity of pain perception?

Answer 25

1. pain gating in the dorsal horn 2. descending regulation of nociceptive transmission in the dorsal horn

Question 26

describe how pain gating in the dorsal horn is able modulate the intensity of pain perception

Answer 26

* nociceptive neurons synapse with projection interneurons in the dorsal horn * painful stimulus sends AP along nociceptor axon * activity induced glutamate release from nociceptor terminal depolarises interneuron sending AP to **thalamus** * LTMs branch in dorsal horn to synapse with local inhibitory interneurons * activity in LTM causes depolarisation of inhibitory interneuron * = release GABA (inhibitory neurotransmitter) onto presynaptic nociceptor terminal * **presynaptic inhibition** * LTM branches also synapse with inhibitory syanpses making synaptic connections with projection interneurons * **postsynaptic inhibition**

Question 27

what are the different types of descending regulation of nociceptive transmission in the dorsal horn?

Answer 27

**serotenergic descending control** **noradrenergic descendind control**

Question 28

describe how serotenergic descending control of nociceptive transmission in the dorsal horn is able modulate the intensity of pain perception

Answer 28

neurons involved produce serotonin * input to the PAG from * spinomesencephalic tract * Amygdala * Hypothalamus * Cingulate cortex * Prefrontal cortex * PAG neurons project (bilaterally) to nuclei raphe magnus neurons within the rostral ventral medulla (RVM) * Serotonergic raphe neurons project to the dorsal horn via the dorsolateral funiculus * Synapse with either DRG neuron terminals, local interneurons or projection neurons * Descending raphe neurons can either * Inhibit nociceptive transmission in the dorsal horn (OFF neurons) or facilitate it (ON neurons) * Depends on serotonin receptor type expressed by DRG or projection neurons

Question 29

describe how noradrenergic descending control of nociceptive transmission in the dorsal horn is able modulate the intensity of pain perception

Answer 29

Neurons produce noradrenaline * PAG neurons also project bilaterally to noradrenergic neurons within the pontine locus coeruleus (LC) * Noradrenergic LC neurons project to the dorsal horn of the spinal cord * Synapse with either DRG neuron terminals, local interneurons or projection neurons * Noradrenergic LC neurons inhibit nociceptive transmission in the dorsal horn * **Always inhibit**

Question 30

what interactions do descending modulatory fibres make with dorsal horn neurons?

Answer 30

* Descending neurons make presynaptic connections with c- and Aδ-fibres * Descending neurons make presynaptic connections with excitatory and inhibitory interneurons * Descending neurons make postsynaptic connections with dorsal horn projection neurons * Serotonergic descending neurons : * hyperpolarise neurons expressing 5-HT1/5-HT7 metabotropic serotonin receptors * (inhibitory) * Depolarise neurons expressing 5-HT3 (ligand gated cation channel) receptors * (excitatory) * When damaged, DRG neurons increase expression of 5HT3 and decrease expression of 5HT1/7 * Noradrenergic descending neurons : * hyperpolarise neurons expressing metabotropic α-2 adrenergic receptors * (inhibitory)

Question 31

what are endogenous opioids? what actions in nervous system?

Answer 31

Small peptides that are produced by the body (mainly the nervous system and in particular the **hypothalamus/pituitary**) in response to physical exertion, pain, excitement and sexual pleasure Have several actions in the nervous system one of which is analgesia

Question 32

what are the analgesia endogenous opioids?

Answer 32

Question 33

what are opioid receptors? examples? what are the receptors expressed by?

Answer 33

G-protein coupled cell membrane receptors that upon ligand binding alter the excitability of the neurons that express them Opioid receptors expressed by: * Primary nociceptors * PAG neurons * Raphe 'off' projection neurons