lecture 26: neurochemistry: pleasure and pain I

Question 1

What is pain?

Answer 1

• an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage - International Association for the Study of Pain

Question 2

What is the pain experience?

Answer 2

• pain is always subjective (there are no objective measures)
• pain is an experience, with sensory and emotional aspects
• the relationship between tissue damage and pain is variable, so the size of an injury can be a poor guide as to how much pain someone is in
  
  • the signals the body sends from an injury site are referred to as nociceptive signals
  • these signals only become experienced as pain when they reach the conscious brain, and the person interprets them as pain
  • that interpretation is influenced by many factors, including past experience, beliefs, and the situation
• pain is expressed in behaviour - that is how we communicate it to others, and an important effect of pain is on behaviour

Question 3

What is the psychobiology of pain?

Answer 3

• the cortical pain network and modes of activation
• schematic to show how quite different inputs can activate the pain network - from peripheral nociceptors triggered by tissue injury to purely mental processes

Question 4

What is the somatosensory system?

Answer 4

• pain fundamentally is a property of the specialised function of the somatosensory nervous system
• key parts:
  
  • sensory neurons that project to all parts of body
  • skin, muscle, bones
  • dorsal root ganglia
  • project into spinal cord
  • trigeminal nerves receive info from face and head
• majority is involved in mechanosensation/proprioception
• peripheral axon, central neuron, secondary pathway
• even at this level we have difference
• pain uses nociceptors
• project into dorsal horn directly onto second order neurons

Question 5

What is a dorsal column pathway for visceral pain?

Answer 5

• particular nociceptors e.g. from gut run up dorsal column
• dorsal column pathway
• can be shown experimentally
• dorsal column lesions disrupt visceral perception of pain

Question 6

What are cutaneous mechanoreceptors?

Answer 6

• mediate sensation of touch
• hair follicles
  
  • light brush
  • G-hair (Abeta)
  • D-hair (Adelta)
  • RA, LT
  • small receptive field
  • skin movement
• meissner corpuscle
  
  • dynamic deformation
  • below epidermis in dermis
  • abeta
  • RA, LT
  • small receptive field
  • skin motion, detecting slipping objects
• pacinian corpuscle
  
  • vibration
  • abeta
  • low in dermis
  • RA, LT
  • large receptive field
  • vibratory cues transmitted by body contact when grasping an object
• merkel cell-neurite complex
  
  • indentation depth
  • abeta
  • multiple below epidermis
  • SA, LT
  • multiple small receptive fields
  • fine tactile discrimination; form and texture perception
• ruffini corpuscle
  
  • stretch
  • abeta in mid dermis
  • SA, LT
  • moderate receptive field
  • skin stretch, direction of object motion, hand shape and finger position

Question 7

What are low-threshold C-fibre mechanoreceptors?

Answer 7

• sensory and affective (pleasure)
• C-fibre LTM
• touch
• C-fibre
• SA, LT
• pleasant contact; social interaction

Question 8

What are high threshold C-fibre nociceptors?

Answer 8

• sensory and affective (noxious pain/itch)
• mechano-nociceptor plymodal nociceptor
• injurious forces
• C-fibre
• adelta
• SA, HT
• small receptive fields
• skin injury; pain

Question 9

What are nociceptors in other tissues?

Answer 9

• joints
• type 1
• type 2
• type 3
• type 4
• this relationship is not unique to skin
• same basic pattern
• some specialised mechanosensors with specialised endings
• nociceptors which have very simple structures, very fine, very few specialisations

Question 10

What is sensory transduction and transmission?

Answer 10

• single unit recording of electrical activity in one afferent fibre in a nerve bundle projecting the to finger
• mechanosensors respond to mechanical deformation
• electrical activity closely follows stimulation of nerve
• nociceptors only start to get activated after threshold is met
• many continue to fire when the stimulus is removed but the tissue has been damaged

Question 11

What is TRPV1?

Answer 11

• transducer in polymodal nociceptors
• specialised pain receptors
• TRPV1 most well characterised

Question 12

What are functional nociceptor classes?

Answer 12

• thermal - Adelta
• mechanical - Adelta
• polymodal - C-fibre
• silent
• heat:
  
  • TRPV1
  • non-TRPV1 heat-sensitive channel
• cold:
  
  • TRAAK
  • TRPM8
  • TREK-1
  • Non-TRPM8 col-sensitive channel
  • NaV1.8
• polymodal
  
  • peptidergic
    
    • Non-TRPV1 heat sensitive channel
    • TRAAK
    • TRPV1
    • TRPA1
    • TREK-1
    • mechano-transduction channel
  • nonpeptidergic
    
    • TRAAK
    • TREK-1
    • mechano-transduction channel

Question 13

What are channel families?

Answer 13

• peripheral terminal
  
  • transient receptor potential channels (TRPs)
  • voltage activated sodium channels (Nav)
  • pressure, heat, cold, pH, chemicals
  • depolarisation AP initiation
  • skin, organs
• peripheral axon
  
  • hyperpolarisation-activated cation channels (HCN)
  • potassium channels delayed rectifier, 2-pore, calcium-activated etc (Hv, K2P, Kca, Kna)
• central axon and synapses
  
  • voltage-activated calcium channels (Cav2.2, Cav3.2)

Question 14

What kind of fibres are nociceptors?

Answer 14

• Adelta
  
  • pain, temp
  • free nerve endings
  • 1-5µm
  • 5-30m/s
• C
  
  • pain, temp, itch
  • free nerve endings
  • 0.2-1.5 µm
  • 0.5-2m/s

Question 15

What is the propagation of action potentials?

Answer 15

• the myelination/size has implications for the propagation of action potentials
• the first APs to arrive are somatosensory → 1 or 2 miliseconds
• after delay adelta → ~ 10ms
• C fibres even slower → 30-40ms

Question 16

What is the response to noxious heat?

Answer 16

• becomes basis for discriminating different types of pain
• spatial → back of hand has Type II A and C-fibres, whereas palm only has C-fibres
• different types of pain being created
• early sharp by Type II A
• slow bunring C fibre

Question 17

What is first and second pain?

Answer 17

• difference in timing propagates through entire pain pathway
• initial delay due to activation of terminals
• different conduction velocity
• separation of inputs in spinal cord
• two types of pain perceived based on different classes of afferent

Question 18

What is the spinothalamic tract?

Answer 18

• this is showing spinothalamic tract and neurons
• different classes of afferents coming in also show functional and anatomical separation within the spinal cord itself
• most pain related information is in superficial layers - laminin 1 and 2 (receives from C and adelta), or 3 and 4 (adelta)
• segregation of nociceptive information as it comes into CNS

Question 19

What are nociceptor projections within spinal cord?

Answer 19

• nerve terminals can run several spinal cord segments (either rostrally or caudally)
• drop projections into dorsal horn over a number of different segments

Question 20

What are defensive spinal reflexes?

Answer 20

• nociception without pain
• only about 5-10% of neurons in dorsal horn are projection neurons
• local neurons illicit fast, protective reflexes
• spinal reflexes that mediate fast withdrawal response
• local circuits that project down onto motor neurons in the ventral horn
• nociceptive reflexes can occur independently of the perception of pain
• the brain doesn’t have to be involved
• activity of nociceptors doesn’t necessarily correlate with the perception of pain
• difference bw nociception and pain

Question 21

What is referred pain?

Answer 21

• spinal cord circuitry also has a role in referred pain
• damage to visceral organ becomes referred to some part of the abdomen
• happens with heart attacks
• use to be thought because there were single nerves that innervated both peripheral targets, whilst there is some evidence, majority seems to be due to inputs converging on common pain pathways within the spinal cord circuit

Question 22

What is hyperalgesia?

Answer 22

• fundamental to clinical pain conditions
• amplification of pain
• effect of a burn - originally done with capsaicin
• measured pain threshold (mechanical pain threshold) at different sites
• after inducing damage with capsaicin or burn
• decrease in pain threshold (allodynia)
• increase in amount of pain perceived
• important feature is that you see in region of damage, but also area around the region of damage

Question 23

What is primary hyperalgesia?

Answer 23

• damaged tissue releases a complex array of chemicals e.g. cytokines , histamine, nerve growth factor
• released by tissue and immune cells
• act on the peripheral nociceptor terminals
• causing peripheral sensitisation - primary hyperalgesia
• terminal more sensitive to stimulation
• will sensitise and recruit nociceptors - surrounding areas
• doesn’t apply to undamaged skin

Question 24

What is sensitisation?

Answer 24

• primary: change within nociceptor
• central: increased activity in sens. noci. changes the circuitry within the spinal cord, allowing low-threshold neurons to sense pain (mechanosensors will not normally drive pain)
• activity dependent plasticity

Question 25

What is secondary hyperalgesia?

Answer 25

• can cause dramatic expansions of sensitivity
• initial site
• injecting saline is very good and generating large areas of hyperalgesia
• involves spinal cord circuitry
• inputs from these regions contribute to perception of pain

Question 26

What is the somatosensory cortex?

Answer 26

• primary somatosensory cortex
• topographic mapping
• representation of body
• humunculus proportion of areas

Question 27

What is pain in phantom limbs?

Answer 27

• functional implications of topographic map
• amputatees often don’t lose representation of that limb in primary somatosensory cortex
• very uncomfortable
• even though they have no limb they can perceive pain
• different areas - sometimes entire, sometimes specific parts
• telescopy
• in some cases pain is related to sensory/nociceptive activity coming from stump
• prevailing view is that this is not the only cause

Question 28

With what does phantom pain correlate?

Answer 28

• functional remapping (fMRI)
• evidence that after amputation, remapping, patients that have no pain - can map other representations normally
• in phantom limb/spinal cord injuries - remapping of the regions spreads activation
• no longer reliably

Question 29

What is functional activation of non-somatosensory regions during pain perception?

Answer 29

• normal somatosensory cortex
• decoding information about touch
• areas of the pain that are activated during pain perception are much more diverse
• shown simply: insula, SI, SII, posterior parietal cortex, prefrontal cortex, anterior cingulate gyrus
• associated with higher brain function
• linked to non sensory cortex

Question 30

What is the thermal-grill illusion of pain?

Answer 30

• discovered by thunberg, 1896
• one bar is warm, one is cold
• even though the warm bars and cool bars are not noxious the perception is of burning pain
• warm sensory and cold sensory fibres being integrated to give sense of pain

Question 31

What is fMRA during thermal grill test?

Answer 31

• if you just activate cool bars only, normal, warm bars normal
• same parts of the brain activated as with noxious heat
• occur in non somatosensory areas
• illustrates that the perception of pain is not purely somatosensory

Question 32

What is the perception of cold with the thermal grill?

Answer 32

• within the pain pathways we recognise a division between lateral and medial spinothalamic tract
• lateral = greater role in sensory discrimination in painful stimulation
• medial = effective or emotional dimensions of pain

Question 33

What are the multiple pain pathways?

Answer 33

• classic sensory-discriminitve pathway
  
  • ventral posterior nucleus
• in addition have ascending inputs going through medial
• input to non cortical regions of the brain

Question 34

What is the central pain network?

Answer 34

• when considering pain it is not just a set of lines
• there’s a complex anatomy and complex pattern of activation
• include other non somatosensory regions
• bottom up inputs from brainstem into amygdala and basal brain stem
• focusing or distracting yourself from bain can change the intensity (and unpleasantness) of pain
• also emotional modulation - good mood, bad mood, work more to affect unpleasantness

Question 35

What is neurobiology of pain as an emotional experience?

Answer 35