Pain and Anagesia

Question 1

Define Pain.

Answer 1

Integration and processing of nociceptive input by the brain allowing it to be recognised as pain (cortical recoginition)

Question 2

Define nociception.

Answer 2

Information regarding a noxious insult relayed from periphery to the CNS

Question 3

Outline the three aspects of pain (S, M, C)

Answer 3

1. Sensory - Recognition 2. Motivational - Affective 3. Cognitive - Evaluative (recognise consequences)

Question 4

Name the different types of pain.

Answer 4

Phys/Path Somatic/ Visceral Acute/ Chronic

Question 5

Describe the difference between somatic and visceral nociceptors.

Answer 5

S - numerous and widespread, small receptive fields, assoc with skin, muscle, bone & joints, respond to chemical, thermal and mechanical stimuli. V - sparsely distributed, large receptive fields, respond to ischemia, distenstion and inflammation, stimuli threshold depends on area affected rather than intensity.

Question 6

Describe the difference between somatic and visceral pain.

Answer 6

S - localised to site of injury, sharp/ stabbing pain. V - Poorly localised and diffuse pain, autonomic associated, may be referred.

Question 7

Functional/ anatomical adaptation of NS in response to environment/ physiological processes. What can be the consequences of this process?

Answer 7

Neuroplasticity - hyperalgesia, allodynia, chronic pain

Question 8

Allodynia

Answer 8

Normally innocuous stimuli being percieved as painful

Question 9

Hyperalgesia

Answer 9

Exaggerated response to normally painful stimuli

Question 10

Define multimodal analgesia.

Answer 10

Formulation of an analgesic plan which affects multiple steps in the nociceptive pathway: transduction, transmission, modulation and perception

Question 11

Describe the different stages of the nociceptive pathway.. (x4)

Answer 11

1. Transduction - Applied stimuli converted into an electrical signal (AP) by activation of nerve end receptors
2. Transmission - Conduction of impulses to and from the CNS (& of ascending and descending impulses within the CNS)
3. Modulation - Alteration at the spinal cord level due to alteration of neuronal sensitivity and NT release
4. Perception - CNS centres - RAS, thal/hypothal, cingulation gyrus, amygdala, hippocampus, cortex

Question 12

Name and describe nociceptor receptors..

Answer 12

• Free nerve endings
• Higher activation thresholds than specialised receptors
• A delta and C fibres
• Prolonged stimution results in sensitisation

Question 13

Which nociceptive have the highest activation thresholds?

Answer 13

A delta fibres < C fibres

Question 14

Name substances which can cause activation of nociceptors.

Answer 14

1. Cell damage products - prostaglandin E2, H+, K+, ATP, Leucotrienes
2. Sensory nerve endins - substance P, CGRP
3. Plasma, platelets and mast cells - hisamine, bradykinin and serotonin

Question 15

What is peripheral sensitisation?

Answer 15

When inflammatory mediators and products of cell damage lower nociceptor threshold and recruit silent nociceptors.

Results in primary hyperalgesia, primary allodynia

Question 16

How do NSAIDs act to produce analgesia?

Answer 16

COX inhibitors - they reduce the production of inflammatory mediators which cause receptor sensitisation (transduction and modulation effects)

Question 17

Describe the difference between COX 1 and 2 receptors.

Answer 17

COX 1 - constitutive - maintain GI mucosa, platelet aggregation and renal blood flow

COX 2 - inducible - BUT also expressed consititutively in CNS, kidney, eye and repro organs

Question 18

What factors can lead to differences in NSAID action?

Answer 18

1. COX selectivity of the drug
2. Selectivity differs between species
3. Individual variation
4. Affects LOX pathway

Question 19

What is the function of a first order neurone?

Name the three main types we are concerned with and where they synapse.

Answer 19

Transmits information from the periphery to CNS

Cell body in DRG, axon extends into grey matter of dorsal horn of spinal cord:

• Aδ fibres – synapse in laminae I and V. First pain; mechanical and thermal stimuli
• C fibres – synapse in laminae I and II. Interneurones connect with lamina V. Dull persistent pain; chemical, mechanical and thermal stimuli
• Aβ fibres – synapse in laminae II, III, IV, V.

Question 20

What are the two main types of 2nd order neurone?

Describe their function.

Answer 20

1. Inter-neurones - within the grey matter
   
   1. Excitatory/ inhibitory - modulation of pain signals
2. Projection neurone - ascend spinal cord to higher centres
   
   1. Nociceptive specific, high threshold
   2. Adelta and c fibres only
   3. Wide dynamic range

Question 21

Name the five different anatomical tracts of projection neurones.

Answer 21

• spinothalamic
• spinoreticular
• spinomesencephalic
• spinohypothalamic
• spinocervical

Question 22

Sodium channel blockers which prevent generation and propagation of APs

Answer 22

Local Anaesthetics

Question 23

What is the function of a third order neurone?

Answer 23

• processing, integration and recognition of a harmful or painful experience

Question 24

Do animals need to be conscious to percieve pain?

Answer 24

Yes

Question 25

Which centres of the brain are involved in pain perception?

Answer 25

* reticular activating system * affective and motivational aspects * thalamus and hypothalamus * sensory, discriminatory and affective aspects * cingulate gyrus * behavioural responses * amygdala * learned responses (anxiety and fear) * hippocampus * memory * locus coeruleus * behavioural (arousal) responses * cortex * conscious perception

Question 26

Which substances are involved in neuronal modulation?

Answer 26

* Excitatory transmitters increase cation (Na+/Ca2+) conductance of axonal membrane * presynaptically increasing transmitter release * postsynaptically destabilising membrane potential or increasing expression and sensitivity of receptors * Glutamate + aspartate act on N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors (ligand gated non-specific cation channels) * Substance P and neurokinin A act on neurokinin (G-protein coupled) receptors

Question 27

How do inhibitory transmitters work to modulate neuronal substances?

Answer 27

1. Increased Cl- conductance of axonal membranes - causes hyperpolarisation of glycine and GABAa receptors 2. Increased K+ conductance of axonal membrane - GABAa - prevents NT release

Question 28

Outline the pain gate theory.

Answer 28

* Input from Aδ or C fibres inhibits activity of inhibitory interneurones facilitating nociceptive signalling * Innocuous sensory input from Aβ fibres activates inhibitory interneurones suppressing nociceptive signalling

Question 29

Outline descending inhibition.

Answer 29

Periaquaductal grey tracts which project to the spinal cord. They contain endogenous opioids and opioid receptors and are inhibitory to ascending pain neurones.

Question 30

Outline the MOA of paracetamol.

Answer 30

* weak **PG synthesis inhibitor** (better centrally than peripherally) * stimulates **descending serotonergic inhibitory pathway**s * inhibits reuptake of **endogenous cannabinoids** * acts centrally at **modulation** stage of nociceptive pathway

Question 31

1. A mu partial agonist 2. A mu antagonist, kappa agonist 3. 2 mu agonists Sort these - Butorphanol, pethidine, morphine, methadone, fentanyl, buprenorphine

Answer 31

1. Buprenorphine 2. Butorphanol 3. Others

Question 32

Order these opioids in terms of their duration of effect. ## Footnote Butorphanol, buprenorphine, pethidine, morphine, methadone, fentanyl

Answer 32

Fentanyl, Butrophanol, Pethidine, Morphine, methadone, Buprenorphine

Question 33

Describe the mechanism of action of alpha-2-agonists.

Answer 33

Agonise Alpha2 adrenoceptors Activate descending serotonergic and noradrenergic inhibitory pathways Analgesia synergists with opioids

Question 34

Describe central sensitisation What can it result in?

Answer 34

Increased second order neurone activity due to recruitment and upregulation of post synaptic receptors in response to sustained or massive release of excitatory neurotransmitters. Interneurone mediated sensitisation of adjacent primary afferents decreasing their threshold for recruitment. Can lead to secondary hyperalgesia and secondary allodynia