Pharmacology of pain /

Question 1

Opiates and opioids

Answer 1

Opiates derived from opium - poppies
Opioids have opiate-like effect

Question 2

What are the different forms of opiates and opioids?

Answer 2

Natural opiates - alkaloids found in opium
Semi-synthetic opiates - synthetic derivatives of natural opiates
Synthetic opioids - synthetic compounds
Opioid peptides - endogenous peptides

Question 3

What are the principal effects of morphine? (10)

Answer 3

• Analgesia
• Reduced GI motility
• Respiratory depression
• Cough suppression
• Pupil contraction
• Formication (histamine release)
• Nausea/vomiting
• Sedation/anaesthesia
• Euphoria/dysphoria
• Tolerance/dependence/withdrawal

Question 4

What is the pharmacology (target and activity) of morphine?

Answer 4

Primary target:
mu receptor
Activity: full agonist - high affinity
Secondary target:
k receptor
Activity: partial agonist
Secondary target:
d receptor
Activity: full agonist

Question 5

What is the physiological action of morphine?

Answer 5

Decreased AC/cAMP/PKA
Decreased Ca2+ channel opening
Increased K+ channel opening
Decrease action potential generation
Decrease axon AP transmission
Decrease NT release
Increased descending inhibition
Decreased ascending transmission
Decreased signal generation

Question 6

What are the desired effects of morphine?

Answer 6

• Analgesia
• Euphoria
• Anti-diarrhoeal
• Anti-tussive
• Sedation

Question 7

What are the adverse effects of morphine?

Answer 7

• Respiratory depression
• Nausea/vomiting
• Constipation
• Dependence

Question 8

What are different opiate receptor subtypes?

Answer 8

mu receptor
kappa receptor
delta receptor

Question 9

Agonist vs antagonist

Answer 9

Agonist: drug that binds to the receptor and produces similar response to NT/hormone/ligand
Antagonist: drug that binds to the receptor which stops the receptor from producing a response

Question 10

What is Kd?

Answer 10

Dissociation constant
The concentration of a drug at which 50% of receptors are occupied

Question 11

What is the general pathway of pain signals from stimulus to motor response?

Answer 11

Noxious stimulus
Impulses sent along afferent fibres towards the CNS, enter the spinal cord. Have cell body in dorsal root ganglion
Efferent fibres have cell bodies in ventral horn.
Impulses sent away from CNS to the peripheral NS - somatic and autonomic > motor response

Question 12

Pain signals in the peripheral NS

Answer 12

Pain signal generation
Nociceptors - free nerve endings
Ad fibres: sharp/fast/localised
C fibres: dull/slow/diffuse/throbbing

Question 13

Pain signals in the spinal cord

Answer 13

Pain signal transmission
Spinothalamic tract - pain and temperature
Multiple synapses in dorsal horn - 1st 2nd order

Question 14

Pain signals in the brain

Answer 14

Pain signal perception
Thalamus - relay centre
Cortex
Limbic system

Question 15

What are the different nerve tissues?

Answer 15

White matter: myelinated axon tracts. Outside surface of spinal cord
Grey matter: neuronal cell bodies and capillaries. Inner spinal cord, outer surface of cerebellum
Black matter (substantia nigra): modulates movement

Question 16

What are the different parts of spinal cord grey matter?

Answer 16

Sensory pain fibres terminate and synapse with the dorsal horn
Ad fibres: release glutamate
C fibres: release neuropeptides
Laminae: rexed layers 1-10
Substantia gelatinosa: rexed layer II
Motor fibres originate in ventral horn

Question 17

Spinal cord white matter

Answer 17

Consists of ascending and descending neural tracts
Pain transmitted in spinothalamic tract:
- Peripheral afferents both Ad and C fibres
- 1 or more synapses in spinal cord
- Fibres cross through the anterior white commissure > contralateral

Question 18

What pathway is Ad fibres part of?

Answer 18

Impulse sent along 1st order Ad afferent fibre
Neuronal cell body in dorsal root ganglion and synapses in dorsal horn using glutamate as NT, with 2nd order nociceptive neurone
2nd order neurons decussate up the spinothalamic tract and synapses with the thalamus

Question 19

What pathway are C fibres part of?

Answer 19

Impulses sent along 1st order C fibre, neuronal cell body in dorsal root ganglion. Synapses in dorsal horn. Uses NT substance P
2nd order nociceptive neurone
Most 3rd order nociceptive neurones decussate via anterior white commissure. Ascend in spinothalamic tract. Synapses in thalamus which relays signal to sensory cortex

Question 20

What are the neuronal pain modulation circuits?

Answer 20

Gate control:
- Non-noxious stimuli can suppress noxious stimuli
- Decrease impulse transmission up spinothalamic tract
Descending inhibitory circuits:
- Descending spinal pathways from CNS can inhibit ascending spinothalamic pathways
- Decrease impulse transmission up spinothalamic tract

Question 21

Where can neuronal regualtion occur?

Answer 21

Cell body: receptors, NTs, inhibitory/excitatory
Synapse: pre-synaptic receptors, post-synaptic receptors, NTs, inhibitory/excitatory

Question 22

What are G coupled receptor signalling cycle

Answer 22

G protein heterotrimer is associated with receptor. Ga is bound to GDP
Agonist binding causes exchange of GDP for GTP and dissociation of receptor and a and By subunits
Both a and By subunits can interact with effector molecules to propagate a signal
Intrinsic GTPase activity of the Ga subunit cleaves GTP to GDP bringing the signalling cycle to a close

Question 23

What is the structure of G proteins?

Answer 23

Form a heterotrimeric complex
Membrane associated
alpha and beta-gamma subunits

Question 24

What interacts with G proteins?

Answer 24

G protein-coupled receptor (GPCR) interacts with and signals through G proteins

Question 25

How do opioid receptor signal?

Answer 25

All signal through Gi/o (subunit of the G-alpha subunit)
G-alpha i/o: decreases adenylate cyclase > decrease cAMP > decrease PKA > decreased VG Ca2+ channel opening > decreased Ca2+ entry > decreased NT release
GBy subunits: increased G protein-coupled inwardly rectifying K+ channels (GIRK) > increased K+ conductance > decreased AP generation
Overall effect = INHIBITORY

Question 26

How do opioid effect the pre-synaptic receptors?

Answer 26

Activates pre-synaptic receptors
- Reduces NT release
- e.g. in substantia gelatinosa
- decreased glutamate release from Ad fibres
- decreased substance P release from C fibres

Question 27

How do opioids effect the post synaptic receptors?

Answer 27

Post-synaptic receptor activation
- Reduces AP firing
- e.g. in dorsal horn interneurones
- GIRK channels

Question 28

How do opioids reduce GI motility?

Answer 28

Pre-synaptic mu receptors on post-ganglionic parasympathetic fibres in the gut
- mu receptor activation > decreased ACh release > decreased GI motility
Clinical effects: anti-diarrhoeal
Adverse: constipation

Question 29

Which opioids reduce GI motility?

Answer 29

Loperamide:
Peripherally-acting mu receptor agonist - substrate for P-glycoprotein (BBB) > low concentration to the brain > reduced diarrhoea

Question 30

What are the different types of opioid mediated analgesia?

Answer 30

Supraspinal: mediated via action in brain - injected into brain
Spinal: mediated via action in spinal cord - morphine injected into substantia gelatinosa reduces neuronal firing in spinal cord
Peripheral: mediated via action in periphery - at site of injury on nociceptor free nerve endings, opioid receptors on nerve endings modulate stimulus generation