W2: Pharmacology of Pain Flashcards
1
Q
How is pain indicated in anatomical terminology?
What are some examples of this?
A
- ‘algia’
Proctalalgia - pain in pelvic region from muscle spasm of pelvic floor and external anal sphincter and rectum
Neuroalgia - nerve pain often feels like a shooting or stabbing pain.
2
Q
What is pleurodynia?
A
Pain in the chest or upper abdomen when you breathe.
3
Q
What is meant by phantom pain?
A
The perception of pain or discomfort in a limb that is no longer there.
4
Q
What is referred pain?
A
Pain that is felt in one region of the body but the painful stimuli is acting on another.
5
Q
What is neuropathic pain?
A
Pain that occurs when the nervous system is damaged or not working correctly.
6
Q
Whay is hyperalgesia?
A
Symptoms that causes unusually severe pain in situations where pain is normal but the patient experiences pain more severe than what it should be.
7
Q
What is allodynia?
A
Pain due to stimulus that does not normally provoke pain
8
Q
What is normalgesia?
A
The sensation of a normal amount of pain for a given stimuli**
9
Q
What is hypoalgesia?
A
Diminished pain in a response that typically promotes pain
10
Q
What is analgesia?
A
The inability to feel pain
11
Q
What is paresthesia?
A
An abnormal sensation, typically tingling or prickling caused by pressure or damage to peripheral nerves.
usually painless and temporary
12
Q
What is dysesthesia?
A
Abnormal sensatoin that can become intesnse or painful
Usually a burning, prickling or aching feeling
Normally in limbs or feeling like being squuexed around the abdmonen
13
Q
What is anaesthesia?
A
Insensitivity to pain
Loss of sensation
14
Q
What is hyperesthsia?
A
Increased sensitivity of any of your sense including sight, sound, touch and smell
15
Q
What is hypoesthesia?
A
Reduces or numbness of senses
Normally touch sensation or loss of sensitivity to sensory stimuli.
16
Q
What is synethesia?
A
brain routes information through multiple unrealted senses causing you to experience more than one sense simultaneously
Such as tasting words or linking colours to numbers and letters.
17
Q
What is graphesthesia?
A
The ability to regocnise writing/symbols when traced on the skin.
18
Q
When are opioids often prescribed?
A
For moderate-to-severe pain often following surgery or injury or for health conditions such as cancer.
19
Q
Suggest what type of painkillers should be given for different conditions?
A
Arthiritis - steroid
Cancer - opiates
Colic - anti-muscarinics
Fibromyalgia - anti-depressants
Gout - xanthine oxidase inhibitors
Iatrogenic - local anaesthetics
Injury - NSAIDs
Itch - anti-histamine
Migraine - triptans
Muscle spasm - benzodiazepines
Shingles - anti-virals.
20
Q
How does capsaicin cause pain?
A
Binds to an activates TRPV1 receptors on nerve cells.
21
Q
What drug class is morphine?
A
Opiate analgesic
22
Q
What are some historical opium preparations?
A
Laudanum - main components is 10% opium (all alkaloids) in alcohol , used as a cure for all.
Paregoric - camphorated tincture of opium.
23
Q
What is the difference between opioids and opiates?
A
Opiates - derived from opium
Opiods - have opiate like effects.
24
Q
What is meant by a nautrual opiate?
What are some examples?
A
Alkaloid found in opium
Morphine, codeine and thebaine
25
What is meant by a semi-synthetic opiate and what are some examples?
Synthetic derivates of natural opiates
Heroin, etorphine and oxycodone
26
What are synthetic opiods and what are some examples?
Synthetic compunds
Pethidine, fentanyl and methadone
27
What are opiod peptides?
Endogenous peptides that mimic the effect of opiates.
28
What are some of the effects of opium on the body?
Anti-diarrhoeal (reduce GI motility)
Analgesic
Sedative
Causes pupil constriction
Formication (histamine release)
Nausea/vomitting
Euphora/dysphoria
Anti-tussive (prevent coughs)
Lethal is high dose - cause respiratory depression**
Addicition
29
What is the active components of opium?
Main components is morphine
Also contains codeine, thebaine etc
30
What is heroin?
A di-ecetylated derivated of morphine - semi synthetic opiate
Used as a cough suppresent (TB and pneumonia in 1890s)
31
How does the principle of strucutre activity relationships apply to opium?
Many different modifications at different sites within the active compounds
Some modifications result in active metabolites and others in inactive metabolites.
32
What is the active metabolite of morphine?
Morphine-6-glucoronide
33
What is the active metabolite in heroin?
6-monoacetylmorphine
34
What is the active metabolite in codeine?
Heterocodeine
35
What is the role of nalorphine?
Is a structural modification of morphine, has a lower IC50 than other opioids hence effect is more penetrative at low doses.
At low doses - acts as a receptor antagonist to inhibit the analgesic effect of morphine.
However at high doses can have morphine like effects
Is a precuros for naloxone and naltrexone.
Can be used to treat alcohol and opiod disorders
36
What are the different opiod receptors?
What drug normally acts on them?
μ or mu receptor - acted on by morphine
k or kappa - acted on by ketocyclzocine
σ or sigma receptor - bound to be SKF (N-allylnormetazocine.
37
What are the three different types of opioid receptors?
Mu receptor - μ
Kappa receptor - k
Sigma receptor - σ
38
What are the presence of receptor sub-types important when considering opiates/opiods?
Opiates/opiods can have slightly different effects based on which receptor they are selective or preferntial for
Describes the differences in effectiveness/side effects of different opiates.
39
Compare the receptor selection of nalorphine and naloxone
Nalorphine - compeitive antagonist at mu recepotrs and a partial agonist as kappa receptors
Naloxone - antagonisit at mu receptors and less at kappe receptors.
40
What are the effects of the mu receptor when activated?
Decrease pulse rate, respiratory rate, temperature
Pupil constriction
Large decrease in flexor reflex and skin twitch reflex
Causes addiction in morphine and cylazocine
41
What are the effect of the kappa receptor when activate?
Constriction of pupils
Decrease flexor reflex and skin twitch reflex to a less extend
Cause addiction to cyclazocine
42
What are the effects of activation of the sigma receptor?
Increased pulse rate, RR, temp
Pupil vasodilation
Decreased flexor reflex.
43
What is the affinity of nalorphine for different receptors?
High affinity but no efficacy at mu receptors - antagonists
High affinity and low activity as kappa - partial agonist
Low affinity and low activity an sigma receptor.
44
What is the activity of morphine at different opioid receptors?
Has a high affinity and high activity - at mu receptors
Has a moderate affinity and high activity at kappa receptors
Has a low or no affinity and low or no activity at sigma receptors.
45
What is the difference between affinity and efficacy?
Affinity - binds to receptor
Efficacy - causes an effect
46
What is meant by the dissociation constant Kd?
The concentration of drugs at which 50% of receptors are occupied.
Measures affinity
47
What is meant by EC50?
The concentration of drug at which 50% of maximal efficacy is seen
Is a measure or potency.
48
Give an example of an antagonist at opioid receptors?
Naloxone
49
Give examples of agonists of opiod receptors?
Morphine
Normorphine
Met-enkephalin
Tyr-Gly-Gly-Phe
50
What is the function of the delta opiod receptor?
Inhibitory transmembrane GPCR
Enkephalins are its endogenous ligand
51
Why are the effects of opiods complicated?
Many different receptor subtypes
Distribution of receptors varies by tissue
Different agonsits have different potencies
Antagonists have diffeernt affinities
Ligans can have different efficacies at different receptors.
52
What is the chemistry of morphine?
Is an opiod analgesic
Can be derived from poppy naturally so is a natural ligane
Metabolised to active morphine-6-glucuronide
53
What is the pharmacology of morphine?
Primary target with highest affinity: mu receptors acts as fully agonist
Secondary target - kappa receptors partial agonist
- delta receptor full agonist
54
What are the desired effects of morphine?
Analgesia
Euphoria
Anti-diarrhoeal
Anti-tussive
Sedation
55
What are the adverse effects of morphine?
Respiratory depression (over dose)
Nause/vomtting
Constipation
Miosis (small constricted pupil)
Somnolence (fatigue)
Addictive
Tolerance
Dysphoria
56
What type of axons are involved in nociception?
How are their roles different?
Alpha delta fibres - fast, sharp and localised pain
C fibres (unmyelinated) - dull, slow, diffuse and throbbing pain
57
What is the process of pain signalling from a physiology perspective?
Periphery - transduction - nociceptors on free nerve endings are activated by noxious stimuli and generate an action potential, not stimulus can be polymodal
Transmission - up alpha delta fibres or c fibres (primary neuron), travels in the spinothalamic tract.
The pain signal is perceived in the brain, mainly processes in the thalamus but the limbic system and cortex are also involved
58
What is the specific role of Alpha delta fibres in the dorsal horn?
Synapse in laminae 1,2 and 5
Release glutamate
59
What is the exact role of c fibres in the dorsal horn?
Synapse in laminae 1 and 2 (substantia gelatinosa_
Release neuropeptides such as substance P
Actives interneuron
Synapses with 2 order neuron in lamina IV VIII
60
What is meant by rexed laminae?
Ten layers of grey matter in the spinal cord
Used to help anatomically divide the spinal cord
61
Where is the dorsal horn do primary neurons in the spinothalamic tract synapse?
The substantia gelatinosa (lamina 2)
The nucleus prorius
Lamina 1 - for alpha delta neurons - release glutamate
62
Where do fibres in the spinothalamic tract desiccate?
The anterior white commissure
63
What is the role of the thalmus?
Relay for information between cerebral cortex and subcortical centres
Regulates sleep
Regulates sensory information (expect smell)
Motor realy function is less well understood
64
Why do we often have two sequential pain sensations from a single stimulus?
Activates of both alpha delta and c fibres
Alpha delta more rapidly travelling - sharp pain
C fibres - smaller diamter so slwoer transmission - delay before dull pain
65
What primary neuron does local aneathetic preferntially inhibt?
C fibres
66
What is meant by descending inhibitory circuits in pain modulation?
Descending spinal pathways from the CNS can inhibit ascending spinothalamic pathways.
This decreases impulse transmission up the spinothalamic tract.
67
What are the functional effects of of morphine?
(physiology)
Decreases action potential generation
Decreases axon AP transmission
Decreased Neurotransmitter released
Decreased signalling up the spinothalamic tract so reduced pain transmission and perception
68
Describe the effect of morphine at its receptor/
Binds to target receptor (mu receptor), this is a GPCR.
Causes an exchange of GDP to GTP
Receptor dissociates into alpha and beta gamma subunits.
Gαi/o subunit and The G beta gamme subunits bring about effects
Overall effect is inhibtory.
69
What happens at the opiod receptor in the absence of a ligand?
Is a GPCR
Intrinsic GTPase activity of the Galpha subunit cleaves GTP to GDP bringing signalling effects of the receptor to a close
Requires ligand interaction t be reactivated.
70
What is the effect of the Gαi/o is opiod receptor signalling?
Inhibits adenylate cyclase
Decreased cAMP
Decreased PKA activation
Decreased voltage-gated Ca2+ channel opening
Decreased Ca2+ entry
Decreased neurotransmitter release
71
What is the effect of Gβγ subunits in opiod receptor signalling?
Activates GIRK channels
This increases K+ conductance - K+ moves out of the neuron - results in decreased action potential generation
72
What signalling pathway is thought to be responsible for dependence to opiods?
MAPK activation
73
What are the effects of opiods at pre-synpatic receptors?
Reduce neurotransmitter release e.g in the substantia gelatinosa
Decrease glutamate from alpha delta fibres
Decrease substance P from C fibres
74
What are the effects of opiod at the post synapatic receptors?
Reduces action potential firing
Such as in dorsal horn interneurons
Mainly brought about by GIRK channels
75
Describe how opioids such as loperamide reduce GI motility
Peripherally acting mu receptor agonist.
Low oral bioavialability means acts mainly in the gut
Acts on pre-synaptic mu receptors on post-ganglionic parasympathetic fibres in the gut.
Causes reduced ACh release leading to reduced GI motility.
Therefore acts as an anti-diarrhoeal
76
What is the role of methylnaltrexone?
Is a peripherally actin mu receptor antagonist - decreases constipatory effect of opiate analgesics.
Is a quarternay ammonium
Found in low concentration in the brain
77
How can the effects of opiods be divided anatomically?
Supraspinal
Spinal
Peripheral
78
What are the supraspinal affects of opiods?
Injected and act in the brain - causes analgesia
Mediated by mu and kappa receptors more than delata receptors
Increases descending inhibition
79
What are the spinal effects of opiods?
Morphine is injected into the substantia gelatinosa
Reduces neuronal firing in the spinal cord
Decreases ascending transmission
Blocked by naloxone
80
What are the peripheral effects of opiods?
Act at the site of injury on alpha delta and C fibres nociceptive free nerve endings
Modulate the generation of a action potential from a stimulus
Decreases signal generation
81
What is a concerning side effect specific to pethidine?
Anticholinergic effects
82
What are the neurological mechanism behind the gate control of pain modulation?
Non-noxious stimuli is able to suppress noxious transmission up the spinothalamic tract.
Often activation of alpha beta mechanoreceptors and associated alpha beta neurons by pressure, these neurons also project into the dorsal horn.
Act directly on the spinothalamic tract at the point of synapse between primary and secondary neuron in the substantial gelatinosa by axonal branch releasing inhibitory neurotransmitters
Or can act indirectly by activating inhibitory interneurons that release GABA.
Note that the pain fibres may also have branches fibres that can inhibit the activation of the inhibitory interneuron.
83
What is the neurological mechanism underpinning the descending pain control pathway?
The descending tract originates in the periaqueductal grey matter in the midbrain.
Can project to the nucleus raphe magnus nucleus that releases seratonin and enkephalins
Activates descending pathways that reduce impulse transmission in the spinothalamic tract.
84
What are the different sources of descending inhibitory control over pain?
Periaqueductal grey
Nucleus raphe magnus
Locus coerulus
Nucleus reticularis paragigantocellularis
