Drugs and afflictions Flashcards
1
Q
Describe the spectrum of opoid effects on the body and their consequences
A
• Analgesia o For acute, severe pain o Used in anaesthesia • Nausea, vomiting • Respiratory depression o Major cause of death by opioid overdose • Constipation • Reward o Cause euphoria • Tolerance o Development of tolerance to opioid • Addiction o Opioid dispensing episodes increased 15-fold in the last 20 years o Now the leading cause of accidental death in the USA
2
Q
What are specific nerve pathways that are activated by noxious stimuli?
A
• Specific nerve pathways are activated by noxious stimuli
o Specific sensory nerve pathways
o Specific parallel pathways from spinal cord
o Descending modulatory pathways to spinal cord
3
Q
Describe how noxious stimuli is transported to and regulated by the brain
A
• Nociceptors are responsive to noxious stimuli and transmit information into the spinal dorsal horn, which ascends into the brain
o Brain asserts descending control to determine how effective the pain transmission is going to be
There are environmental conditions that are counteractive to experiencing pain
4
Q
What are the two main pes of fibres for pain?
A
• Two main types of fibres for pain
o C fibres-
o Aδ fibres
5
Q
Describe the speed, myelination and role of C fibres
A
o C fibres-
1.5 m/s APs
Unmyelinated fibres
Second pain
6
Q
Describe the speed, myelination and role of Adelta fibres
A
o Aδ fibres
6-25 m/s APs
Myelinated fibres
First pain
7
Q
Where are opioid receptors generally located and where do opioids act?
A
• Opioids act primarily on C-fibre synapses (central terminals of the fibres, but there are some in the periphery)
o Opioids act mostly on C-fibres that transmit noxious information in sensory neurons
Act on Aδ fibres a bit as well
o μ opioid receptors are located on nociceptive nerve terminals (main actions are in the central nervous system
o Opioids act at all levels of pain pathways
Forebrain- lateral sensory system (thalamus, cortex), medial system emotional responses (limbic system)
Midbrain and brainstem- descending systems (PAG, raphe nuclei)
Spinal cord- sensory modulation (dorsal horn)
8
Q
Describe the physiological actions of opioids
A
Presynaptic inhibition
• Opioids close calcium channels
Postsynaptic inhibition
• Opioids open potassium channels
• Opioids act to block neurotransmitter release and action potential activity
o Alpha and betagamma subunit release from G receptor:
Opens potassium channels that reduce excitability of the cell
Shut voltage gated calcium channels in the synapses that allow calcium into the nerve terminal that triggers sequences of events that releases neurotransmitters
• Inhibits N-type calcium channels
Inhibit cyclicAMP formation
Inhibits synaptic potentials
• Opening GIRK blocks action potentials and hyperpolarize the cell membrane (locus coeruleus neuron)
9
Q
How does the brain modulate pain signals (descending pathways) and the consequences of this on drug design to relieve pain
A
o Opioid action and descending inhibition
Descending NA and 5HT modulate sensory synapses (filled terminals are inhibitory, open terminals are excitatory)
• Predominantly utilise norepinephrine and serotonin
NA and 5HT excite enkephalin (ENK) neurons and inhibit projection neurons (synergism). Enkephalin inhibits sensory synapses
• Inhibit projection neurons to C fibres, (which contains opioid receptors)
• Safer because the enkephalin neurons which release enkephalin are target to pain system and don’t reach respiratory system
Noradrenaline and serotonin transport inhibitors relieve pain
• Important in chronic pain
Mixed function drugs (tramadol, tapentadol) act directly on both opioid and monoamine systems synergistically
• Tramadol μ-receptor and SERT
• Tapentadol μ-receptor and NET
Mixed function drugs are dose sparing, so safer
• Don’t have to stimulate μ opioid receptor as much if the other receptors are already being stimulated
10
Q
What are the 3 main families of endogenous opioids? Describe their features and location
A
main families- o Proenkephalin (nerve cells, adrenal) Tyr-gly-gly-phe-leu Tyr-gly-gly-phe-met Enkephalin immunoreactivity in periaqueductal grey o Prodynorphin (nerve cells) Alpha-neoendorphin Dynorphin A and B Predominantly on the kappa receptors o Pro-opiomelanocortin (pituitary, brain-restricted) ACTH B-endorphin
11
Q
What are the 3 main opioid receptor types and what are their actions when activated?
A
o μ (mu)- strong analgesia, constipation, nausea, respiratory depression, cough reflex, tolerance and dependence
Nearly all clinically used opioids are very μ-receptor selective
o δ (delta)-mild spinal analgesia (convulsions, cardiovascular complications)
o κ (kappa)- moderate analgesia, diuresis, hallucinations (dysphoria)
12
Q
What is the main structure of opioid receptors and what is their structural change when they become activated?
A
o G-protein coupled receptor
o Ligand sticks in barrel of helices
o Active state crystal has small shift in orientation of intracellular domains of the receptor that switch on the G protein
13
Q
What are the physiological consequences of mu opioid receptor activation?
A
• Inhibition of adenylyl cyclase
o Inhibition of voltage-dependent pacemaker Ih- cation non-selective current activated at hyperpolarised potentials to depolarise membrane (sensory nerve)
• Increase in potassium conductance
o All three ORs activate GIRK potassium conductance through membrane delimited beta/gamma subunits, inhibits action potentials
• Decrease in calcium conductance
o Similar to potassium channels, beta/gamma subunits, directly inhibit neurotransmitter release
14
Q
What are the main types of opioid drugs?
A
• From opium (poppy) o Morphine Analgesics o Codeine (methyl morphine) o Heroin (diacylmorphine) o Hydromorphone o Oxycodone • Agonists (duration of action varies) o Methadone o Fentanyl • Partial agonist o Buprenorphine • Mixed actions o Tramadol o Tapenntadol • Antagonists o Naloxone o Naltrexone
15
Q
What opioid started the opioid crisis and why?
A
o Oxycodone
Root cause of opioid crisis-> overpromotion of oxycodone
16
Q
What is the use of buprenorphine?
A
Good drug in dependency management
17
Q
What is the use of naloxone?
A
o Naloxone
Used to reverse overdose
18
Q
What is the use of naltrexone?
A
o Naltrexone
Used to combat alcoholism
19
Q
Why are heroin and codeine inactive forms of morphine and how do they become active forms?
A
Inactive form of morphine= reason
o Heroin= diacetyl (3,6)
o Codeine= CH3 (methyl) and glucuronide (M3G)
What makes the opioid active
o Heroin to 6-Acetyl Morphine
o Codeine to Morphine-6-Glucuronide (M6G)
How an opioid goes from inactive to active state-
o From heroin -> 6-Acetyl Morphine
Esterases strip off acetyl group
o From codeine -> Morphine-6-Glucuronide
CYP2D6 strips off methyl group
• Up to 10% of individuals are deficient in CYP2D6
• Up to 10% have excessive activity in CYP2D6
20
Q
What does the strength of G-protein signalling (due to morphine binding) depend on?
A
Strength of G-protein signalling (due to morphine binding) depends on:
o Intrinsic efficacy of agonist (not the same as potency)
o Capacity of receptors to signal
o Capacity of cell to translate signal
o Tolerance modifies capacity of receptor and cell to signal
21
Q
Why does buprenorphine give a weak G-protein signal and how does it behave when the person is tolerant to opioids?
A
If there is a weak G-protein signal (such as due to buprenorphine(partial agonist)) depends on:
o Buprenorphine binds very tightly so other agonists and antagonists cannot compete
o Problem when there is a weak G-protein signal in the first place as well as when tolerance decreases signal, there may be no signal from this drug in the first place
o When tolerance has developed there may be no signal- that is buprenorphine behaves almost as an antagonist
22
Q
Does high or low G-protein efficacy improve opioid drug safety? Why?
A
Low G-protein efficacy improves safety
o Don’t have to get a lot of receptor occupancy to get maximum pain relief
o Get to more severe levels of respiratory depression at higher levels of occupancy
23
Q
Could safer opioids be developed using signalling bias? Why/why not?
A
• Safer opioids could be developed using property of signalling bias
o The consequences are still uncertain. Category B (moderate intrinsic efficacy, unbiased) were thought to produce less side effects only if extended to no arrestin signal and would thus be very safe in overdose
o But all studied very biased drugs developed so far actually have very low intrinsic efficacy (like buprenorphine)
o Structural basis of bias or low efficacy is still not understood
24
Q
How can safer opioid drugs be developed?
A
• In summary, safer opioids can be developed by:
o Reducing the intrinsic efficacy of μ-opioids
Mu receptor has to be stimulated enough to relieve pain but not stimulated enough to induce respiratory depression
o Using mixed function drugs for dose sparing (e.g. tapentadol for NET or tramadol for SERT)
Tapentadol and tramadol have low intrinsic efficacy at the μ-opioids
o Using drug mixtures (e.g. NSAIDs with opioids) for dose sparing
NSAIDs alone not effective for all human pain, but good experimentally
25
What are the major types of drugs used for pain?
• Opioids (e.g. codeine, oxycodone,morphine,heroin)
• Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. aspirin, ibuprofen and diclofenac)
• Antidepressants (inhibitors of noradrenaline [NET] and serotonin [SERT] transport)
o Important for chronic pain relief
• Gabapentanoids (e.g. pregabalin) and anticonvulsants
26
When was morphine discovered and when were endogenous opioids implicated for pain relief?
o Morphine was discovered in early 19th century: first plant alkaloid ever isolated and purified
With the advent of hypodermic syringe, became widely used
o 1970s- electrical stimulation produced analgesia (periaqueductal grey) reversed by opioid antagonists implicating endogenous opioids
27
What mediators are relleased in injury and inflammation? (Give the stimulus and its representative receptor)
```
Stimulus on the left, representative receptor on the right
Stimulus Representative receptor
NGF=TrkA
Bradykinin=BK2
Serotonin=5-HT3
ATP=P2X3
H+=ASIC3/TRPV1
Lipids=PGE2/CB1/TRPV1
Heat=TRPV1/VRL-1
Cold=TRPM8
Pressure=DEG/ENaC
```
28
What peripheral pain pathway for NSAIDs inhibit?
```
o The other major class of pain-relieving drugs (e.g. aspirin) act on the prostaglandin pathway
Prostaglandins sensitise nociceptive sensory nerves (C-fibres) and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit this
```
29
What is the process of the prostaglandin pathway and what part of this pathway does NSAIDs inhibit?
```
o Stimulus-> phospholipase A2 activation->breakdown of arachidonic acid-> either lipoxygenase or cyclo-oxygenase (COX)
Lipoxygenase
• HETE’s
• Leukotrienes
• Lipoxins
Cyclo-oxygenase (COX) (inhibited by NSAIDs)
• Prostaglandins
• Prostacyclin
• Thromboxane
```
```
o Prostaglandins (PGE2) excite and sensitive nociceptive nerve endings (Gs coupled receptor)
Gs coupled receptors activate adenyl cycle, phosphorylate protein kinase A, and that phosphorylation turns up the activity of certain ion channels
o NSAIDs block synthesis from amino acids
Block PGE (prostaglandin signal) arachidonic acid pathway
```
30
What drugs can be used in conjuction with opioids to enhance opioid actions on nerve endings
• Non-steroidal anti-inflammatory drugs (NSAIDs) can synergise and enhance opioid actions on nerve endings
31
What is tolerance and when can it develop?
• Tolerance- an increase in the dose needed to produce a given pharmacological effect
o Tolerance can develop rapidly (days) following repeated administration
32
What are the effects of opioid tolerance and what is the pharmacological consequences of it (physiological and physical effects)
o For morphine, tolerance extends to most of the pharmacological effects including analgesia, euphoria, respiratory depression etc.
o Less tolerance is observed for constipating and pupil-constricting actions
Therefore an addict may take large doses and still have marked constipation and constricted pupils
o Usual dose escalations are 10-30 fold clinically. Up to 1000 fold has been documented
• Tolerance reduces signalling efficacy
o Receptor is phosphorylated, arrestin binds-> weaker G-protein signal
• Receptor regulation differs for different agonists (contributes to tolerance)
Phosphorylation of receptor-> binding of arrestin-> formation of encoded pit->internalisation of receptor
33
How is acute pain treated?
• Treatment of acute pain is of great concern, but it is generally served by current analgesics, e.g. opioids, NSAID, etc
34
What is chronic pain? Why is it a problem?
• A major clinical presentation is chronic pain
o Pain persisting beyond the acute phase- following wound healing and recovery
o The definition- beyond 3 months pain= chronic
o It is highly prevalent and costly
35
What are the two main types of chronic pain?
o Inflammatory pain
| o Neuropathic pain
36
What is inflammatory chronic pain caused by?
Tissue injury and inflammation processes, e.g. arthritis
| Often ongoing nociceptor activity-> maintains the pain
37
What is neuropathic chronic pain caused by?
o Neuropathic pain
Lesion or disease affecting the somatosensory system
Peripheral and central lesions
Caused by:
• Trauma to peripheral nerves- accidents, surgery
• Central injury- spinal cord injury, stroke
• Disease (post-herpetic neuralgia, diabetes, HIV, MS, etc.)
• Chemotherapy induced
38
Why is neuropathic chronic pain a problem?
Particularly difficult to treat
| The pain can persist even after the injury resolves
39
What is neuropathic chronic pain characterised by? Which of these factors is most distressing for patients?
Abnormal pain syndrome characterised by:
• Spontaneous pain-pain/burning sensations in the absence of stimulation
• Allodynia- normally innocuous stimuli perceived as painful, such as light touch, brushing, cool/cold
• Hyperalgesia- painful stimuli more painful, reduced threshold to pain response
Spontaneous pain and allodynia are particularly distressing for patients
40
In addition to pain, what can chronic pain cause?
• Chronic pain is a multi-dimensional experience and can also include:
o Disturbances of familial and social relationships
o Sleep disruptions
o Metabolic and endocrine disturbances
o Reduced movement
o Loss of interest in external events
o Depression
o Viscious cycle: Pain leads to anxiety which leads to disturbed sleep which leads to increased anxiety and more pain
41
What are current medications used for neuropathic chronic pain?
o Anticonvulsants, e.g. gabapentin (Neurotin) and pregabalin (Lyrica)
o Voltage gated calcium channel blockers (VGCCs) e.g. Ziconotide (prialt)
o Antidepressants
o Opioid agonists (have ben include as first-line, but opioid crisis)
o Tramadol (partial opioid agonist + SNRI)
o Topical drugs, e.g. capsaicin, local anaesthetics
42
What are anticonvulsant drugs for chronic neuropathic pain based on and what channel do they target?
These are GABA analogues
Best current practice for chronic pain
Similar end-target to VGCCs, but different mechanism
43
Describe the original use, current use, common name, pharmacokinetic profile and side effects of gabapentin and pregabalin
Gabapentin and pregabalin-
• Originally used as anti-convulsants
• Proven efficacy vs placebo in several neuropathic pain conditions. The current best practice neuropathic pain medication
• Pregabalin (lyrica-pfizer) and gabapentin (Neurontin)
• Pregablin has better pharmacokinetic profile (better, more reliable absorption)
• Side effects- dose-dependent dizziness, sedation, incoordination, memory…
o And recent controversy about abuse potential
44
How do anticovulsants alleviate neuropathic pain? How/why does this work?
• Analogue of the neurotransmitter GABA- crosses the blood-brain barrier. Thus gets into brain and spinal cord
• Unlike GABA, gabapentin does not bind to GABAA or GABAB receptors, or the benzodiazepine site
o Don’t act through GABA receptors
• Gabapentin- binds to the α2δ subunit of some VGCCs, e.g. L, N and P-type
o VGCCs are made up of subunits. One of these, the α2δ, helps:
Trafficking and tethering of VGCC to the membrane
Channel activation
o When gabapentin binds to the α2δ subunit it:
Reduces VGCC trafficking to the membrane and tethering
Also reduces VGCC activation
• The end effect is reduced transmitter release from nerve terminals
• When this occurs on afferent nerve terminals-pain relief
45
Describe the mechanism of gabapentin and why it works well for neuropathic pain
Gabapentin-mechanism:
• In neuropathic state:
o VGCC α2δ-subunit expression enhanced on many afferent types
o More VGCCs, so more release from afferents and more pain transmission
• Gabapentin administration-
o Binds to the VGCC α2δ-subunit
o Decreases VGCC membrane expression in central terminals of afferents and they are less active
o Less neurotransmitter release when afferents are activated
o Reduces pain transmission
46
What is the advantage of targeting VGCCs for alleviation of neuropathic chronic pain
o Wide distribution of VGCCs in afferents so it affects allodynia (unlike opioids)
47
What is a limitation of gabapentin use for treatment of chronic neuropathic pain
o Takes time for effect as alters trafficking of VGCCs, not an acute inhibition of channel opening (such as by VGCC blockers, or opioids)
Can take days or weeks to feel full blown effect of drug
48
What are the types of voltage gated calcium channel blockers that can be used to treat chronic neuropathic pain? How are they administered and why?
Great for chronic pain, but has to be delivered spinally due to major systemic side-effects
Mediate neurotransmitter release
Multiple types- L, N, P/Q, T-type VGCCs
49
Where do N-type VGCC blockers act in neuropathic pain relief? How is it delivered due to this?
N-type VGCC in :
• Afferents, including central presynaptic terminals of afferents entering the spinal cord
• Wide distribution in afferents- so many sensory modalities
o Better pain relief, especially in chronic pain (e.g.allodynia)
• Wide distribution elsewhere- side effects
• Intrathecal (spinal delivery), as of systematic side-effects if given systematically
50
What are N-type VGCC blockers made from? Give an example
N-type blockers- toxins from cone snails e.g. ziconotide (prialt)
51
How do VGCCs relieve neuropathic chronic pain? What allows them to do so? Why are they such good neuropathic pain relievers?
Mechanism-
• VGCCs on all afferent terminal inputs into the spinal cord
• They have a crucial role in synaptic transmission
• In neuropathic state-
o VGCC expression is increased, so more release from afferents-> so there is greater pain transmission
• VGCC blockers:
o Bind to VGCCs
o Reduces calcium influx into afferent terminals
o Less transmitter release
o Less transmission- all modalities from nociceptors and non-nociceptors (allodynia)
• Due to wide distribution of VGCCs in afferents (both nociceptors and non-nociceptors), allodynia is targeted (better than opioids)
52
What older antidepressants were used to relieve neuropathic chronic pain
Older= tricyclic antidepressants (TCAs) e.g. amitriptyline, nortiptyline
53
What newer antidepressants are used to relieve neuropathic chronic pain
Newer= dual serotonin/noradrenaline reuptake inhibitors (SNRIs) e.g. duloxetine (Cymbalta), amy.nortriptyline and desipramine, venlafaxine (Effexor), milnacipran (savella) developed for fibromyalgia
• SNRIs have proven efficacy. Also some evidence for NRIs but SSRIs not so effective (that is blockade of noradrenaline is essential)
54
Describe the strengths and limitations of using antidepressants for neuropathic chronic pain?
Effective in several types of neuropathic pain
Commonly used but there are side effects
Presence of depression not required for their analgesic effect (that is, SNRI > SSRI). But may be particularly useful in patients with inadequately treated depression
55
Describe the mechanisms behind antidepressant allevation of chronic neuropathic pain
Mechanism-
• Blockade of NA and 5HT transporters- elevation of endogenous NA and 5HT
o More subtle effect than globally acting agonists, fewer side-effects
• Have some mixed actions at a number of receptors- 5HT2,H1/2, mAChR, etc.
• Some TCAs, such as amitriptyline, are also channel blockers (VGCS blockade)-possible analgesic mechanism
56
What is the role of 5HT antidepressants in modulating factors involved in chronic pain?
• 5HT-activates central descending systems (and also spinal action)- involved in mood modulation of pain systems
57
What is the role of NA antidepressants in modulating factors involved in chronic pain?
• NA- released from lateral descending pathways in spinal cord which inhibit ascending pain transmission
o In spinal cord, NA acts on α2 receptors, Gi/o-coupled receptor (inhibitory)
o α2-receptors on primary afferent terminals- reduce glutamate release from nociceptive afferents and possibly other afferents
o α2-receptors on dorsal horn neurons directly inhibit pain pathways
58
How do opioids treat acute pain?
Opioids- acute pain
• Mu-opioid receptors (uORs) on:
o Nociceptor terminals
o Ascending pain tract neurons
• Process-
o Morphine activates opioid receptors on nociceptor terminals
Reduces calcium influx (critical for transmitter release)
Reduces transmission onto ascending pain tract neurons and less pain signalling in the brain
o Morphine activates receptors on ascending pain tract neurons
Directly inhibits neurons
Reduces activation of ascending pain tract neurons
• Less ascending pain transmission= analgesia
• Opioids act at other sites- other parts of ascending, plus descending analgesic pathways
59
How do opioids alleviate chronic neuropathic pain and how does this work? What are its limitations and why?
Opioids and chronic neuropathic pain-
• If nerve is damaged, can get downregulation of opioid receptor
o Some reduction in opioid receptors
• Opioid receptors not on non-noxious afferents
o No effect on pain transmission from non-noxious afferents
• But opioid receptors on ascending pain tract neurons
o So some reduction in activation of ascending pain tract neurons
• As chronic neuropathic pain results in a bit less ascending pain transmission, opioids can only offer some analgesia- but less than for acute pain
60
Why are opioids not great for long term use in chronic pain?
Opioids and chronicity
• The problem is that chronic pain is a chronic condition, so drug treatment has to be chronic- this has led to the opioid crisis
o Addiction, overdosing, tolerance
61
What receptors does capsaicin act on? Give examples of receptors in that receptor class and what they do
• Acts on transient receptor potential ion channels- LGICs-
o TRPV1: senses painful heat (above 40 degrees)
Gets activated first in hotplate assay
o TRPV2- senses very painful heat (above 52 degrees)
o TRPM8- senses cool (below 28 degrees)
o TRPA1-senses some noxious chemicals and maybe intense cold
62
Where is TRPV1 located and what is its role?
• TRPV1
o Located on a major group of nociceptive afferents- in their terminals within the skin
o TRPV1- normal role is to sense painful heat (protective)
63
How is capsaicin administered for relief of neuropathic chronic pain?
• If apply capsaicin to skin, it results in intense thermal pain
o Nerves are damaged by capsaicin, but can be repaired quickly
• Capsaicin can be used for localised neuropathic pain- diabetic, shingles, amputation, etc
• Apply to skin- cream, patch
o Either high or low dose capsaicin is given- if a high dose is given, people usually have to be sedated as it hurts quite a lot
64
How does capsaicin relieve neuropathic chronic pain?
• Paradoxically it reduces neuropathic pain, particularly spontaneous pain
• Long-lasting mechanism- animal work suggests that is due to
o Dysfunction of nociceptors
o Depletion of nociceptors- loss of dermal afferent fibres
o Requires TRPV1 agonism. This is known because:
TRPV1 antagonists not as good
TRPV1 antagonists reverse neve loss caused by capsaicin
65
Is only a singular chronic pain treatment used most of the time?
o People often receive combination treatment
66
What other approaches besides pharmacology can be used to manage chronic pain?
• Multifaceted approach: in addition to pharmacology
o Psychological interventions- helping people manage mood/cognitive/sleep disorders
o Physiotherapy- movement
o Electrical stimulation- e.g. spinal cord (dorsal column)
Mimic pharmacological approaches
67
What are the animal models used to study neuropathic and inflammatory chronic pain? Describe
• Animal models
o Some basic models in rodents (rats, mice) mimic the injury associated with that form of chronic pain
o Neuropathic pain can be stimulated with:
Peripheral nerve injury e.g. sciatic nerve partial damage
Spinal cord injury
• Mechanical force on spinal cord, chemical injury
Disease e.g. diabetes (streptozotocin), cancer (bone cancer etc.)
Chemotherapy drugs, e.g. paclitaxel
o Inflammatory pain
Intraplantar inflammation, e.g. Complete Freund’s Adjuvant, carrageenan
• Inject these under the hind paw of the animal-> induces inflammation that lasts for differing amounts of time
68
What simple measures are used to measure amount of mechanical allodynia in mice? Give an example
Mechanical allodynia-sensitivity to mechanical stimuli that aren’t normally painful
• E.g. von Frey filaments (push onto paw)- measure the threshold force for pain-like response NB: range of hairs from 0.1-30 grams force
o Graded response
69
What techniques are used to measure amount of cold allodynia in mice? Give an example
Cold allodynia- sensitivity to cool stimuli that aren’t normally painful
• E.g. acetone drop (around 20 microlitres)- measure number of pain-like responses (acetone evaporates and cools paw).
70
What techniques are used to measure amount of mechanical hyperalgesia in mice? Give an example
Mechanical hyperalgesia-things that were painful that are now even more painful
• E.g. Randall-Sellito device (applies pressure to paw)-measure threshold force for paw withdrawal
o Normal rat will pull away at 200g
o Injured rat will pull away at 50g or less
71
What are simple measures of chronic pain reflexes?
Mechanical allodynia
Cold allodynia
Mechanical hyperalgesia
72
Are assays of acute pain the same as assays of chronic pain?
o Assays of acute pain are mostly different: e.g. for chronic pain the stimulus to assess allodynia is not painful in normal animals
73
What can be inferred from a dose-response graph for a drug?
o To assess potency and efficacy of drug, should construct dose-response curve of the drug
o Can determine therapeutic window of known side effects by constructing dose- response
74
What is the aim of analgesic drugs and why?
o Ascending and descending pathways
Ascending nociceptive pathway
Descending analgesic pathway
• Aim of analgesic drugs-
o Decrease ascending pain transmission (spinal cord and higher levels)
o Activate descending systems which then release transmitters in spinal cord that inhibit ascending pain transmission
75
What does injury of peripheral afferents cause and what are the consequences of this? (how does it cause neuropathic pain)
• Changes in neuropathic pain
o Injury of peripheral afferents causes:
Changes resembling those active during development= neurotrophins released (a role for the immune system)
Changes in the surviving peripheral afferents- all of them = nociceptors and non-noxious
o Consequences:
Reduced threshold to activate and increased sensitivity of afferents
• Reduced thresholds and increased pain responses= hyperalgesia
Some surviving nerve fire spontaneously (nociceptors and non-noxious)= spontaneous pain
Nerve sprouting and non-noxious afferents activate pain circuits= allodynia
There are also changes in the brain
o Both noxious and normally non-noxious afferents access pain pathways
Pain pathways are more sensitive
76
In what order are drugs for chronic pain used? What are the first, second and third line of defense?
• First line drug treatments are NPS
o Gabapentin, pregabalin, amitriptyline and duloxetine
• But others are used, or recommended, as 2nd/3rd line in various countries
o Ziconotide
o Opioids and tramadol
o Local- capsaicin and lignocaine (systemic)
o Cannabinoids
o Plus others
77
What percentage of people do migraines affect? Describe the gender division
• Affects 10-15% of population
| o 18% in females and around 6% in males
78
At what age do migraines usually begin/peak?
o Onset is usually in adolescence
| o Peak prevalence between ages 35-45
79
What are the two main types of migraines and what % of migraines are they responsible for?
o Classical migraine (with aura) is about 20%
o Common migraine (without aura) is about 80%
o Other forms including hemiplegic migraine
80
What are the phases of migraines?
```
o Interictal phase
Between attacks
o Prodrome and aura (in 20% of sufferers)
o Headache
o Termination
o Postdrome
```
81
What are the symptoms of a migraine?
• Symptoms of migraine
o Aura may precede headache
Zig-zag lines, blurred vision or blind spots (scotoma)
Sometimes aphasia (impaired production/comprehension of speech), chills, tremor, vertigo and parasthesia (weakness/numbness of limbs)
Progresses slowly across an area of the visual field
Unilateral, localised, throbbing
• May spread to contralateral side
Nausea (and vomiting), photophobia (light sensitivity), phonophobia (sound sensitivity) and prostration (have to lie down)
82
How long do migraines persist for?
o Headache persists 4-72 hours
83
What is the pathogenesis of migraines?
• Pathogenesis
o Headache originates from extracerebral structures- meninges and large arteries
Innervated by nociceptive sensory nerves of trigeminal pathway
o Migraine now considered a neurovascular disorder
Highlights important interaction between nerves and blood vessels
84
What are the causes of migraines?
• Causes-
o What triggers migraines is not well understood- dependent on individual
o May be:
Abnormal neuronal discharge triggered by biochemical event
Many environmental triggers
May be heritable (but polygenic)
Rare familial cases involve genetic mutations in calcium channel or sodium/potassium/ATPase
Maybe a form of hyperalgesia, allodynia or sensitisation
• May get lowered threshold to previously innocuous stimuli
85
What are the anatomical components in the neurogenic inflammation theory of migraine?
• Neurogenic inflammation theory of migraine
o Trigemino-cerebrovascular system
Trigeminal nerves/ganglia
Major vessels for regulating cerebral blood flow
Smaller vessels in meninges
o Trigeminal ganglion cells innervate:
Large cranial vessels
Smaller meningeal vessels
Meninges
Trigeminal nucleus caudalis and spinal cord trigeminocervical complex
• Trigeminocervical complex- includes Spinal nerve I, spinal nerve II, trigeminal nucleus caudalis
86
Describe the peripheral sensitization process of the neurogenic inflammation theory of the migraine
o Process in the periphery- (peripheral sensitization)
Something triggers constriction of intracranial blood vessels
Constriction causes antidromic release of CGRP from ophthalmic division of trigeminal nerves, as well as substance P, nitric oxide and NKA release
• These vasodilate intracranial and meningeal blood vessels
o Results in plasma protein leakage
• Cause mast cell degranulation
o Results in secretion of serotonin, bradykinin, histamine and prostaglandins
• Leads to sterile inflammation, which causes neurogenic inflammation and peripheral sensitisation
o Sterile inflammatory process causes sensitisation. lowering the threshold to pain responses
Circular process- positive feedback
87
Describe the CNS sensitization process of the neurogenic inflammation theory of the migraine
o Process in the CNS- (central sensitization)
Trigeminal nerve fibres provide a pathway for nociceptive information originating in the meninges to be transmitted to CNS
• Trigeminal nerves release further CGRP
The trigeminal nerves synapse on the trigeminal nucleus caudalis (in the brainstem) via the spinal tract
The trigeminal nucleus caudalis synapses on the ventroposterior medial thalamus via the trigeminothalamic tract
• Important region of the brain involved in experience of pain, nausea, vomiting associated with migraine
The ventroposterior medial thalamus synapses on the somatosensory, insula and cingulate cortices
• Register pain at a conscious level
88
What types of fibres are trigeminal nerves?
C fibres
89
What are C fibres and what can they be triggered by?
C fibres-small unmyelinated fibres that conduct polymodal sensory information from the periphery to the CNS
o Can be triggered by thermal, mechanical or chemical stimuli that the body considers noxious
90
What is the process of non-sterile inflammation (how does inflammation occur after tissue injury)?
o When there is non-sterile inflammation (tissue injury)
Release of inflammatory mediators: bradykinin, 5HT and prostaglandins
This triggers C fibres (act on C fibres)
This triggers release of substance P and CGRP (calcitonin G related peptide)
This leads to mast cell degradation and subsequent release of histamines
This makes C fibres sensitized
• Synapse on dorsal horn of spinal cord and activate ascending pain pathway
91
How are CGRPs correlated with migraines?
• CGRP is released in parallel with pain of migraine
• As CGRP concentration increases, migraine pain increases
o Concentration correlates with intensity of headache experienced
92
What is 5-HT?
• Monoamine-indoleamine
93
How many 5-HT1 receptors are there?
• 7 receptor types (5-HT1-7)
94
What are the two types of receptors important for migraines?
• Receptors important for migraines-
o 5-HT1 receptors
o 5-HT2 receptors
95
Describe 5-HT1 receptors in terms of activation product, coupled protein and isoforms
o 5-HT1 receptors
Inhibitory
Gi protein coupled
Isoforms: 5-HT1A,1B,1D,1E,1F
96
Describe 5-HT2 receptors in terms of activation product, coupled protein and isoforms
o 5-HT2 receptors
Excitatory
Gs protein coupled
Isoforms: 5-HT2A, 2B, 2C
97
How was the role of 5-HT during migraines elucidated?
90% of serotonin comes from the gut
o Platelet concentration of 5-HT falls-plasma concentration in 5-HT isn’t as important in influencing arterial tone but may influence other aspects of migraine
9% of serotonin from platelets
1% of serotonin from brain
o Migraine sufferers show perturbation of 5-HT metabolism and transmission
98
Where are 5-HT1b and 5-HT2 receptors found and what are they responsible for in migraines respectively?
o 5-HT1B and 5-HT2 receptors found on intracranial blood vessels
5-HT1B -> vasoconstriction
5-HT2 -> indirect vasodilation via release of nitric oxide when activated
• 5-HT2 receptors on meningeal blood vessels
99
What types of receptors are trigeminal ganglion and nucleus cell bodies/terminals rich with? Describe
o Trigeminal ganglion and nucleus cell bodies and terminals rich in 5-HT1B/1D/1F receptors
5HT1 receptors are inhibitory
5-HT1B/1D on trigeminal ganglion cell body
5-HT1D on trigeminal ganglion presynaptic terminal
5-HT1B/1D/1F on trigeminal nucleus caudalis cell body
100
What drugs were used to treat migraines in the pre-19th century and what was the problem with those drugs?
```
• Pre-19th century (all these cures are painful)
o Potassium cyanide
o Strychnine
o Atropine
o Digitalis
o Hashish
o Hemlock
```
101
What drugs were used to treat migraines in the post-19th century and what was the problem with those drugs?
```
• Post-19th century
o Ergot derivative (ergotine)
Fungus derivative (found on wheat)
Precursor to LSD
Hallucinogen
```
102
What drugs are used to treat acute migraine attacks?
Non-steroidal anti-inflammatory drugs (NSAIDs)
Ergotamines
Triptans
103
What are the limitations of NSAIDs for migraine management?
Non-steroidal anti-inflammatory drugs (NSAIDs)
• More effective when given early during an attack
• Not good for severe migraine
104
Describe the biochemical pathway of inflammation (production of inflammatory agents)
• Process of inflammation:
o Membrane phospholipids produces arachidonic acid via phospholipase A2 activity
o Arachidonic acid produces:
5-HPETE via 5-lipoxygenase
• Produces leukotrienes
Cyclo-endoperoxidases via cyclo-oxygenase activity
• Produces thromboxane, prostacyclin and prostaglandins
105
How do NSAIDs provide migraine pain relief?
• NSAIDs inhibit cyclo-oxygenase (inhibit production of inflammatory agents thromboxanes, prostacyclin and prostaglandins
o By inhibiting prostaglandin synthesis, decreases inflammation (reduces neurogenic inflammation)
106
What are the targets of ergotamines and why are they effective in migraine management?
• E.g. ergotamine, dihydroergotamine
• 5-HT1D partial agonists
• Also act at other monoamine receptors (5-HT1, 5-HT2, D1,D2, α1 and α2 receptors)
• Cause vasoconstriction (including coronary vessels)
o Contraindicated in cardiovascular disease
• Block trigeminal nerve transmission
107
What are the advantages and limitations of using ergotamines for migraine management?
• Adverse effects include nausea and vomiting
o Because of their location and role of the area postrema in the brainstem
• Can be given into a headache (not necessarily before, but can be given during)
• Whilst they are effective, not great for everyone
o Can amplify side effects and cannot be taken if pregnant (fetal damagers)
108
Which drugs are ideally used for acute migraine management?
Triptans
| • First line of treatment
109
What are the targets of triptans and why are they so effective in acute migraine management?
• Many types available with different half lives (depending on their functional group)
• 5-HT1B/1D/1F agonists
• Inhibit trigeminal nerve transmission peripherally (ganglia) and centrally (trigeminal nucleus caudalis)
o Inhibit release of neuropeptides from trigeminal ganglia (CRGP, SP and NO release)
o Inhibit trigeminal ganglia activation
o Inhibit trigeminal transmission
o Inhibit trigeminal nucleus caudalis activation
• Inhibit release of vasoactive peptides from meningeal blood vessels
o Reduce neurogenic inflammation
• Stimulate 5-HT1B receptors-> vasoconstriction: helps restore normal vascular tone
• Reduce both peripheral and central sensitization
110
What are the advantages and disadvantages of using triptans for acute migraine management?
• As these drugs only act on 5-HT, will relieve nausea and vomiting as well (little side effects)
• Limitations-
o Contraindicated in ccardiovascular disease due to vasoconstrictor properties (can’t take them if you have cardiovascular disease)
5-HT1B receptors on coronary arteries
o 70-80% of patients respond to triptans within 2 hour administration: can take 30-60 minutes to work
There is a treatment-resistant group
o 20%-40% of people taking them get a headache occurrence 24 hours after the initial relief (rebound)
111
When is prophylactic treatment needed for migraines?
2 attacks of migraine per month
112
What are the abilities of prophylactic drugs for migraines?
o These drugs can reduce migraine intensity and can reduce migraine frequency (by 50%)
113
What drugs can be used for prophylactic management of migraines?
```
Beta-adrenoceptor antagonists
Antidepressants
5-HT2 receptor antagonists
Anticonvulsants
Calcium channel antagonists
CGRP receptor monoclonal antibodies
```
114
How do beta-adrenoceptor antagonists work to manage prophylactic migraines? What are their limitations?
```
Beta-adrenoceptor antagonists
• E.g. propranolol, metoprolol
• Mechanism of action unknown
• Contraindicated in asthma
o Cannot be taken with asthma
• Side effects include fatigue and bronchoconstriction
```
115
How do antidepressants work to manage prophylactic migraines?
• Tricyclic antidepressants
• 5-HT and NA transport inhibitors -> leads to increased 5-HT and NA concentration-> increased inhibition of spinothalamic neurons due to increased activity of rostroventromedial medulla
o Blocking 5-HT reuptake- further activates descending pain pathway which inhibits ascending pain pathway
• Rostroventromedial medulla- contains 5-HT cell bodies that originate in the nucleus of Raphe magnus
o Part of the descending pain pathway
• When rostroventromedial medulla activated, it projects to dorsal horn of spinal cord- further inhibits incoming noxious stimuli
• By blocking 5-HT uptake, can increase activity of the descending pain pathway and block activation of ascending pain pathway
116
How do 5-HT2 receptor antagonists work to manage prophylactic migraines? What are their limitations?
* E.g. pizotifen, cyproheptadine, methysergide
* Prevents 5-HT2 receptor-induced vasodilation (secondary to NO) and consequent inflammation
* Adverse effects include weight gain, antimuscarinic effects (not completely selected for 5-HT2)
117
How do anticonvulsants work to manage prophylactic migraines? What are their limitations? Under which theory of migraines does this work under?
Anticonvulsants
• E.g. sodium valproate, gabapentin, topiramate
• Range of mechanisms
• Reduce cortical excitability by altering ion channel activity
o Reducing cortical excitability= reduce incidence of migraine attacks
o Decrease trigeminal neurotransmission
o Decrease cortical spreading depression (a phenomenon observed in migraine with aura)
• Teratogens (can’t take the if you are pregnant)
118
How do calcium channel antagonists work to manage prophylactic migraines? Under which theory of migraines does this work under?
Calcium channel antagonists
• E.g. nifedipine, verapamil
• Decreasing calcium entry reduces cellular excitability
• In alignment with the theory that migraines are caused by cortical excitability
119
How do CGRP receptor monoclonal antibodies work to manage prophylactic migraines?
CGRP receptor monoclonal antibodies
• Erenumab
• Potently and specifically competes with CGRP-> inhibits function of CGRP receptor
• Acts on CGRP receptor
• Proven to be effective for patients with frequent attacks of migraine
120
What needs remain for improved drugs for acute migraines? Give examples
• Need remains for improved drugs for acute migraine
o Greater selectivity
o Fewer side effects
o Better response rate
• Need for drugs acting selectively at receptor isoforms
o Drugs acting selectively at 5-HT1D/1F receptors on trigeminal ganglion cells
Removes 5-HT1B-induced constriction of coronary and cerebral arteries
Lasmiditan- 5-HT1F antagonist under investigation
o CGRP antagonists- liver toxicity
o Drugs inhibiting neuropeptide release
121
What is addiction?
• Addiction- a state where drug use continues in spite of serious potential or actual harm to the user or others
o Compulsive drug seeking
122
What two factors are the drivers of long-term drug addiction?
o Counter-adaptations and tolerance is driver to long-term addiction
When chronic use is stopped these counter-adaptations result in withdrawal and drug craving
Need to consider counter-adaptations in treatment strategy
123
Describe the drugs and percentage of drug use in Australia in the last 12 months
```
o In the last 12 months
Alcohol- 84% (39% weekly, 7.2% daily)
Nicotine- 17% (1.5% weekly, 15.9% daily)
Cannabis- 11%
Methamphetamine/cocaine-5%
Pharmaceuticals- 4%
• Opioids, benzodiazepines
Ecstasy- 4%
Inhalants- 0.6%
Heroin-0.5% (1/2 in treatment)
```
124
What issues are there in studying illicit drug use?
o Issue in drug use studies that people may underreport illicit drug use
125
What age group has the highest drug use in Australia?
20-29 year olds
126
Why do people take drugs?
```
• People take drugs:
o To feel good
New sensations (MDMA/ecstasy)
New experiences (LSD)
Pleasure (euphoric drugs- opioids)
Community (sharing) (alcohol/nicotine)
o To feel better (a lot of alcohol in this category)
Escape problems (worry, despair, boredom)
Lessen anxiety
Reduce fear
Reduce depression
To feel something
```
127
What is the problem with people continuing to take drugs?
• People continue to take drugs to continue to feel good or better but:
o Need more drug to achieve same effect (drug tolerance)
o Start feeling bad when the drug wears off (Drug withdrawal)
o Start wanting the drug all the time (drug craving)
o Drug use starts to interfere with daily life
128
What is the cost of alcohol?
o Alcohol- 18.3 billion dollars
129
What is the cost of nicotine?
o Nicotine- 31.5 billion dollars (1/8 of disease burden in Australia)
130
What is the cost of illicit drug use?
o Illicit drug use- 8.2 billion dollars
131
How can % of people addicted by calculating using drug use data?
• Work out % of addicted people using drug use data by looking at how many people are actually using the drug
132
What natural rewards are the reward centres triggered by?
• Activated by natural rewards- food, sex and water
133
What areas produce reward when electrically stimulated and why?
• Electrical stimulation of VTA (ventral tegmental area) and nucleus accumbens is rewarding
o VTA have dopaminergic cell bodies and send their axons to the nucleus accumbens and prefrontal cortex to release dopamine in these areas: associated with reward and reinforcement
134
What system do major drugs of abuse stimulate? How? What does this produce?
* All major drugs of abuse stimulate dopamine activity in this neural system
* Microinjection of heroin, cocaine and nicotine in these areas is rewarding although molecular mechanisms of action differ
* Anticipation of drug use promotes dopamine release in this system in animals and humans
* Reward centres are there to respond to environmental stimuli that are pro-survival so that we are encouraged to do these activities again
* Drugs of abuse disrupt natural reward signal so that high dopamine concentration extracellularly-> means more activation of dopamine receptors and higher reward
135
What are the brain circuits associated with addiction and what aspect are they responsible for?
• Brain circuits associated with addiction
o Reward prediction and pleasure-initial drug use
Nucleus accumbens and ventral pallidum
o Cognitive control- decisions about drug use
Prefrontal cortex
Anterior cingulate cortex
o Motivation drive and salience attribution-drive and importance: assign the reward value to an object
Orbitofrontal cortex
o Learning and memory- associate drug use with particular environment or use
Amygdala
Hippocampus
136
Is addiction more commonly associated with anatomical or cellular changes?
• There are morphological changes due to addiction, but more on a cellular level than a gross anatomical level
137
What are the risk factors of addiction/factors that make people susceptible to addiction?
```
o Complex disease- mix of biological and environmental factors determine susceptibility
• Risk factors of addiction
o Biology/genes
Genetics
• Neurotransmitter proteins
• 40%-60% of your vulnerability
• People can have more impulsive traits than others
Gender
• Being male is an increased risk factor-> due to later developmental timeline of prefrontal cortex
Mental disorders
o Environment
Chaotic home and abuse
Parent’s use and attributes
Peer influences
Community attitudes
Poor school achievement
o Drug
Use of administration
Effect of drug itself
Early use
Availability
Cost
```
138
What are approaches for long-term harm minimization to treat heroin/opioid addiction?
```
• Medically assisted detox
• Replacement therapy-
o Mu(μ)-agonist
o Mu(μ)-antagonist
o Mu(μ)-partial agonist
• Anti-craving
• Cognitive behavioural therapy-some evidence
• Vaccines-
```
139
Can cultural/society influences influence treatment method of opioid addiction?
• Cultural/society attitudes influences treatment
140
How does medically associated detox work in treating heroin/opioid addiction and what are its advantages/disadvantages?
• Medically assisted detox
o Provide support/drugs to reduce symptoms of withdrawal signs
o Clonidine (alpha2 agonist), benzodiazepines
o High relapse rate
But doesn’t do anything about craving
o Not a great option for long-term harm minimisation
141
How does mu agonist therapy work in treating heroin/opioid addiction and what are its advantages/disadvantages?
μ agonist with long half-life t1/2=22 hours (good for dosing)
• People will come in every day and need to ensure they have taken the dose
Users don’t like it as much as heroin
• Due to pharmacokinetics
Stops withdrawal and craving without intoxication at correct dose
Overdose possible- multiple doses of naloxone (antagonist) needed
Works best with counselling and social support
Used for over 30 years- results in low illicit drug use, injecting prostitution, high retention
• Very good harm minimisation outcomes
Used by 70% of opioid treatment patients in Australia
In some countries heroin available too
• Harm-minimisation heroin
142
How does mu antagonist therapy work in treating heroin/opioid addiction and what are its advantages/disadvantages?
o Mu(μ)-antagonist-Naltrexone
Orally active antagonist
Occupies receptor and prevents agonist binding-> doesn’t produce rewarding effects
Need to detox before use
Poor compliance because although it occupies the receptor, it doesn’t do anything about the craving
Poor outcomes for long-term reduction of opioid use
143
How does mu partial agonist therapy work in treating heroin/opioid addiction and what are its advantages/disadvantages?
o Mu(μ)-partial agonist-Buprenorphine
Occupies receptor and prevents full agonists like heroin producing effect
Partial agonism should reduce craving
Less overdose risk than methadone
Prevents withdrawal in all but the most addicted
• Some people will want to go straight back to heroin
Not all patients stable on buprenorphine (may change to methadone)
• Trickier to stick to
More freely available than methadone-doesn’t have the same abuse potential as methadone
• Don’t need to go to clinic as much
Can be combined with naloxone to prevent injection
• To make sure people are taking it orally-> if injected and go straight to the brain, buprenorphine will not have an effect
Used by 30% of opioid treatment patients in Australia
144
What are the disadvantages of using vaccines to treat opioid addictions?
• Vaccines-still in development but may have some problems as antagonists
o Need a vaccine for every type of opioid
o Don’t do anything about opioid craving
145
What are the best approaches/most successful treatments to reduce illicit opioid use and why?
• Best approaches/successful treatments to reduce illicit opioid use (harm minimization) target craving:
o Agonist and partial agonist method as they address the cravings
Some occupation of receptors means craving circuit is not going into overdrive
146
What are the two main characteristics of a highly addictive opioid?
• Characteristics of a highly addictive opioid
o Quick entry into the brain
o Efficacious agonist
147
Why is heroin such a highly addictive opioid and what changes does it have to undergo to be so?
Heroin and its metabolite 6-monoacetylmorphine are more lipophilic than morphine= faster into brain= greater rush
Heroin has low affinity for opioid receptors-> needs to be made into morphine by chopping off acetyl group (which replaced OH of morphine) before it can act at receptor
Pharmacokinetic property of heroin that makes it a very desirable elicit opioid
148
What is opium derived from and how long has it been used?
o Opium is derived from the juice of the opium poppy, Papaver Somnifferum
o Opium extract has been used for thousands of years
149
When was morphine first isolated from opium?
o 1806 morphine was first isolated from opium
150
By whom and when was heroin first synthesised?
o Heroin was first synthesised in 1874 by CR Alder Wright
151
What was the original use of heroin?
o 1898-1910 heroin was sold by Bayer as a non-addictive substitute for morphine and as a cough suppressant
152
What is the colour of street heroin?
o Street heroin is white, brown powder or black tar
153
What was the initial use of oxycodine and which crisis is it responsible for now? Why? What is the oxycodine situation in Australia?
• Prescription opioids-oxycodine
o Heroin use stable at 0.5% and was dominant opioid abused
o 1995 slow release oxycodone and morphine came on the market- crushed for injection
o Higher use resulted in higher diversion and misuse- massive increase in last 15 years
o 2.5% of Australians report recent use of pain-killers for non-medical purposes
154
How can heroin be self-administered?
o Can be snorted, injected or smoked- all routes can result in addiction
155
What is the result of heroin administration?
```
o Injection results in a surge of euphoria but also:
Dry mouth
Warm flush of skin
Heaviness of limbs
Clouded mental function
Nausea/vomiting
```
156
How is heroin administered for optimal enjoyment?
o Non-injection may miss the rush but get other effects
| o Euphoria is better when drug is smoked or injected than taken orally
157
Where are opioid receptors expressed in the brain and how is this related to addiction?
• Opioid receptors are expressed throughout the brain
o Expressed in regions of the ventral tegmental area, nucleus accumbens and amygdala
o Expressed in regions important for initial effects of drugs and other subsequent effects
158
What is the effect of heroin stimulation of the brain (where, how and consequences)
• Heroin stimulation of the reward pathway
o Receptors for opioids are located on the GABA interneurons (mu receptors) and not on the dopaminergic neurons
o Therefore, morphine bind on mu receptors of GABA cells and dampens down their activity-> they release less GABA-> there is less inhibition-> neighbouring dopamine neurons are more excited->release more dopamine in the nucleus accumbens and prefrontal cortex
o The speedy response increases the associative power: easier to address euphoric feeling to heroin cue
Very important in addiction
o But there are also a lot of opioid receptors in the medulla
Areas in the medulla control respiratory depression, blood pressure, arousal, nausea/vomiting and constipation
159
What are problems with regular heroin use (especially from the street)?
• Problems with regular heroin use:
o Street drug means dose unknown- 60% users overdose
o IV users have high rate infection- 60% HepC
o Injection of contaminated/toxic street drugs result in:
Collapsed veins
Heart and heart valve infections
Abscesses
Liver and kidney disease
Clogged blood vessel damage target organ
Due to both the fact that it’s a street drug (contamination) and heroin
o Poor outcomes for use during pregnancy
o Social exclusion as spend time chasing drug/money
o Contact with criminals
160
What is the impact of chronic heroin use?
• Chronic heroin use results in neuroplasticity
o Tolerance
o Counter-adaptations
161
Why can tolerance occur as a consequence of chronic heroin use?
Decreased response to same dose
| Can be due to changed receptor response
162
What counter-adaptations can occur as a consequence of chronic heroin use and what are the consequences of these
o Counter-adaptations
Attempt to compensate for ongoing/frequent opioid inhibition
• If acutely take morphine, will activate opioid receptors and inhibit adenylyl cyclase
• Apply morphine over 24 hours-> adaptations in terminals/cells to restore cAMP levels up to baseline (can involve restoration of adenylyl cyclase activity)
o But when stop taking drug, opioid inhibition of adenylyl cyclase is stopped but the adaptative increase of adenylyl cyclase is still occurring
cAMP overshoot seems to be extremely important in opioid withdrawal and cravings
• cAMP is stimulatory-> can drive neurotransmitter release during opioid withdrawal which drive withdrawal behaviours
o Increased cAMP levels due to loss of opioid inhibition but continuation of adaptation mechanism means that an increased amount of GABA is released-> dopamine release is inhibited-> results in dysphoria
Result in craving and physical withdrawal if opioid use stops
• Due to aberrant excitability of cells due to previous drug use
163
What are the symptoms of heroin withdrawal and how long do they last?
• Withdrawal is intensively aversive and unpleasant
o Restlessness
o Muscle and bone pain
o Diarrhea
o Vomiting
o Cold flashes with goose bumps (cold turkey)
o Kicking movements (kicking the habit)
• Short-term (relative to craving) and only lasts for a few days but impediment to completely stopping
164
What are the cellular mechanisms of opioid withdrawal?
• Cellular mechanisms of opioid withdrawal
o Higher activity of adenylyl cyclase-> promotes activity of GABA transporter which depolarises the neurons and makes them release a lot more GABA
Subvert the neural circuits that they are regulating
Inhibit more strongly cells in the hypothalamus and medulla-
• Hypothalamus- change in temperature responses
• Medulla- dysregulation of pain responses
165
What are the end points of addiction studies?
• Need to define end points for study- could be
o Abstinence
o Reduced use
o Harm minimization
166
Why are addicted populations very difficult to study?
• Testing any drug for effectiveness produces a variety of responses
• Addicted populations are very difficult to study
• Results highly variable between studies
o Due to population or heterogeneity of addictions
167
How is tobacco used?
• Tobacco- can be used in cigarettes, pipes, snuff, chewing tobacco
o Cigarettes has the fastest rise time
168
Why are cigarettes the most common form of tobacco use? What other things besides tobacco is there in cigarettes?
• Cigarettes- most common
o Efficient and highly engineered
o Rapidly deliver nicotine (first peak <10 seconds after smoke inhalation)
o High associative learning
Fast change in occupation of receptors and activation of reward centres is extremely good for associative learning
• Smoke contains more than 4000 chemicals including nicotine, carbon monoxide, formaldehyde, cyanide and ammonia
169
Describe tobacco usage in Australia vs now and the groups which have an increased risk of using tobacco
• Tobacco usage-
o In 1964, almost half of Australians over the age of 15 smoked
o In 2000s, now only 16% of Australians smoke
Higher use in 40-49 year olds, males, low SES, Aboriginal/Torres Strait Islander, remote communities, mental health issues, people in prisons, people who inject drugs
Australian use is low compared to many other countries
170
What are the cellular and physiological effects of tobacco/nicotine? Are these all due to nicotine/tobacco?
o Nicotine increases release of adrenalin from the adrenal glands
Increased blood pressure
Increased heart rate
Increased respiration
Increased blood glucose
o Increases dopamine release in reward centres
o Increases alertness, reduces anxiety and tension
o May be other active compounds- e.g. acetaldehyde which produces other active effects
171
What kind of drug is nicotine?
o Nicotine agonist at nicotinic receptors- multiple sub-types
172
Describe how nicotine stimulates the reward pathway
o Nicotine stimulation of the reward pathway-
Nicotinic receptors on the dopaminergic terminals in VTA, when nicotine binds to the receptors, it will depolarise the terminals and stimulate neurotransmitter/dopamine release from these terminals into the nucleus accumbens and prefrontal cortex
But nicotinic receptors- also on excitatory and inhibitory inputs to dopamine neurons
173
What are the problems with smoking/nicotine use?
o Legal freely available drug-can be financial stress (pack a day > $7000 a year)
o Problems due to smoke and nicotine
Smoke contains >4000 chemicals including- nicotine, carbon monoxide, formaldehyde, cyanide, ammonia. Many of these are carcinogenic
o 1/3 all cancer deaths in Australia due to smoking
Lung cancer
Chronic obstructive pulmonary disease
Ischaemic heart disease
Stroke
Oesophagus cancer
Other
o 1/6 pregnant women smoke- increases complications, premature birth, stillbirth, SIDS (sudden infant death syndrome)
174
How is alcohol produced and why is it used so much?
* Alcohol is produced by the fermentation of yeast, sugars and starches
* Ethyl alcohol, or ethanol, is an intoxicating ingredient found in beer, wine and liquor
* Used by most cultures in the world
* Use is entwined in social/cultural activities which promotes its use
175
How is alcohol absorbed?
• It rapidly absorbed from the stomach and small intestine into the bloodstream
176
Describe alcohol use in Australia
• Use of alcohol in Australia-
o Overall use- not abuse/dependence (84% yearly, 7.2% daily)
o Australian usage is in middle of world use rates
177
What are the effects of alcohol as alcohol consumption increases?
```
• Alcohol experience
o Initial effect-
Drinker feels more relaxed or excited
o Intake increases
Drowsiness
Loss of balance
Poor coordination
Slower reaction times (critical when driving or operating machinery)
Slurred speech
Slowed thought processes
Nausea and vomiting
o More alcohol consumed-
Unconsciousness
Inhibition of normal breathing-this may be fatal, particularly as the person may vomit and can suffocate if the vomit is inhaled
```
178
What are the cellular actions of alcohol?
• Alcohol actions are complicated-no specific target
o Enhance GABAergic and glycinergic synaptic transmission-results in increased inhibition
o Inhibition of Ca channels
o Activation of K channels
o Inhibition of glutamate receptor function
o Inhibition of adenosine transport
o Can make neuronal membranes unstable and wobbly- will not function properly
o Genetic differences in these proteins contribute to addiction potential
179
How does alcohol stimulate the reward pathway?
• Alcohol stimulation of reward pathway
o Many possible sites- likely disinhibition plays a role
Inhibits GABA release so more dopamine release
o Alcohol promotes release of endogenous opioids and endocannabinoids-> involved in alcohol reward
o Starts with increases in dopamine in nucleus accumbens then will start engaging other learning and top-down inhibition
180
What risk factors make people susceptible to alcohol addiction
• People change from alcohol use to misuse to addiction due to:
o Psychiatric disorders- especially anxiety and depression (possibly due to different protein expression or self-medication)
o Severe stressful event
o Genetic contribution
Highest evidence for genetic contribution
181
What are the problems with alcohol dependence?
• Problems with alcohol dependence
o Not an illicit drug
o Engage in high-risk behaviours- drink driving
o Inability to engage in normal behaviours
o Neurological degeneration- including cortex and cerebellum
Morphology of the brain is dramatically changed- ventricles become much larger
o Liver disease- which may result in cirrhosis, failure
o Gastritis-damage to GIT mucosa
o Respiratory depression- risk of pneumonia, lung abscesses
o Immune suppression
o Increased cancer risk-mouth, larynx, oesophagus
o Endocrine changes
o Pregnancy-impairs fetal development
o Males-often feminized and impotent
182
What counter-adaptations does the brain make in response to alcohol and what are the consequences of these?
• Counter-adaptations to alcohols
o Adaptations in the reward centres result in craving
o Adaptation in other brain regions result in withdrawal
Develops after 8-10 hours
Tremor, nausea, sweating, fever
Hallucinations
Then seizures, possibly death (up to 5%)
Then confusion, agitation, aggression
o Serious withdrawal treated with benzodiazepines (allosteric enhancers of GABA receptors)
183
How does chronic alcohol use change the reward pathway?
• Chronic alcohol changes the reward pathway
| o Dopaminergic neurons have more AMPA receptors at synapses- more sensitive to glutamate
184
What percentage of smokers attempt to quit, why, and is this easy? Why?
* Most tobacco users know it is harmful and want to stop
* Each year 20% of smokers attempt to quit but most require multiple attempts (5-6) for long term success
* Like opioid addiction neuro-adaptations occur that result in physical withdrawal and craving if smoking stopped
185
What are the withdrawal effects of nicotine addiction?
• Withdrawal- irritability, attention difficulties, sleep disturbances, increased appetite
o Cells have started to develop counter-adaptations: when stop smoking, people will experience withdrawal effects
186
How long does nicotine craving last?
• Craving persists beyond withdrawal and is often intense for first months
187
What are the approaches for long-term abstinence employed for nicotine addiction?
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• Approaches for long term abstinence
o Agonist therapy/nicotine replacement
o Partial agonist-Varenicline (alpha4beta2), cytisine
o Anti-craving
o Antagonist- mecamylamine
o Vaccines- antibodies produced that bind nicotine and prevent it getting into the brain
o Cognitive behavioural therapy
o Others such as anti-depressants
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188
How does agonist therapy work for long-term abstinence from nicotine addiction, and what are its advantages/disadvantages?
o Agonist therapy/nicotine replacement
Patch, gum nasal spray, inhaler-> eliminates smoke exposure (harm minimization (like methadone))
Agonist at receptor therefore reduces craving
Uncouples temporal cues of smoking from delivery of nicotine-encourages long term abstinence
Gum can satisfy oral craving and decrease weight gain
When added with behaviour therapy it increases abstinence
With gum, 22% abstinent at a year (compared to 15% placebo)
E-cigarettes-
• Significant concerns about the purity of e-cigarettes: nicotinic substance may have carcinogenic contaminants in it
• Does not uncouple temporal cues of smoking-bad for long term abstinence
189
How does partial agonist therapy work for long-term abstinence from nicotine addiction, and what are its advantages/disadvantages?
o Partial agonist-Varenicline (alpha4beta2), cytisine
Reduces craving/reduce smoking satisfaction (similar to buprenorphine)
• Partially binds to nicotinic receptor
Newer evidence suggests slightly better than NRT- highest success of treatments 25% at one year
• A bit more successful than the nicotine gum
Main side effects are nausea, sleep issues but generally well tolerated
Past suicide concern, but that concern has now largely dissipated
190
How does antagonist therapy work for long-term abstinence from nicotine addiction, and what are its advantages/disadvantages?
o Antagonist- mecamylamine
Blocks nicotine reward but no effect on craving
Side effects- significant drowsiness, dizziness and constipation
Some evidence may help reduce smoking when combined with nicotine replacement therapy
191
How does vaccine therapy work for long-term abstinence from nicotine addiction, and what are its advantages/disadvantages?
o Vaccines- antibodies produced that bind nicotine and prevent it getting into the brain
No effect on craving
No better than placebo
May have role in at risk groups-may be used as a preemptive measure
192
What and how does anti-depressant therapy work for long-term abstinence from nicotine addiction, and what are its advantages/disadvantages? Give an example off 2 drugs
Bupropion
• Widely used antidepressant
• Unclear mechanism (DAT, NET,NR,antag)
o Need to find right setpoint
• Modest reduction craving (may be due to inhibiting dopamine uptake)
• Similar efficacy to nicotine replacement therapy of 22% stopped smoking at 1 year (less than varenicline)
• Limitations- lowers seizure threshold and causes sedation
Nortryptyline is a tricyclic antidepressant
• NERT and SERT inhibitor
• 2nd line due to significant side effects
SSRI and MAOI are completely ineffective
Should be combined with cognitive behavioural therapies and strategies
193
What are the best strategies for long-term abstinence of nicotine?
• Best strategies for long term abstinence-
o Nicotine replacement therapy (agonist)
o Partial agonist: Best option
o Bupropion
o Cognitive behavioural therapy in combination with agonist/partial agonist/bupropion
194
What are potential treatments for alcohol addiction?
* Medically assisted detox- very important
* Block alcohol reward/craving
* Make alcohol unpleasant to take
* Unknown mechanisms- acamprosate, topiramate
* Behavioural therapy
195
Why are agonists, partial agonists, antagonists and vaccines not an option for treating alcohol addiction?
not an option due to non-specificity of alcoholic targets
196
How does blocking alcohol reward/craving work as a potential treatment for alcohol addiction and what are its advantages/disadvantages?
• Block alcohol reward/craving
o Reward in part due to endogenous opioids
o Naltrexone is opioid receptor antagonist- reduces craving for alcohol
o Either oral daily or extended release injection monthly
o Reduced relapse (placebo 43%, naltrex 28%) and reduces heavy drinking. Modest effects
o Potentially hepatotoxic at high doses (Injections better)- can be a limitation
197
How does making alcohol unpleasant to take work as a potential treatment for alcohol addiction and what are its advantages/disadvantages?
o Disulfiram- very unpleasant-flush, palpitations, nausea
Due to high level of acetaldehyde
o Inhibits aldehyde dehydrogenase-> keep broken down products of acetaldehyde in the liver
If take alcohol, higher proportion gets stuck in acetaldehyde phase-> makes alcohol unpleasant
o Daily dose but poor compliance
o Monitored dosing best
o Used for high risk occasions-> take when going to places with lots of alcohol
o Can’t blind studies
o No effects on craving
198
How does acamprosate work as a potential treatment for alcohol addiction?
o Acamprosate
May act via inhibition of NMDA receptor (possibly alters plasticity)
May also act to change GABA or glutamate synaptic transmission
Similar efficacy to naltrexone
199
How does topiramate work as a potential treatment for alcohol addiction and what are its advantages/disadvantages?
o Topiramate
Antiepileptic
May alter phosphorylation of sodium, calcium, GABA and glutamate receptor/channels
Unclear mechanism in addiction- may increase GABA and reduce glutamate synaptic transmission
Significant reduction in drinking but variable results
Some evidence that people with polymorphisms in kainate receptors have better treatment outcomes
200
What are the best approaches for long-term abstinence from alcohol addiction?
• Best approaches for long-term abstinence are:
o Medically assisted detox
o Block alcohol reward/craving
o Acamprosate
201
Describe the treatment options for addiction in general, how they work, their advantages/limitations
• Targets craving (generally most successful)
o Agonist- reduces craving through signalling by binding to similar receptor as drug, efficacious, harm minimization
o Reduce craving mechanism- changes craving plasticity or mechanism, some efficacy
o Partial agonist- reduces craving, blocks abuse, efficacious
• Block response
o Antagonist- blocks abuse, low efficacy, poor compliance
o Vaccine- in development, may have same problems as antagonists, may have some role in at risk groups
• Make drug unpleasant-poor compliance, limited use
