Opioids Flashcards
(147 cards)
1
Q
What are the medical uses of opioids?
A
Pain = anti-nociceptive
Safe and effective when used appropriately
2
Q
How do opioids block pain?
A
They block afferent transmission in the spinal cord/brainstem
Periaqueductal gray
3
Q
What is a lethal mix of drugs?
A
Opioids and sedatives
4
Q
What are the 3 major sources of opioids?
A
Natural
Semi-synthetic
Synthetic
5
Q
What are natural sources of opioids?
A
Opium - alkaloid-laden latex
Morphine, codeine
6
Q
What are semi-synthetic sources of opioids?
A
Heroin, hydrocodone, hydromorphone, oxycodone, krokodil
Buprenorphine, etorphine
7
Q
What are synthetic sources of opioids?
A
Methadone, meperidine
Tramdol
Fentanyl
8
Q
What are major narcotics?
A
Morphine (10%)
Codeine (0.5%)
9
Q
What is more potent: morphine or opium?
A
Morphine is 10x more potent than opium
10
Q
What does CYP2D6 convert codeine to in the brain and liver?
A
Morphine
11
Q
What is the result of deficient 2D6?
A
Codeine has no effect
12
Q
What is the result of overactive 2D6?
A
Morphine intoxication
13
Q
How are semi-synthetic opioids produced?
A
Produced by modifying a naturally-derived chemical
14
Q
What makes heroin 10x more lipophilic than morphine?
A
Two acetyl groups
15
Q
What is naloxone?
A
Opioid receptor antagonist
16
Q
What is methadone?
A
mew agnoist
17
Q
When was naloxone synthesized?
A
1960s
18
Q
What does naloxone do?
A
Reverses morphine effects
19
Q
What did Pert and Snyder discover in the brain?
A
Opioid receptors
20
Q
What are the 4 classes of pre and post-synaptic opioid receptors?
A
mew, delta, kappa, and ORL-1
21
Q
What do pre-synaptic opioid receptors do?
A
Modulate NT release
22
Q
What do post-synaptic opioid receptors do?
A
Alter membrane potential
23
Q
How were opioid receptors discovered?
A
Radioligand binding in brain tissue slices
24
Q
Where were opioid receptors found in the brain?
A
Striatal area
Lateral aspect of medial nucleus
Amygdala
Dorsal pons
Periaqueductal gray
Spinal cord
25
How many endogenous opioids are known?
18 peptide ligands and endorphins
26
What are endogenous opioids involved in?
Pain, emotional responses, euphoria, eating, stress, seizures, and alcohol dependence
27
Where are MOR (mew opioid receptors) expressed?
VTA, NAc
PAG
Hypothalamus
LC
Brainstem
Pupils
GI tract
28
What binds MOR?
Most opioids
29
What are MOR involved in?
Reward, addiction
Analgesia
Euphoria
Anxiolytic
Respiration, BP
Nausea
Itch
Constriction
Constipation
30
Where are DOR (delta opioid receptors) expressed?
Neocortex
Striatum
NAc
Substantia nigra
Olfactory bulb
31
What are DORs bound by?
Enkephalins
32
Where are KORs (kappa opioid receptors) expressed?
Pituitary
Hypothalamus
PAG
Spinal cord
Others
33
What are KORs bound by?
Endorphins, dynorphins, PCP, ketamine
34
Where are orphan opioid receptors expressed?
Limbic system
Spinal cord
35
What are orphan opioid receptors bound by?
Buprenorphrine
36
How potent is fentanyl?
100x more potent than morphine
40-50x more potent than heroin
Highly lipophilic
37
Why are fentanyl derivatives even more potent?
Increased affinity for mu receptors + enhanced entry into the brain = higher potency
38
How are opioids distributed?
Lipid solubility
Liver
Lungs
Spleen
GI tract
Brain
39
How are opioids absorbed?
Inhalation
Injection
Ingestion
Insufflation
Sublingual
Rectal
40
What is the chasing the dragon method?
Heat up on tin foil and inhale the fumes
More commonly smoked in a pipe
41
What is chasing the dragon linked to?
Leukoencephalopathy
Spongiform brain tissue with holes
Progresses to ataxia, apathy, akathisia, inability to speak or move
Appears like metal toxicity
42
How is heroin injected?
Mixed with some water on a spoon, acid or heat might help dissolve, drawn up through a cotton ball to remove particulates
43
Why does injecting heroin leave track marks?
Damage to vessels by the needle
Uneven blood flow, thrombosis, clots form
Vessels collapse, need to find a new one
44
Where are opioids metabolized?
Brain
Liver
45
How are opioids excreted?
Kidneys
Feces
46
What are the pharmacokinetics of heroin?
Faster distribution to the brain = higher potency
May be snorted
Metabolized to morphine in the brain
Two intermediates = 3-MAM and 6-MAM
6-MAM binds MOR but 3-MAM does not
6-MAM is not naturally occurring
47
What are the psychological effects of acute opioid use?
Euphoria, well-being, tranquillity
Mental clouding, impaired judgement, decreased attention and memory
48
What are the brain effects of acute opioid use?
Reduced pain
Inhibited cough and slowed respiration
Increased sedation
Constricted pupils
49
What are the cardiovascular effects of acute opioid use?
Dilated blood vessels and lowered blood pressure
50
What are the effects of acute opioid use on the skin?
Lowered body temp
Flushed skin
Itching
51
What are the effects of acute opioid use on muscles?
Muscle relaxation
52
What are the effects of acute opioid use on the renal system?
Decreased urination
53
What are the effects of acute opioid use on the GI tract?
Decreased GI movements and secretions
Constipation
54
What are the effects of acute opioid use on the reproductive system?
Decreased testosterone and estrogen
Lowered sperm production
Diminished libido
55
How does acute opioid use affect the medulla?
Lowers BP
Hypotension, bronchoconstriction, itching from histamine release
56
Why do the pupils constrict with opioid use?
mu/kappa receptors in oculomotor nucleus
57
What is neonatal abstinence syndrome?
Babies are irritable, vomit, diarrhea, seizures, in respiratory distress due to withdrawal
58
How is NAS treated?
Physical contact reduces hospital time
59
What comes from separate Opr genes?
Mu, delta, kappa opioids receptors
60
What do ORL orphan display in relation to other opioid receptors?
Structural homology
61
What are most opioid effects due to?
Mu receptor
62
What do all endogenous opioids contain?
N-terminal tyrosine residues
63
What does morphine mimic?
The structure of tyrosine
64
What type of receptor are all opioid receptors?
GPCRs, linked via Gi/o
65
What does ligand binding on opioid receptors trigger?
alpha-GTP loading
66
Which subunits dissociate after ligands bind opioid receptors?
Aloha and betagamma subunits
67
What does alpha-GTP inhibit?
Inhibits adenylate cyclase which reduces [cAMP] which inhibits protein kinase A
68
What does alpha-GTP activate?
PLCbeta and MAPK pathways
69
What do beta gamma subunits activate (opioids)?
Activates GIRK3 causing hyperpolarization
70
What do beta gamma subunits block?
Ca channels causing reduced intracellular Ca and suppressing neurotransmitter release
71
What does chronic exposure to morphine result in?
G-protein coupled receptor kinase mediated phosphorylation of opioid receptors and binding of beta-arrestin which leads to desensitization
72
What is biased agonism?
Differential activation of signalling pathways by OR ligands
73
What is classic opioid signalling due to?
Biased G-protein effects
74
What does morphine keep low?
Receptor phosphorylation
75
What happens when opioids like fentanyl produce high receptor phosphorylation
Receptor internalization, increase tolerance and dependence
76
What do non-synonymous mutations in MOR affect?
Signalling and function
77
What do non-synonymous mutations in MOR affect?
Signalling and function
78
What receptors are involved in opioid-mediated analgesia?
MORs
79
Where are MORs found in the path pathway?
Thalamus, PAG, rostroventral medulla, dorsal horn of spine
80
What is the pain pathway?
Cortex -> thalamus (doesn't need to tho) -> PAG -> RVM -> DHs
81
What is the mechanism of opioid-mediated analgesia?
Activation of MOR on GABA-ergic RVM interneurons
82
What does tonic firing from the RVM to the dorsal horn do?
Sets the pain afferent threshold
83
What does the activation of MOR on GABA-ergic RVM interneurons do?
Reduces inhibition of RVM OFF projecting cells to the spinal cord
Elevated signaling out of the RVM to the spinal cord
Decreased afferent pain transmission into the spine
84
What does activation of MOR on RVM ON projecting cells to the spinal cord do?
Decreases outputs to the dorsal horn of the spine, adding to analgesic effect
85
What plays an indirect role in modifying pain transmission?
The amygdala
86
What happens in the dorsal horn during opioid-mediated analgesia?
Pre-synaptic MOR activation of afferent pain neurons reduces NT release and pain transmission
87
What neurotransmitters play important roles in opioid-mediated pathways in addictiveness?
Glu, DA, GABA
88
Are NMDARs or AMPARs more important in opioid-mediated pathways in addictiveness?
AMPARs
89
What is the role of hippocampal mu receptors in opioid-mediated pathways in addictiveness?
Disinhibition of CA1 and dentate gyrus cells via GABA-ergic interneurons
Astrocytes also express MORs and activation causes Glu release onto CA1 neurons
Associate conditioning
90
What do D1-like receptors in the NAc co-express?
Dynorphin
91
What do D2-like receptors in the NAc co-express?
Enkephalin
92
How does one become tolerant of opioids?
Opioid receptors are down-regulated
Molecular uncoupling disrupts OR signals
93
What are pharmacokinetic changes?
Changes in distribution or metabolism
94
What are pharmacodynamic changes?
Changes in receptor expression, neuroplasticity
Cellular
95
What is learned tolerance?
Behaving sober when intoxicated
96
What symptoms of opioid use subside over time?
Vomiting, euphoria, respiratory depression
97
What symptoms of opioid use do not subside over time?
Constipation and pupil constriction
98
Where might an individual have a lower tolerance to opioids?
Different/strange locations and isolation
99
What are common techniques to measure tolerance in rats?
Drug treatment regimen to induce tolerance
Tail immersion test
Hot plate test
100
What is used to gauge psychological addiction?
Behavioural sensitization
Escalating behavioural responses to a stimulus like a drug of abuse after a drug-free period
101
What are the factors that contribute to sensitization?
Receptor density
NT levels
Cell signalling deregulation
102
What is behavioural sensitization is driven by?
NAc inputs
Driven by DA-ergic and Glu-ergic projections from the VTA nad PFC to the NAc
103
Blocking what impairs sensitization in rats?
D1 in the NAc
104
What does morphine sensitization coincide with?
Elevated D1 expression in NAc shell plus elevated ERK1/2 MAPK activity
105
What do AMPA/NMDAR antagonists do?
Block the induction of sensitization but not the expression of it
106
What are some characteristics of opioid desensitization?
Rapid
Direct consequence of drug-receptor activation D
Depends on Ca and K activities
Sustained desensitization reduces acute effects but enhances intracellular signaling
107
What are some mechanisms of opioid desensitization?
G-protein uncoupling, alpha-GTP binding is reduced in morphine-treated animal
gRK phosphorylation of MOR causes beta-arrestin binding and reduced euphoria/analgesia
108
What are the symptoms of heroin withdrawal 6 hours after last dose?
Craving, anxiety
109
What are the symptoms of heroin withdrawal 612-14 hours after last dose?
Yawning, sweating, watery eyes, runny nose
110
What are the symptoms of heroin withdrawal 614-16 hours after last dose?
Pupils dilate, goose bumps, hot/cold flashes, fever, diarrhea, aching, no appetite
111
What are the symptoms of heroin withdrawal 2-5 days after last dose?
Weakness, depression, insomnia, elevated BP/HR/respiration, restlessness, hyperglycemia
112
When do heroin withdrawal symptoms subside?
By the 5th day
113
What acute effects of heroin is rapid tolerance developed?
Euphoria, analgesia, respiratory, vomiting effects
114
What acute effects of heroin is slow tolerance developed?
Itching
Urinary retention
115
What contributes to the affective signs of withdrawal?
The mesolimbic system
116
What does naloxone injection to NAc do?
Cause conditioned place aversion
117
What do D2-like receptor agonists injected into the NAc do?
Reduces somatic withdrawal signs
118
What is decreased in the NAc during withdrawal?
DA
119
What are the affective symptoms of opioid withdrawal?
Dysphoria
Anxiety
Irritability
Cravings
120
What symptoms of opioid withdrawal are important targets for therapy and why?
Affective symptoms to prevent relapse
121
How long can anxiety due to opioid withdrawal last?
Up to 80 days
122
How long do conditioned place aversions last?
20 days
123
What opioid receptors are present in the LC?
MOR and KOR
124
What does chronic opioid use do to the LC?
Suppressed LC activity
Less noradrenaline is released
125
How does LC normalize activity in the presence of opioids?
Tolerance
126
What happens to the LC when we remove opioids?
It becomes overactive
Causes noradrenaline surge
127
What opioid withdrawal symptoms does the LC contribute to?
Sweating
Chills
Stomach cramps
Emesis
Diarrhea
Muscle pain
Runny nose and eyes
128
Where is the paragigantocellularis (LPGi) located?
In the rostroventral medulla (RVM)
129
What does the LPGi do?
Stimulates LC via glu-ergic inputs
Modulates opioid withdrawal symptoms
130
What does adolescent opioid exposure do?
Alters longterm activity in brainstem regions and increases severity of adult withdrawal symptoms
131
What are clonidine and lofexidine?
Alpha2-adrenoceptor agonists
132
How does clonidine and lofexidine treat opioid withdrawal?
Prevents noradrenaline release via pre-synaptic alpha2 autoreceptors
Targets the LC and its projections
133
What is buprenorphine?
Semi-synthetic partial agonist
134
How does buprenorphine treat opioid withdrawal?
Used for maintenance
Outcompetes morphine and blocks heroin with mild effects
Taken orally, 37 hour half-life, safer
135
What happens if a user tries to inject buprenorphine?
Contains suboxone = 4:1 buprenorphine-to-naloxone sublingual
The effects are blocked if injected because naloxone does not cross the mucosal membrane
136
What is methadone?
NMDAR antagonist
137
How does methadone treat opioid withdrawal?
Used for maintenance
Long half-life
No adulterants
Mild euphoria, causes constipation
138
Why are adulterants put in street drugs?
To increase bulk or modulate/enhance rushes
139
What are the features of talcum powder and powdered milk as an adulterant?
Inert, increases mass, decreases purity
140
What are the effects of quinidine/quinine as an adulterant in opioids?
Bitter taste mimics heroin
Hypotensive effect feels like a heroin rush
141
What are the dangers of fentanyl and carfentanil as adulterants in opioids?
Fentanyl is found ing >50% of street opioids and is 100x more potent than morphine
Carfentanil is 10000x more potent than morphine
142
What is the main mechanism of depressed respiration in opioid overdose?
Reduce pre-Botzinger complex output
143
What is the role of the RTN/pFRG?
Coupled oscillator that influences motoneurons that produce breathing
144
What factors contribute to depressed respiration in opioid overdose?
Unresponsiveness
Upper airwar obstruction due to reduced upper airway muscle tone = genioglossus
Central respiratory depression = Pre-BotC effects
145
What is the opioid triad?
Coma, depressed respiration, pinpoint pupils
146
What receptors does naloxone target?
MOR, KOR, DOR
147
What is the mechanism of naloxone?
Competitive antagonist at opioid receptors
Short-acting due to metabolism
