opioid 2 Flashcards
1
Q
what are the 4 distinct endogenous opioid-like substances
A
enkephalins
endorphins
endomorphins
dynorphins
2
Q
what are the 3 opioid receptors
A
delta
mu
kappa
3
Q
what is the main receptor for enkephalins
A
delta
4
Q
what is the main receptor for endorphins
A
mu
5
Q
what is the main receptor for endomorphins
A
mu
6
Q
what is the main receptor for dynorphins
A
kappa
7
Q
where do the endogenous opioid-like substances come from
A
different precursor proteins
8
Q
what do all endogenous opioid-like substances CONTAIN and where
A
tyrosine at N terminus
9
Q
what are 3 functions of endogenous opioid-like substances
A
neurotransmitters
neurohormones
neuromodulators
10
Q
what are 4 things that endogenous opioid-like substances are involved in
A
pain
placebo response
acute stress response
social attachment
11
Q
what kind of G protein is the opioid receptors
A
Gi
12
Q
how many transmembrane domains in opioid receptors
A
7
13
Q
what are mu receptors like (physically)
A
large, open binding pocked may allow for rapid exchange of ligans
14
Q
what are 4 things mediated by mu receptors
A
- euphoria
- respiratory depression
- analgesia
- dependence
15
Q
what is 1 thing mediated by the delta receptors
A
analgesia
16
Q
what are 2 things mediated by kappa receptors
A
dysphoria, some analgesia
17
Q
what are the 2 main things Gi does (not ion stuff)
A
inhibit adenylate cyclase
reduce cAMP
18
Q
what are the 2 ions things Gi does
A
inhibit Ca++ influx
enhance K+ outflow
19
Q
which type of Ca++ channels is inhibited by Gi
A
N type
20
Q
what does K+ outflow do to membrane
A
hyperpolarization
21
Q
what do opioids do to neuronal excitability
A
decrease
22
Q
what do opioids do in the reward pathway
A
increase DA in NAc by inhibiting GABA induced inhibition
23
Q
how do opioids increase DA in NAc
A
by inhibiting GABA induced inhibition
24
Q
why do some studies show that there isnt much of a increase in DA in addicts (like 3 flaws in the studies)
A
- they used subQ injections
- individuals were on methadone
- people were addics
25
what is the % DA increase with morphine in opioid-naive individuals
400%
26
what are the things you get physiologically tolerant to with opioids
analgesia, vomiting, euphoria, respiratorry depression
27
what are the things you dont get physiologically tolerant to with opioids
constipation and pupil constriction
28
what kind of dose over baseline can addicts take with little respiratory depression
50X!
29
what is biased agonism
when one agonist preferentially activates certain signalling pathways while another at the same receptor preferentially activates different pathways
30
what are 2 examples of biased agonism
G-protein mediated and beta-arrestin mediated
31
what do different biased agonists do to the receptor
stabilize different receptor conformations that interact with different proteins
32
what happens to activated receptors
they are phosphorylated by kinases
33
what attracts beta-arrestin
activated receptors
34
what do beta-arrestins do
inhibit G-protein signalling to prevent further activation of pathways
35
what happens to receptors bound to beta-arrestins
they can be removed from the membrane or participate in other signalling pathways
36
which pathway does morphine favor (beta-arrestins or G protein)
G-protein
37
which pathway does fentanyl favor (beta-arrestins or G protein)
beta-arrestin
38
what degree of phosphorylation for G-protein pathway
low
39
what degree of phosphorylation for beta-arrestin
high
40
which pathway has a low degree of phosphorylation
G-proteins
41
which pathway has a high degree of phosphorylation
beta-arrestin
42
what 4 effects are the beta-arrestin pathway
down-regulation
side effects
tolerance
dependence
43
what are the beta-arrestin subtypes
1 2 3 4
44
what does GRK do
add phosphate groups (kinase) to agonist-bound receptors
45
what does GRK stand for
G-protein related kinase
46
what happens to tolerance and side effects with beta-arrestin knock out
less side effects and tolerance
47
what happens to tolerance and side effects with drugs that favor the G protein path
less side effects and tolerance
48
what happens to receptors with short term opioid exposure
the receptors are internalized but recycled to the surface in minutes or hours
49
what happens to receptors with long term opioid exposure
they are internalized and destroyed
50
does morphine or fentanyl cause more receptor degradation and why
fentanyl cause it activates beta-arrestins instead of G proteins
51
what are 3 things beta-arrestin binding causes (after G receptor activation and GPCR phosphorylation)
- block further G protein signalling
- redirects signalling to its own alternative pathway
- targets receptors for internalization
52
if G protein does more the analgesic effect, what effects do the beta arrestins cause
respiratory depression, tolerande, bad GI, insufficient analgesia
53
if beta arrestins cause respiratory depression, tolerande, bad GI, insufficient analgesia,
what do the G proteins do
analgesia
54
what causes hyperalgesia with long term treatment of opioids (4)
increase adenylyl cyclase, PKC PKS and NMDA
55
what does the NDMA upregulation in long term opioids do
causes hyperexcitable to pain
56
why does cell make more adenylyl cyclase with long term opioids
to try to make more cAMP (opioids are Gi)
57
what composes the opioid overdose triad
coma
depressed respiration
pinpoint pupils
58
what % of overdose deaths had another depressant in them
85%
59
what % of overdose deaths had a benzo in them
45%
60
what % of overdose deaths had alcohol in them
36%
61
what is naloxone
fast acting opioid antagonist
62
how long does naloxone last
20-40 minutes
63
what can naloxone reverse
resp depression
coma
miosis
death
64
what happens if you give naloxone to someone who is using opioids
it will precipitate withdrawal
65
what happens if you give naloxone to someone who doesnt use opioids
no significant effects
66
how fast can you get opioid withdrawal symptoms
four hours or less after previous use
67
how fast can you feel quite ill after using opioids
608 hours
68
how many injections of opioids do you need daily to stop feeling ill
3-4
69
why do they feel so much pain in opioid withdrawal
because your Body starts to upregulate pain pathways
70
what correlates with intensity and duration of withdrawal symptoms
intensity and duration of drugs effect
71
what kind of withdrawal for heroin
intense but short
72
what kind of withdrawal for methadone
mild but prolonged
73
what are the first symptoms for withdrawal
cravings for drugs, anxiety
74
what are the 2nd symptoms for withdrawal
yawning
sweating
tearing eyes
running eyes
75
what are the 3rd symptoms for withdrawal
2nd + pupil dilation, goosebumps, cold hot flashes, aching, appetite loss
76
what are the 4th symptoms for withdrawal
3rd + insomnia high BP high temp high BP respiration nausea
77
what are the 5th symptoms for withdrawal
4th+curled up position, vomiting, diarrhea, weight loss, spontaneous ejaculation, increased blood sugar
78
what does chronic opioid use do to NA release and how
less NA release because it suppresses firing rate of adrenergic neurons in locus coeruleus
79
what happens to NA firing in tolerance and how
it normalizes because it up-regulates adenylyl cycles and PKA production
80
what happens to NA production when opioids are removed and why
massive NA release and withdrawal symptoms due do hyperactive adrenergic neurons in locus coeruleus
81
what may cause many of the withdrawal symptoms
the massive NA release when you stop taking opioids
82
what are 8 symptoms of the massive NA release with withdrawal
```
chills
sweating
stomach cramps
diarrhea
emesis
muscle pain
runny nose
runny eyes
```
83
what happens with cAMP levels when you take opioids acutely
decrease at first
84
what happens with cAMP levels when you take opioids after awhile
they slowly start to rise as your body upregulates other processes
85
what is clonidine
alpha-2 agonist
86
what is lofexidine
alpha-2 adrenergic agonist
87
how do alpha-2 agonists work
prevent NA release from locus coeruleus
88
where are alpha2 receptors (where in neuron)
presynaptic (autoreceptors)
89
where are alpha2 receptors (where in brain that affect withrawal)
locus coeruleus
90
does clonidine and lofexidine address the psychological issues of withdrawal
no
91
what are the 2 alpha agonists used for withdrawal
clonidine and lofexidine
92
what is a physical side effect of clonidine and lofexidine
low BP
93
what stage of withdrawal is clonidine and lofexidine used for
detox
94
what can clonidine and lofexidine be used alongside with
methadone or buprenorphine
95
what is the class of opioid of methadone (natural synthetic)
synthetic
96
what is the half life of methadone compared to heroin
longer
97
why is methadone good
clean pure free, longer half life
98
is methadone euphoric
yes but not a lot compared to heroin
99
does methadone still cause constipation
yes :(
100
what is the mode of consumption of methadone
oral
101
what is another effect of methadone besides opioid
NMDA glutamate antagonist
102
what does methadone do to NMDA
antagonize
103
what is the mechanism of action of buprenorphine
partial agonist
104
what is the class of opioid of buprenorphine (natural synthetic)
semi-synthetic
105
what receptors does buprenorphine target the most
mu
106
what is the half life of buprenorphine
37 hours
107
how many doses per week of buprenorphine is needed
1-3
108
what is the affinity to mu of buprenorphine vs heroin
higher affinity
109
does buprenorphine have strong effects at mu receptor
no but it has a high affinity
110
can you get respiratory depression with buprenorphine and why
not really cause its just a partial agonist
111
what does buprenorphine do to the effects of heroin and how
blocks because it has a higher affinity at mu receptors
112
does buprenorphine cause constipation
yes in some people
113
is buprenorphine better than methadone
yes
114
why is buprenorphine better than methadone
- lower OD risk
- lower recreational use
- better tolerability
115
whats suboxone
buprenorphine and naloxone (4:1)
116
how is suboxone administered
sublingually
117
what happens when suboxone is taken sublingually
naloxone has no effect and the partial agonist effects of buprenorphine are felt
118
what happens when suboxone is taken via injection
naloxone will cause withdrawal effects
119
how can a patient taking suboxone cause rapid withdrawal symptoms
if the patient isnt in active withdrawal (taking an agonist, they will go from 100-50% and feel terrible)
120
why do patients have to be in active withdrawal to take suboxone
taking suboxone would cause rapid withdrawal symptoms (cause its a partial agonist)
121
which drugs will have an effect with subligual use in suboxone
buprenorphine only (not naloxone)
122
which drugs will have an effect with IV use in suboxone
naloxone prevents buprenorphine effects so it causes withdrawal
123
how does suboxone get absorbed
mucosal membranes
124
do all agonists cause the same degrees of G-protein effects or b-arrestin
no, diff agonists cause diff degrees of these effects
