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BMSc - Neuropharmacology and Behaviour > Opioid Addiction > Flashcards

Opioid Addiction Flashcards

1
Q

What opioids are classified as opium alkaloids?

A

Morphine
Codeine
Thebaine
Oripavine

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2
Q

What is heroin?

A

Refined opium; diamorphine

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3
Q

Does heroin bind directly to the mu receptor?

A

No; it must cross through the BBB to be modified by enzymes to morphine

Rapid absorption and rapid decay

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4
Q

Describe endogenous pepties?

A

Endorphins; beta endorphin
Enkephalins e.g. met-enkephalin
Dynorphin
Endomorphins

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5
Q

What are the 3 different opioid receptors?

A

Mu
Delta
Kappa
7 membrane spanning regions. Agonist binds to extracellular part of transmembrane protein resulting in a conformational change that is transduced across the membrane

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6
Q

Which opioid receptor is linked to addictive behaviour?

A

Mu

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7
Q

Which gene codes for mu receptors?

A

OPRM1

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8
Q

Which G protein do all opioid receptors activate?

A

Gi/o

Inhibitory alpha subunit - inhibit adenylyl cyclase activity

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9
Q

Describe the basic cascade when opioid receptors are activated?

A

Replacement of GDP by GTP - dissociation of alpha subunit from beta/gamma subunit

Decreased cAMP
Decreased Ca2+
Increased K+
MAPK (kinase)

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10
Q

Which additional receptor can opioid receptors recruit?

A 
Beta-arrestin receptors 
This acts to activate MAPK
Increased Src 
Increased AKT 
These allow different cellular signalling events to occur

Interact with beta adrenergic receptors

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11
Q

What is the role of beta-arrestin in membrane trafficking?

A

Endocytoses the mu receptor into the cell

Thought to be involved with opioid tolerance

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12
Q

What are the mechanisms of morphine tolerance?

A

Receptor tolerance
Cell tolerance and withdrawal
System tolerance and withdrawal
Synaptic plasticity in tolerance and withdrawal

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13
Q

Describe the mechanism of receptor tolerance in opioid tolerance?

A

Reduction in number of surface receptors (endocytosis using beta-arrestin)
Reduced coupling of receptor to adenylyl cyclase and other effector molecules
Receptor protein is less abundant
Receptor RNA is downregulated
Reduced inward K+ movement

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14
Q

Describe the mechanism of cell tolerance/ withdrawal in opioid tolerance

A

With tolerance comes withdrawal potential

Initially with opioid use; cAMP levels decrease (Gi)
The cell will begin to adapt/ show tolerance and the cAMP levels will begin to rise
When naloxone is administered/ morphine stopped abruptly the adaptations via the cell will be unmasked resulting in a large jump in cAMP production - hypertrophy of cAMP signalling

Naloxone precipitated withdrawal

Withdrawal; enhanced pain response, increased agitation, increased excitation, aggressive

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15
Q

Describe system tolerance and withdrawal in opioid tolerance

A

Systems feedback adaptations occur in opioid-sensitive networks to tolerance and withdrawal
New synapses are formed that have opposing effects of those of receptor stimulation

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16
Q

Describe the role of synaptic plasticity in tolerance and withdrawal

A

Changes in synaptic plasticity driven by altered presynaptic release probability, which is well established as opioid sensitive GABAergic synapses
Mechanisms resembling LTP +/- LDP involve AMPAR insertion into synapses which produces long term changes in synaptic strength
Formation of new memories associated with drug taking activity

Permanent changes in synapses results in life long craving

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17
Q

How long does positive reinforcement last in drug misuse?

A

Around 10 mins
Returns to a state that is non euphoric but will still be heavily sedated (profound hypotension) - lethargy
There will be a strong incentive to return to the euphoric state
However, the euphoric feeling/ positive reinforcement will reduce in length
Brain will become less responsive to the drug

There will be no pleasure to the drug anymore but withdrawal will occur when it is stopped

Positive reinforcement turns to negative reinforcement

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18
Q

In terms of the behavioural signs; describe the development of drug dependence

A

Acute drug state; reinforcement, reward

Chronic drug state; tolerance, sensitization, dependence

Short-term abstinence; withdrawal

Long term abstinence; craving, stress-induced relapse - up to 80% of opioid users will relapse

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19
Q

In terms of molecular changes; describe the development of drug dependence

A

Acute drug state; increase mesolimbic DA and 5HTergic

Chronic drug state; receptor adaptation; increased cAMP (hypertrophy of cAMP), increased CREB (cAMP dependent transcriptional changes), increased FosB

Short term abstinence; increased glutamergic, NAergic, decreased DAergic and 5HTergic, increased CRF

Long term abstinence; synaptic remodelling, increased CRF and glucocorticoids

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20
Q

What areas of the brain are involved in binge/ intoxication?

A

VTA
Thalamus
Globus pallidus
Substantia nigra

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21
Q

What areas of the brain are involved with withdrawal/ neg effect of drugs?

A

Brain stem
NA, CRF
Hypothalamus (stress response)
Central nucleus of amygdala

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22
Q

What areas of the brain are involved with preoccupation/ anticipation “craving”?

A

Hippocampus
PFC
Insula
Basolateral amygdala

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23
Q

What is the allostatic model of drug dependence?

A

Impulsive reward seeking behaviour (drug experimentation)
Repeated exposure; hedonic effects diminish
Thereafter compulsive drug use to avoid withdrawal becomes dominant

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24
Q

What is allostasis?

A

The process of achieving stability/ homeostasis through physiological or behavioural change
Carried out by; alteration of HPA axis, ANS, cytokines

An altered hedonic set point - flattened reward system in absence of drugs pushing the homeostatic set point

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25
Q

What is the typical cycle of heroin high to withdrawal?

A

Around 6 hours

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26
Q

What is the role of methadone maintenance?

A

Changes patients from heroin to methadone (mu agonist with a more stable pharmacokinetic profile)

Longer half life than heroin - taken once a day

Causes tolerance of receptor; if they do take heroin then they won’t recieve the same high

Prevents a high or withdrawal to enable individual to return to a more normal environment

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27
Q

What are the therapies for opioid use ``disorder?

A

Psychosocial therapies; CBT
Methadone (mu receptor agonist)
Buprenorphine (mu receptor partial agonist and kappa receptor antagonist). Combined with naloxone in suboxone with reduce potential for diversion
Naltrexone (opioid antagonist)
Detoxification - symptomatic relief; anti-inflammatory’s, antiemetics, anti-diarrhoeal
Lofexidine (alpha adrenergic receptor agonist)

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28
Q

What is the action of opioids in the central dopaminergic pathway?

A

Acts inhibit the presynaptic GABAergic neuron onto the DA neuron; increasing DA release in N. Acc
Patch clamp studies show GABA mediated IPSCs are inhibited by morphine in the post synaptic DA neurons == inhibition of the inhibitory neuron equals an increase in DA release

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29
Q

What is the evidence that inhibitors of opioid receptor activity can reduce addictive behaviour?

A

Attenuation of cocaine and heroin seeking behaviour by mu receptor antagonism
Alcohol seeking behaviour = naltrexone
Reduction in binge eating behaviour
Only drug for tx of gambling addiction is naltrexone

Opioid receptors are involved in the reward pathway in all addictive behaviour

30
Q

What evidence is there to show that mu receptors are required for morphine reinforcement?

A

Knockout mu receptor mice have no significant difference after conditioning in the amount of time the mouse spends in the morphine chamber

31
Q

Describe condition place preference

A

Day 1; habituate on either side of box
Day 2/3/4; conditioning (AM saline, PM morphine 10mg/kg s/c) - saline in one chamber, morphine in other chamber
Day 5 test; see what side the mouse moves to
Condition place preference

32
Q

What is the evidence that mu receptor number affects the potency of morphine’s condition place preference?

A

In comparison to WT mice; MOP +/- (heterozygous; contains 50% of mu receptor potential) at the same dose (10mg/kg s/c) have no significant difference CPP
HOWEVER; if the dose of morphine is increased to 10 mg/kg s/c; there is a significant difference and a change in CPP

More morphine is required in MOP +/- to cause CPP; morphine has become less potent but has the same efficacy

Downregulation of mu receptor = reduction in potency of mu opioid receptor agonists. Consistent with tolerance; where individuals require more opioid to initiate same DA release

33
Q

In summary; what are mu receptors required for?

A 
Analgesia
Resp depression 
Immunosuppression 
Constipation 
Tolerance, withdrawal, dependence
Reward/ reinforcement
34
Q

What is the role of mu receptors and beta arrestin?

A

They recruit it
Allows for endocytosis of mu receptors and cascade signalling
Evidence to show that beta arrestin is involved in resp depression, constipation and addictive qualities of opioids

35
Q

What evidence is there to show that the absence of beta-arrestin reduces morphine tolerance (conversely; beta arrestin is responsible in part for tolerance in opioid use disorders)

A

Knockout beta arrestin mice respond differently to WT

Mouse tail dipped in hot water; amount of time that it takes for mouse to remove tail is an indicator of pain threshold

Morphine causes a prolongation of tail withdrawal due to analgesic properties - as dose of morphine increases, the tail withdrawal is prolonged

In WT; there is a dose dependent curve to tail withdrawal, On day one; morphine is potent. However the animals develop tolerance; (lose potency but efficacy remains)

In beta arrestin knockout mice; there is no tolerance development. Tail withdrawal latency is longer

36
Q

What is the evidence to show that there is basal mu analgesia in the absence of beta arrestin 2?

A

There is an increased latency in tail withdrawal in untreated beta arrestin knockout mice

This effect is diminished by the introduction of naloxone

Suggests constitutively active mu opioid receptors in beta arrestin knockout mice

37
Q

Are receptors always inactive until binding of an agonist?

A

No; receptors fluctuate between an active and inactive state
Drugs can either bind selectively to and stabilize the active state = agonist
Drugs can bind selectively to and stabilize the inactive state = inverse agonist
Drug that doesn’t selectively bind to an active or inactive state but binds to both equally in a competitive manner = competitive antagonist. Neutral efficacy

38
Q

Describe the full agonist, competitive antagonists and full inverse agonists in terms of opioid receptors

A

Full agonist; DAMGO, morphine, fentanyl
Full inverse agonist; naltrexone, naloxone, nalmefene
Competitive antagonist; CTAP, alpha naloxol, beta naloxol, beta naltrexol

39
Q

What is the evidence to show that b-arr2 knockout mice have basal analgesia by mu constitutive activity (not increase in endogenous peptides such as enkephalins)

A

Only full inverse agonists have a reduction in tail withdrawal latency

If there was to be an increase in endogenous peptides; both full inverse agonists and competitive antagonists would increase tail withdrawal latency

40
Q

Do b-arr2 knockout mice show any difference in morphine reinforcement?

A

At 10 mg/kg s/c; there is no difference between WT and b-arr2 -/- mice in morphine reinforcement

However

At 3mg; in WT mice; there is no significant difference in the preference score, BUT in b-arr2 -/- mice there is an increase in morphine preference

This suggests that morphine becomes more potent in b-arr2 -/- in terms of rewarding/ hedonic effects

41
Q

In b-arr2 -/- mice; is there an enhanced reward without stimulation of opioids (in a similar manner to an increase in basal analgesia due to constitutively active mu receptors) ?

A

No; there is no difference in WT and b-arr2 -/- mice in their aversion to naloxone

If the constitutively active mu receptors were to play a role in the euphoria associated with opioids; an aversion to naloxone would be expected

42
Q

What is the summary of the role (or lack thereof) b-arr2 on opioid actions?

Based on b-arr2 -/- mouse

A

Increased basal analgesia mediated by constitutively active mu receptors
Decreased morphine tolerance/ dependence
Decreased constipation
Decreased locomotion
Increased reward with lower concentrations of morphine

43
Q

What nT does the locomotor and reward actions of opioids rely on?

A

Dopaminergic pathways

Suggested that the action of b-arr2 is mediated at DA receptors instead of mu receptors

44
Q

What are the effects of morphine on locomotion in mice?

A

Increased locomotion

45
Q

Does the locomotion seen in morphine injected mice require mu receptors?

A

Yes; when WT. mu -/- and b-arr2 -/- mice were compared;

WT and b-arr2 -/- mice showed a significant increase in locomotion after morphine
However; mu -/- mice did not show a significant increase

46
Q

What is sensitization?

A

WT mice:
Day 1; distance travelled is substantial
Day 2; distance travelled is higher
Day 3; distance travelled even higher

Injection of morphine shows an enhanced effect; similar to craving (unlike analgesia or euphoria; the effects of craving go up with repeated administration of the drug)

47
Q

Describe the relationship between mu receptors and sensitization

A

In mu +/- mice; there is no significant difference between distance travelled on days 1, 2, and 3 = no sensitization

Even at higher doses of morphine (30 mg/kg s/c); there is slight sensitization but it is not as high in WT mice. This suggests that mu receptor downregulation has a role in efficacy of morphine.

48
Q

Describe the role between b-arr2 and sensitization

A

In b-arr2 -/- mice; at 3 mg/kg there is reduced locomotor
However; at 10 mg/kg there is a significant rise (albeit smaller than WT) but characteristic sensitization is observed

Full locomotor response is dependent on b-arr2 - a lack of b-arr2 will reduce morphine stimulated locomotion = reduce craving in humans

49
Q

What dopaminergic pathway does the locomotor effect of morphine utilise?

A

Substantia nigra
Projects to the caudate and putamen
Contains D1 and D2 projections

50
Q

What does dopamien regulate?

A 
Locomotion 
Cognition 
Reward
Emotion 
Endocrine function 
Highly expressed in striatum
51
Q

Describe the dopamine dependent disorders

A 
Schizophrenia
BAD
Depression 
PD
Drug abuse and dependence
52
Q

How is DA synthesized?

A

Tyrosine hydroxylase

53
Q

What pathways utilise DA?

A 
Nigrostriatal 
Mesolimbic
Neocortical
Tuberoinfundibular 
Tuberohypophysial
54
Q

Describe the nigrostriatal DA pathway

A

DA neurons originate in substantia nigra and VTA

Project to caudate, putamen and nucleus accumbens

55
Q

How many dopamine receptors are present?

A

D1-5
D1 like; D1 and D5
D2 like; D2, D3 and D4

56
Q

Describe the D1 like signalling

A

Activate adenylyl cyclase - couple to Gs

Activated by dopamine
Apomorphine and bromocriptine are partial agonists

Less action via anti-psychotics

57
Q

Describe the D2 like signalling

A

Inhibit adenylyl cyclase; Gi/o coupling

Activated by dopamine, apomorphine and bromocriptine

Majority of anti-psychotics will target D2 like receptors (D2, 3, 4)

58
Q

Are D2 receptors required for morphine CPP (self-administration paradigm)?

A

Yes
At 3 mg:
+/+ D2 receptors; robust CPP
-/- D2; no stimulation of CPP

10mg;
+/+ D2; CPP
-/- D2; no CPP

Was there a difference in CPP when food reward was looked at?
Yes; knockout mice still showed food preference - therefore D2 receptors are involved in opioid CPP but not food CPP

59
Q

Did tyrosine hydroxylase (TH) -/- mice show locomotion after morphine?

A

No; TH is required for the synthesis of DA

DA deficient mice showed no morphine locomotion

Morphine locomotion was restored by an L-dopa injection

60
Q

Do TH -/- mice exhibit morphine reward?

A

Yes; morphine CPP is present without dopamine

61
Q

What receptors is morphine mediated mouse locomotion dependent on?

A

D1/2 receptors
B-arr2
Stimulation of mouse locomotion is dependent on D1 activation/ phosphorylation of ERK

Morphine stimulated b-arr2 pERK association, D1 receptors are required

Morphine recruits b-arr2 in the presence of pERK

D1 receptors are not required for morphine CPP

D1 mediates barr2 dependent locomotor effects of morphine. This signalling cascade from D1 involves recruitment of barr2 and phosphorlyation of ERK. Signalling cascade that is mediated through D1

62
Q

Summarise the roles of barr2 at D1 an D2

A

D1 receptor; ERK allowing dopamine to phosphorylate ERK = locomotion

D2; recruitment of other kinases

B-arr2 = desensitization, tolerance, signalling role (locomotion)

63
Q

Summarise b-arr2 on behavioural effects of opioid

A 
B-arr2 -/- mice: 
Increased basal analgesia 
Decreased morphine tolerance/ dependence 
Decreased resp depression 
Decreased constipation 
Decreased locomotion (D1)
Increased reward
64
Q

Is there any evidence to suggest that ELA modifies addiction behaviour?

A

Increases opioid relapse behaviour

Potentiates opioid seeking behaviour

65
Q

Describe ELA model

A

ELA paradigm/ fragmented care paradigm
Raised metal grid floor; mother unable to make full nest
Mother leaves pups more frequently
Increased early life stress; less bonding

Behavioural studies performed post-natal day 60

66
Q

What is extinction behaviour in mice in regards to opioid use?

A

How long it takes mice to stop self administering opioids when there is no drug available

67
Q

What is the difference in extinction behaviour in control and ELA mice (opioid) ?

A

CTL mice stopped pressing the lever around 6 days - realising there is no reward from the level

ELA mice; take longer (10 days) to stop pressing the lever
CTL mice reached extinction criteria earlier than ELA mice

68
Q

Describe the difference in cue induced reinstatement in CTL and ELA mice

A

No cue; very few active lever pressing after extinction

Cue reinstated; much more lever pressed. This is greater in ELA mice

In heroin primed reinstatement; the active pressing behaviour is even more pronounced

69
Q

What is the evidence that adverse childhood experiences increase the likelihood of addiction?

A

4 or more ACEs; much higher rate of smoking, IVDU, suicide attempts, early sexual behaviour, depression and liver disease (alcoholism)

ACEs are the single greatest unaddressed public health threat facing our nation toady

67% of the population have at least on ACE

70
Q

What are the different types of ACEs?

A

Abuse; physical, emotional, social
Neglect; physical, emotional
Household dysfunction; mental distress, incarcerated relative, mother treated violently, substance abuse, divorce

BMSc - Neuropharmacology and Behaviour (27 decks)

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