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Translational psychiatry and neurology > Opioids > Flashcards

Opioids Flashcards

1
Q

Endogenous opioids look very structurally different to opium alkaloids (opiates). Name some examples of opiates and endogenous opioids.

A
  • Opiates include morphine, codeine, thebaine and oripavaine
  • Endogenous opioids include endorphins, enkephalins, dynorphin and endomorphins
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2
Q

Why is heroin more fast acting that morphine?

A
  • Heroin crosses the BBB more quickly than morphine and is metabolised in the brain into morphine.
  • Morphine can then bind to opioid receptors
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3
Q

Activation of opioid receptors causes activation of specific G proteins. Which G proteins are these a?

A
  • Inhibitory G proteins, Gi.
  • They inhibit adenylyl cyclase which reduces cAMP accumulation.
  • They also activate K channels and inhibit voltage-gated Ca channels
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4
Q

What is alternative splicing?

A
  • Pre-RNA starts the initiation site of the gene and copies all the exons and introns in the genes.
  • Splicosome then removes the introns from pre-RNA and also some exons.
  • Alternative splicing is the removal of specific exons
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5
Q

Opioid receptor activation causes recruitment of beta-arrestins. What is the role of beta-arrestin 2?

A
  • Enables mu opioid receptors to communicate with other signal transduction pathways, including the protein kinases AKT and c-Src.
  • This signalling pathway is responsible for some of the negative effects of mu opioid receptor agonists
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6
Q

What is the role of beta-arrestin 2 in the development of opioid tolerance?

A

Beta-arrestin 2 is involved in receptor endocytosis which likely contributes to opioid analgesic tolerance

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7
Q

How does receptor tolerance occur?

A

Receptor tolerance at the mu opioid receptor is due to loss in the coupling of the receptor to the G-protein that regulates the inwardly rectifying K channel

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8
Q

How does cellular tolerance and withdrawal occur?

A

Cellular tolerance and withdrawal is due to multiple adaptations to intracellular signalling cascades - hypertrophy of cAMP signalling is the best established

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9
Q

How does system tolerance and withdrawal occur?

A

Systems feedback adaptations in opioid sensitive networks can develop and contribute to tolerance and withdrawal

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10
Q

How is synaptic plasticity involved in tolerance and withdrawal?

A

Changes in synaptic plasticity are driven by altered presynaptic release probability, which is well established at opioid sensitive GABA-ergic synapses. Importantly, mechanisms resembling LTP (long-term potentiation) and/or LTD (LT depression) probably involving AMPA receptor insertion in synapses may also produce long-term changes in synaptic strength

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11
Q

What are the clinical features and brain features in the acute drug state?

A
  • Reinforcement and reward
  • Increased mesolimbic dopamine
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12
Q

What are the clinical features and brain features in the chronic drug state?

A
  • Tolerance, sensitisation, dependence
  • Receptor adaptations; increased cAMP pathway increased CREB
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13
Q

What are the clinical features and brain features during short-term abstinence from an opioid drug?

A
  • Withdrawal
  • Increased glutamatergic and noradrenergic signalling
  • Decreased dopaminergic and serotonergic signalling
  • Increased corticotrophin releasing factor (CRF)
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14
Q

What are the clinical features and brain features during long-term abstinence from an opioid drug?

A
  • Possibly synaptic remodelling
  • Increased CRF, glucocorticoids
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15
Q

What happens if someone takes heroin whilst on methadone?

A

There is cross tolerance between methadone and heroin so if someone takes heroin whilst on methadone they are unlikely to get a high

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16
Q

What therapies exist for opioid dependence?

A
  • Replacements - methadone (mu receptor agonist), buprenorphine (mu receptor partial agonist and kappa receptor antagonist) +/- naloxone, naltrexone (opioid antagonist)
  • Detoxification - use symptomatic relief e.g. anti-inflammatories, anti-emetics, anti-diarrhoeal medications
  • Behavioural therapy
17
Q

What therapies are there for nicotine replacement?

A
  • Nicotine patch or varenicline, a selective a3B2 agonist.
  • Bupropion (anti-depressant) can also help
18
Q

What medications are there for alcoholism?

A

Disulfiram, acamprosate, naltrexone, nalmefene

19
Q

What is suboxone and why is it used in opioid dependency?

A
  • Suboxone = naloxone + buprenorphine
  • Patient gets beneficial effects from buprenorphine but doesn’t get inhibitory effects from naloxone unless they inject heroin, in which case they will not get high
20
Q

What is the main cation in a neuron?

A

Potassium

21
Q

What is the main cation outside a neuron?

A

Sodium

22
Q

What does opening of K channels do to the cell membrane?

A

Causes hyperpolarisation (more negative) and closing of K channels causes depolarisation of the cell membrane

23
Q

How does K get back into the cell?

A

Na/K ATPase pump - pumps K in and Na out of the cell

24
Q

What is the main anion in a neuron?

A

Chloride

25
Q

What happens when GABA binds to the GABA-a receptor in neurons?

A

Chlorine channel opens which allows chloride ions into the cell - hyperpolarisation (more negative)

26
Q

Is the number of mu receptors important when it comes to response to opioids i.e. condition placed preference?

A

Yes - mice study:

  • if mice lack both alleles for mu receptor, the mice are resistant to analgesia and reward
  • if mice lack one of the alleles they have 50% of their mu opioid receptors, they become resistant to dose of morphine that previously gave them reward (tolerance)

Downregulation of the mu receptor could be a contributing factor to tolerance

27
Q

Are mu opioid receptors required for the effects of opioids to occur?

A

Yes - mice lacking mu receptors don’t exhibit any effects of opioids such as analgesia, respiratory depression, constipation, tolerance, withdrawal, reward, reinforcement

28
Q

What is the relationship between beta-arrestin 2 and pain?

A

Theoretically we’d all be less resistant to pain if we didn’t have beta-arrestin 2.

Mice study:

  • Time taken for wild type mice to remove their tail from hot water becomes slower as you remove beta-arrestin 2 i.e. they become less resistant to pain
29
Q

What is an inverse agonist? Name some examples

A
  • Inverse agonists preferentially bind to their receptor in its inactive conformation, effectively has the opposite effect of an agonist e.g. agonist could be analgesic and an inverse agonist would cause more pain
  • Examples of these are nalmefene, naloxone and naltrexone
30
Q

What is a neutral competitive antagonist?

A
  • Neutral competitive antagonists bind to receptor but don’t allow the conformation to change so that agonists and inverse agonists cannot bind
  • Examples of these are alpha-naloxol, beta-naloxol and beta-naltrexol
31
Q

Beta arrestin 2 puts the brakes on the mu receptor in terms of analgesia and reward, so what happens when beta-arrestin 2 is removed?

A

Tolerance increases and drug such as morphine becomes even more potent as analgesics

32
Q

What is condition placed aversion?

A

If the subject is dependent on a drug (e.g. morphine) then naloxone will throw the subject into withdrawal, causing the subject to avoid the chamber it received the naloxone in

33
Q

What substance is involved in synthesis of DA in neurons?

A

Tyrosine hydroxylase (TH)

34
Q

Describe the nigrostriatal pathway

A

Dopamine neurons originate from the substantia nigra and VTA, projecting to the caudate nucleus, putamen and nucleus accumbens

35
Q

There are 5 DA receptors D1-5. Which of these are D1 -like and which are D2-like?

A
  • D1 like = D1 and D5
  • D2 like = D2, D3 and D4
36
Q

What is the main difference between D1-like and D2-like DA receptors?

A
  • D1-like receptors stimulate adenylate cyclase
  • D2-like receptors inhibit adenylate cyclase
37
Q

Morphine causes increased locomotion in mice. What does lack of tyrosine hydroxylase do to this locomotion effect and how can this be remedied?

A
  • No morphine induced locomotion if mice lack TH as they cannot synthesise DA
  • Levodopa can be used to replace dopamine due to lack of TH
38
Q

Why do dopamine deficient mice still respond to morphine?

A

During development the mice may have developed an alternative reward system e.g. serotonin-based reward system instead of dopamine-based reward system

Translational psychiatry and neurology (8 decks)

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