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Neuropharmacology > Chapter 11: The Opioids > Flashcards

Chapter 11: The Opioids Flashcards

1
Q

Opioids

A

Class: narcotic analgesics

*reduce pain without producing unconsciousness but do produce sense of relaxation and sleep

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2
Q

Opiate narcotics are derived from […]

A

Opiate narcotics are derived from poppy plant

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3
Q

Natural Narcotics (Opiates)

A

Opium
Morphine
Codeine- less analgesic effects and fewer side effect than morphine
Thebaine

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4
Q

Opioids consist of:

A

Semisynthetic narcotics
Synthetic narcotics
Endogenous neuropeptides

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5
Q

Semisynthetic narcotics

A 
Derived from morphine:
         - Heroin
         - Hydromorphone (Dilaudid)
Derived from thebaine:
         - Oxycodone (Percodon)
         - Buprenorphine (Buprenex)
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6
Q

Synthetic narcotics

A 
Pentazocine (Talwain)
Meperdine (Demerol)
Fentanyl (Sublimaze)
Methadone (Dolophine)
LAAM
Propoxyphene
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7
Q

Endogenous Neuropeptides

A 
Enkephalins
Endorphins
Dynorphins
Endomorphins
Nociceptin/ orphanin FQ
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8
Q

Partial Opioid Agonists

A

Pentazocine (Tolwin)
Narbuphine (Nubain)
Buphrenone (Beprenex)

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9
Q

Pure antagonists

A

Naloxene (Narcan)

Nalorphine

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10
Q

Endogenous opioids are derived from […]

A

Endogenous opioids are derived from pro-peptides

  • POMC
  • Proenkephalin
  • Prodynorphin
  • Pronociceptin/ophanin FQ
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11
Q

POMC

A

Beta- endorphins (B-END)
Mu and delta receptors

  • found in pituitary gland and releases variety of hormones
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12
Q

Proenkephalin

A

Met- and leu-enkephalin (ENK)
Delta receptors
Inhibited by peptidases RB-101, RB-120, RB-3007

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13
Q

Prodynorphin

A
  • a- and B-neoendorphin
  • dynorphin (DYN) A and B
  • kappa receptors
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14
Q

Pronociceptin/ ophanin FQ

A

NOR receptors

Phenylalanine and glutamine

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15
Q

BU08028

A

Dual MOR-NOP-R agonist

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16
Q

There are 4 opioid receptors

A

High opioid affinity (highly selective)

  • Classical subtypes: mu, delta, kappa
  • NOR

*biased agonism

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17
Q

Mu receptors

A
  • high affinity for morphine
  • medial thalamus, peri aqueduct all gray (PAG), median raphe, and clusters in spinal cord
  • feeding and positive reinforcement
  • cardiovascular and respiratory depression
  • nausea and vomiting
  • sensorimotor integration
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18
Q

Delta receptors

A
  • forebrain: neocortex, striatum, olfactory areas, substantia nigra, and nucleus accumbens
  • olfaction, motor integration, reinforcement, and cognitive function
  • similar to MOR
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19
Q

kappa receptors

A
  • high-affinity binding to ketcyclazocine
  • striatum, amygdala, hypothalamus, pituitary
  • pain perception, gut motility and dysphoria
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20
Q

NOR

A
  • cerebral cortex, amygdala, hippocampus, and hypothalamus

- analgesia, feeding, learning, motor function, and neuroendocrine regulation

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21
Q

Opioid receptors are […] receptors

A

Opioid receptors are GPCR receptors

  • inhibitory
  • increased gk- opens channels
  • decreased gca- closes channels
  • adenylyl cyclase- inhibits activity (longer term effects)
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22
Q

Opioid receptor isolation, transfection, receptor cleaning, and molecular sequence

A
  1. Specific nucleic acid sequence
  2. AA of protein can be identified
  3. Transfected cells used to study intracellular changes
  4. In situ hybridization: visualize cells that synthesize receptors
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23
Q

Neuropeptides reduce synaptic transmission

A

*inhibition of endogenous opioids

  1. Postsynaptic inhibition: open K+ channels
  2. Axoaxonic inhibition: close Ca2+ channels (usually GABAergic neurons)
  3. Presynaptic autoreceptors: reduce transmitter release
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24
Q

Inhibition of […] and […] is important because they are used to transmit pain signal

A

Inhibition of Glu and Substance P is important because they are used to transmit pain signal

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25
Q

Biased Agonism

A

Receptor activated dictates which signal is activated

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26
Q

Opioids in CNS

A

Decreased body temp and blood pressure, pupils restricted, and increased blood CO2

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27
Q

Opioids in GI tract

A

Relief of diarrhea and dysentery acid

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28
Q

Opioids induce several behavioral effects

A

Analgesia:
- most effective pain-reliever

Changes in mood

   - euphoria (MOR, DOR)
   - dysphoria (KOR)

Drowsiness
- sleep

29
Q

Opioid PNS effects

A
  • pinpoint pupils
  • vomiting
  • cough suppression (codeine)
  • constipation
30
Q

Death by opioid

A
  • respiratory depression

- cardiac depression

31
Q

Opioid overdose triad

A

Pinpoint pupil, unconsciousness, respiratory depression

  • treat using Narcan
32
Q

Acutely MOR agonist are […] and […]

A

Acutely MOR agonist are analgesic and reinforcing

  • Analgesia
  • Reward
33
Q

Analgesia

A

Spinal- release endorphins that inhibit activation of spinal projection neurons

Supraspinal- above spinal cord

34
Q

Reward

A

Increased DA release in NAcc

  • B- endorphins are similar
  • K-agonists: decreased DA
35
Q

Analgesic properties of opioid are due to agonism of MOR located in brain and spinal cord

A
  • Midbrain periaqueductal gray matter
  • Locus coeruleus
  • Raphe nuclei
  • Dorsal horn of spinal cord
  • anterolateral system- ascending pain information
36
Q

Opioids regulate pain

A
  1. In spinal cord by small inhibitory interneurons
  2. Descending pathways originating in periaqueductal gray (PAG)
  3. At higher brain sites (emotional and hormonal aspects)
37
Q

MOR agonists directly […] neurons and have reward properties

A

MOR agonists directly activate mesolimbic DA neurons and have reward properties

  • ICSS
  • Self-administration
  • Microinjection studies
38
Q

ICSS (intracranial self-stimulation)

A

opioids decreases the threshold current required for ICSS

  • morphine or selective mu- agonist and place preference
39
Q

Median forebrain bundle

A

Bar press rewards

40
Q

Self-administration

A

IV use gradually increases over time

- similar to pattern seen in humans

41
Q

Microinjection studies

A

Intra-VTA microinjection increases firing rate and DA release from VTA

Induces CPP and decreases threshold for ICSS

42
Q

Opioids […], increases their firing rate, causing more DA release in N. Acc.

A

Opioids disinhibition VTA neurons, increases their firing rate, causing more DA release in N. Acc.

43
Q

6-OHDA lesions […] self-administration, showing the rewarding properties of opioids also involve other, non-DA mechanisms

A

6-OHDA lesions reduce self-administration, showing the rewarding properties of opioids also involve other, non-DA mechanisms

44
Q

Chronic opioid use produces increased craving, physical dependence and tolerance

A
  • incentive sensitization
  • pharmacodynamic tolerance
  • withdrawal/ abstinence syndrome
45
Q

Incentive sensitization

A
  • increased invention salience
  • craving; “wanting”

(Craving undergoes sensitization)

46
Q

Pharmacodynamic Tolerance

A
  • also metabolic and behavioral tolerance

- cross-tolerance with other OR agonists

47
Q

Withdrawal/ abstinence syndrome

A

Loss of inhibitory opioid action at all receptors as blood levels of drug decline

*rebound hyperactivity

48
Q

Cross- tolerance

A

Tolerance to one opioid drug—> other chemically related drugs also show reduced effectiveness

49
Q

Detoxified

A

When abstinence signs end

50
Q

Cross Dependence

A

Readministering any opioid will stop/ reduce withdrawal symptoms

51
Q

Physical dependence occurs following long-term occupation of opioid

Acute action: withdrawal symptoms

A

Analgesia: pain and irritability
Respiratory depression: panting and yawning
Euphoria: dysphoria and depression
Relaxation and sleep: restlessness and insomnia
Tranquilization: fearfulness and hostility
Decreased blood pressure: increased blood pressure
Constipation: Diarrhea
Pupil constriction: pupil dilation
Hypothermia: hyperthermia
Drying of secretions: tearing, runny nose
Reduced sex drive: spontaneous ejaculation
Flushed and warm skin: chilliness and “gooseflesh”

52
Q

Neuroadaptations underlie the transition to addiction

A

Nucleus accumbens
Locus Coeruleus
Periaqueductal Gray

53
Q

Abrupt removal of opioid in tolerant/ dependent animals leads to a withdrawal syndrome

A

Normal

Begin morphine treatment: acute

Tolerance and dependence

Withdraw morphine (abstinence)

Withdrawal and normal

54
Q

Neuroadaptations following chronic opioid use are related to […] and […]

A

Neuroadaptations following chronic opioid use are related to tolerance and withdrawal

55
Q

Tolerance

A
  • MOR desensitization: uncoupling of MOR and G protein occurs rapidly (min)
  • MOR down-regulation and internalization occur more slowly (1-3 days)
56
Q

Withdrawal (WD)

A

Intracerebral injection of naloxone to

  • LC/ PAG - physiological symptoms of WD
  • N. Acc.- aversive qualities of WD (depression, dysphoria)
57
Q

Neuroadaptations following chronic opioid use are related to tolerance and withdrawal

A

Acute
Chronic
Induce WD

58
Q

Acute Use

A
  • activate MOR in LC

- Hyperpolarization; less AP firing

59
Q

Chronic Use

A
  • LC neurons gradually increase AP firing
  • cAMP/ PKA activity gradually increases
  • chronic morphine doesn’t change number of receptors (tolerance)
60
Q

Induce WD

A
  • administer naloxone to dependent animal
  • LC neurons are over-excited
  • cAMP/ PKA over-activated
61
Q

Neurobiology of Opioid Addiction

A

Increased cAMP
PMOR
Increased LC
Increased DA release

POST NEUROADAPTATION;

MOR desensitization
MOR internalization
Tolerance
LC hyperactivity
Anti-reward

Positive feedback loop: LC to Central Nucleus of Amygdala and back

62
Q

Innovative pain control

A

Dual- inhibition of peptidases

Dual MOR/NOR agonists

63
Q

Dual-inhibition of peptidases

A
  • inhibition of both ENK degrading enzymes
  • fewer side-effects
  • low abuse potential
64
Q

Dual MOR/ NOR agonists

A
  • potent, effective analgesia
  • no respiratory depression or cardiac side effects
  • no physical dependence, low abuse potential
65
Q

2 components of pain

A

Early- immediate sensory component; signals onset of noxious stimuli and precise location

  - Ad fibers
  - Spinothalamic tract —> posteroventrolateral (PVL) nucleus of thalamus —> primary and secondary somatosensory cortex

Late- strong emotional component (unpleasantness)

    - C fibers
    - Thalamus —> hypothalamus, amygdala, anterior cingulate cortex
66
Q

Environmental cues have role in tolerance, drug abuse, and relapse

A
  • Triggers- cues that act as secondary messengers

- Learning is critical in opioid use disorder

67
Q

Detoxification is assisted using […] and […]

A

Detoxification is assisted using methadone and clonidine

  • methadone maintenance program
68
Q

Buphrenorphine (Buprenex) maintenance

A

Opioid partial agonist used to similarly to methadone

  • High affinity, low Africans MOR
  • Antagonist at KOR
69
Q

Naltrexone (Trexan)

A

Commonly used narcotic antagonist

Neuropharmacology (15 decks)

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