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Molecular Neuroscience III > 6 - Opioids > Flashcards

6 - Opioids Flashcards

1
Q

What does activation of μ opioid receptors cause intracellularly?

A
  • Inactivation of adenylyl cyclase and reduction in protein kinase A (PKA) activity
  • Reduces phosphorylation of channel and pumps responsible for depolarization and other cAMP pathways that are important for other proteins
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2
Q

_____ that act on δ opioid receptors do what?

A

Enkephalins act on δ (delta) receptors

  • Rescue ionic homeostasis during hypoxic/ischemic stress
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3
Q

How do opioids affect sensory perception?

A

Reduces pain, but does not reduce other sensations (eg. touch, temperature)

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4
Q

How are endogenous opioids pleasurable?

A

Opioids stimulate release of dopamine from VTA and nucleus accumbens

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5
Q

The majority of the striatum is GABAergic neurons that co-express _____

What does this cause?

A

dynoprphins

Stimulate release of dopamine

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6
Q

About 50% of heroin and cocaine addiction can be attributed to what?

A

Opioid gene variants

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7
Q

What are the opiate withdrawal syndromes? (5)

A

Involved in activation of adrenergic system.

  • High blood pressure/temperature
  • Diarrhea
  • Weight loss
  • Restlessness, anxiety
  • Depression

Some opiates have low side effects from slowing of these processes

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8
Q

How would a heroin vaccine help addicted individuals?

A

A vaccine would induce production of antibodies that bind to opiate molecules to prevent them from binding to their receptors?

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9
Q

Using nanorod-siRNA to silence DARPP-32 would do what?

A
  • Silencing dopamine-and cAMP-regulated neuronal phosphoprotein
  • Prevent or treat addiction to opiates.
  • Dopamine- and cyclic AMP-regulated phosphoprotein.
  • Affects dopamine, glutamate and adenosine; and there is some support for a role of the gene in schizophrenia, as well as being involved in the action of multiple drugs including cocaine, amphetamine, nicotine, LSD, caffeine, PCP, ethanol and morphine.
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10
Q

True or false? Opiates are the MAIN and MOST EFFECTIVE treatments for pain

A

True

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11
Q

Chronic opiate use results in what gross neuroanatomy changes

A

Cortical and limbic structure neuronal change

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12
Q

List the four opioid receptors and their prototypic ligand(s)

A

μ: morphine

δ: Met/leu-enkephalin

κ: Ethyl Ketocyclazocine

ORL-1: Nociceptin/OFQ

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13
Q

What are endogenous opioid peptides synthesized from?

A

High molecular weight precursors.

  • Proopiomelanocortin: beta-endorphin
  • proenkephalin: met/leu-enkephalin
  • Prodynorphin: Dynorphins and endorphins
  • Pronociceptin/OFQ: nociceptin/OFQ
  • Proendomorphin: endomorphin 1 and 2
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14
Q

What are two responses to opioid peptides by activation of PLA2?

A

All result in inhibition of adenylate cyclase

  • Activation of PLCβ and PLD2 inhibits voltage gated potassium channels
  • Activation of MAPK (MAP kinase) activates inwardly rectifying potassium channels
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15
Q

Which opioid receptor mediates the rewarding properties of non-opioid drugs of abuse, including cannabinoids, alcohol and nicotine (or even social interaction)?

Why is research of this receptor hard?

A

μ (primary morphine receptor)

m receptors therefore represent a key molecular trigger for reward, and most likely contribute to the initiation of addictive behaviors.

Research of mu receptors is challenging because dozens of m receptors splice variants exist and they have the ability to form both homodimers and heterodimers with other members of the opioid receptor family as well as unrelated G protein-coupled receptors.

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16
Q

What do κ receptors mediate?

A

k receptors mediate dysphoric activities of both k opioids and cannabinoids and oppose m receptors in regulating the hedonic tone.

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17
Q

What do δ receptors do?

A

δ receptors functions are very distinct from m and k receptors, they regulate emotional responses and show anxiolytic and antidepressant activity.

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18
Q

Describe the behavioural effects of opioid receptors and their ligands (3)

A
  • Morphine and β-endorphins activate μ receptors for reward and analgesia
  • β-endorphins, enkephalins and dynorphins activate δ receptors for emotional reactivity and analgesia
  • Dynorphins, β-endorphins and enkephalins activate κ receptors for analgesia and dysphoria (feeling unwell/unhappy)
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19
Q

What are the four genes encoding opioid receptors?

A
  • Oprm1 (μ)
  • Oprd1 (δ)
  • Oprk1 (κ)
  • Oprl1 (orphanin FQ/nociceptin).
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20
Q

For a decade, mice lacking μ, δ, or κ receptors, as well as preproenkephalin, preprodynorphin, or b-endorphin, have been created by…? What do these models show?

A

gene-targeting (knockout mice). Single mutant mice, or even the triple receptor knockout mice, are viable and fertile and show no obvious developmental deficit, indicating that the opioid system is not essential for survival.

m, d, and k receptor-deficient mice all exhibit enhanced pain sensitivity. This indicates that the three receptors, activated by endogenous opioid peptides, tonically inhibit nociceptive responses.

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21
Q

Describe orphanin FQ/nociceptin receptors in relation to the other 3 opioid receptors

A

The fourth member encoding the orphanin FQ/nociceptin receptor. and its endogenous ligand share high structural homology with the opioid receptors and peptides. However, the receptor does not bind opioids and the peptide orphanin FQ/nociceptin shows no affinity toward μ, δ, or κ receptors

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22
Q

Describe the μ opioid signalling pathway (3)

A
  • μ opiood receptor couples to Gi/o and its activation inhibits adenylyl cyclase (AC), reduces levels of protein kinase A (PKA) activity and reduces phosphorylation of the channel or pump responsible.
  • Inhibition of the cAMP pathway also decreases the phosphorylation of many other proteins and, thereby, affects numerous other neuronal processes.
  • Opiates inhibit
    neuronal exctability by increasing the conductance of an inwardly rectifying K+ channel and indirectly by inhibiting PKA-dependent opening of Na+ conductance. N
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23
Q

Describe δ opioid receptor signalling

A
  • Delta receptor signaling was shown to rescue ionic homeostasis during hypoxic/ischemic stress. d receptor overexpression and delta receptor stimulation increases cell survival in animal models of hypoxia/ischemia.
  • Delta receptor signalling was also found to have cardioprotective properties.
  • Delivery of opioid agonist inhibited ischemia-induced TNF-a expression in the rat retina.
24
Q

Describe κ opioid signalling (3)

A
  • Activation of kappa receptors inhibits cAMP and activates G-protein coupled receptor kinase3 (GRK3) and downstream signaling cascade including: Arrestin, extra- cellular signal-regulated kinase (ERK) and p38 mitogen activated protein kinase.
  • The other induced enzymes include src family tyrosine kinases that may activate c- Jun N-terminal Kinase (JNK).
  • ERK and p38 signalling induces pCREB and zif268 transcription factors respectively.
25
Q

What are σ opioid receptors?

A

σ-opioid receptors were postulated receptors, which mediate the “dysphoric” effects (anxiety, hallucinations, bad dreams etc.) produced by some opioids. They are not typical opioid receptors, as many other drugs also interact with them. Of the opioids, only benzomorphans, such as pentazocine, interact with sigma-receptors. The functions of sigma receptors are poorly understood. They do not couple to G proteins neither they are connected to tyrosine kinases.

Another proposed opioid system involved in cell survival/proliferation is “opioid growth factor”

26
Q

Describe opioid control of pain

A
  • Opioids control the pain-transmission pathway directly through actions in the superficial layers of the spinal dorsal horn.
  • Both primary afferent terminals and second-order dorsal-horn neurons bear μ opioid and δ opioid receptors.
  • Spinal application of μ opioid agonists reduces excitatory neurotransmitter release from primary afferent terminals by inhibiting a voltage-gated calcium channel. Opioids also directly depolarize second-order dorsal-horn neurons by opening an inwardly-rectifying potassium channel.
27
Q

What is the result of microinjection of μ opioid agonist directly into the ventral striatum (specifically Nucleus accumbens)?

A

Selectively enhances consumption of palatable food and suppresses responses to noxious stimuli.
- μ opioid agonist injection into the NAc also activates neurons in the lateral hypothalamus and in the dopaminergic brainstem region, the ventral tegmental area. Injection of addicting drugs such as morphine or cocaine into these regions produces both reward and analgesia.

28
Q

Why do rodents freeze when they encounter a threat, such as predator or an environment in which they have received a significant and inescapable noxious stimulus?

A

They typically freeze and become transiently analgesic.

This is probably due to opioid activity in the ventral striatum

29
Q

Opioids exhibit anesthetic effect in multiple sites acting via central and
peripheral opioid receptors.

What type of transmission do they inhibit in sensory neurons?

A

Opioids inhibit glutamatergic excitatory transmission in sensory neurons

30
Q

Endogenous opioid interact with the reward pathway. Describe.

A

Opioids can interact with reward pathway acting directly on the receptors present in the ventral tegmental area (VTA) and nucleus accumbens (Nac). They can also interact with reward pathway indirectly acting via amygdala (AMG), hypothalamus (ARC, LH) periaqueductal gray (PAG) and locus coeruleus (LC).

31
Q

What causes regulation of cAMP response element-binding protein (CREB) by drugs of abuse?

A

Dopamine from mesolimbic pathway stimulate GABAergic neurons in the striatum which also co-express dynorphin. Dynorphins are responsible for negative feedback mechanism in this circuit.

32
Q

Describe alcohol and opioid interaction from acute and chronic alcohol exposure, as well as opioid receptor effectivity of decreasing ethanol consumption.

A
  • Acute ethanol exposure stimulates the release of β-endorphin in the ventral tegmental area and of β-endorphin, enkephalin and dynorphin peptides in the nucleus accumbens. Acute ethanol exposure increased the extracellular concentration of β-endorphin in the central amygdala.
  • Chronic ethanol exposure decrease brain and pituitary β-endorphin content and also decrease the content of enkephalins, but an increase in the content of dynorphins in the brain.
  • In experimental animals, μ and δ-opioid receptor antagonists are more effective in decreasing ethanol consumption than are the κ-opioid receptor antagonists.
33
Q

How can opiates change synaptic plasticity? (3)

A
  • Acute opiates can enhance glutamatergic transmission and inhibit GABAergic synapses in the VTA.
  • Acute opiates can enhance glutamatergic transmission and inhibit GABAergic synapses in the VTA.
  • Chronic opiates, in contrary, inhibit glutamatergic transmission by blocking synaptic release and inducing increased internalization of AMPARs. They also facilitate GABA release
34
Q

What are the opioid gene variants involved in heroin and/or cocaine addiction?

A
  • The G protein-coupled μ opioid receptor (encoded by OPRM1) is the main target of morphine, heroin, and methadone, and it plays an important role in opioid tolerance and dependence. Polymorphism of this gene may be responsible for individual differences in response to opioids.
  • OPRK1 - encodes κ opioid receptor. Dynorphin and the k opioid receptor are localized in several areas of the dopaminergic nigrostriatal and mesolimbic– mesocortical systems, and they play an important role in a modulation of opioid, cocaine, and other rewarding stimuli, presumably through modulation of basal and drug-induced dopaminergic tone. They act opposite to m receptors on dopamine levels in the nigrostriatal and mesolimbic-mesocortical system. Dysregulation of this system may contribute to the development of drug dependences. Single-nucleotide polymorphisms (SNP) of OPRK1 is associated with cocaine and alcohol dependence.
35
Q

List some non-opioid genes involved in opioids and addiction

A
  • Catechol-O-methyltransferase (COMT)
  • Tryptophan hydroxylase genes (TPH1 and TPH2)
  • 5-hydroxytryptamine (serotonin)-1B receptor (HTR1B)
  • myocardin (MYOCD)
36
Q

How is myocardin, MYOCD gene involved in opioid addiction?

A

Recent study using the Affymetrix 10 K GeneChip (Santa Clara, CA),which simultaneously genotyped 10,000 variants to identify genetic variants in genes involved in the vulnerability to develop heroin addiction showed the strongest association with genotype frequency for a variant in the gene coding for the transcription factor myocardin, MYOCD.

37
Q

How is the 5-hydroxytryptamine (serotonin)-1B receptor (HTR1B) gene involved in opioid addiction?

A

The 5-hydroxytryptamine (serotonin)-1B receptor (HTR1B) – mouse knockout has decreased anxiety/increased aggression and increased self-administration of various drugs as well as increased alcohol intake.

38
Q

How are Tryptophan hydroxylase genes (TPH1 and TPH2) involved in opioid addiction?

A

Tryptophan hydroxylase genes (TPH1 and TPH2). Some variants of these genes associated with addiction-related behaviors. Also TPHs are rate limiting for synthesis of melatonin. It is possible that disruption of circadian rhythm is involved in vulnerability to develop an addiction.

39
Q

How is the Catechol-O-methyltransferase (COMT) gene involved in opioid addiction?

A

Catechol-O-methyltransferase (COMT) - A substitution of 472GA (Val158Met) results in a fourfold decrease of activity of COMT, which results in enhanced response to the drug. In humans observed differences between the sexes in COMT Val158Met genotype. In mice COMT homozygous knockout female mice develop increased anxiety in a light–dark model compared to COMT knockout males. A reason can be hormonal since “in vitro” physiological concentrations of 17b-estradiol were shown to down-regulate COMT gene transcription and protein expression.

40
Q

What are the opioid withdrawal symptoms?

A
  • Elevation of temperature and blood pressure
  • Alteration of pulse rate
  • Restlessness
  • Diarrhea
  • Weight loss
  • Anxiety and depression

Most of the physiological aspects of opiate withdrawal are based upon an over-excitability of the noradrenergic system. The locus coeruleus is the major noradrenergic nucleus in the brain and is thought to be involved in physical dependence.

41
Q

Describe the basis for opiate tolerance

A
  • Tolerance develops in response to continuous opioid agonist treatment.
  • At the cellular level, receptor desensitization is caused by phosphorylation of receptor kinases leading to uncoupling of the receptor from the G-proteins.
  • Binding of β-arrestin to the phosphorylated receptor initiates receptor endocytosis, which is followed by receptor de-phosphorylation and recycling to the membrane.
  • A part of the receptors is degraded in lysosomes.
  • Trafficking - opioids differ in their ability to internalize opioid receptors. For instance, morphine and buprenorphine are unable to internalize receptors, whereas methadone and fentanyl induce a substantial receptor endocytosis. Since internalization followed by recycling causes a re-sensitization of the receptors, methadone and fentanyl show a lower development of tolerance.
  • An additional explanation for the differential development of tolerance by opioids is based on the theory of spare receptors. Opioids with a lower intrinsic activity, such as morphine or the partial agonist buprenorphine have to occupy a larger fraction of opioid receptors to produce the same effect. These opioids show therefore a faster tolerance development than opioids with a higher number of spare receptors (i.e., fentanyl or methadone). Moreover, adaptive mechanisms which antagonize opioid action can influence the development of tolerance.
42
Q

Describe trafficking and how it relates to opiate tolerance

A

Trafficking - opioids differ in their ability to internalize opioid receptors. For instance, morphine and buprenorphine are unable to internalize receptors, whereas methadone and fentanyl induce a substantial receptor endocytosis. Since internalization followed by recycling causes a re-sensitization of the receptors, methadone and fentanyl show a lower development of tolerance.

43
Q

Describe how spare receptors can influence opiate tolerance

A

An additional explanation for the differential development of tolerance by opioids is based on the theory of spare receptors. Opioids with a lower intrinsic activity, such as morphine or the partial agonist buprenorphine have to occupy a larger fraction of opioid receptors to produce the same effect. These opioids show therefore a faster tolerance development than opioids with a higher number of spare receptors (i.e., fentanyl or methadone). Moreover, adaptive mechanisms which antagonize opioid action can influence the development of tolerance.

44
Q

List five alternative theories to opiate tolerance

A
  • Activation of delta receptors in a μ/δ heterodimer leads to a diminished response due to degradation of the μ receptor.
  • cAMP theory says that tolerance involves a compensatory increase in adenylyl cyclase.
  • NMDA and NO interactions. MK-801 an NMDA antagonist and NOS inhibitors prevent or reverse tolerance to morphine.
  • P-Glycoprotein theory - P-Glycoprotein (Pgp) is a BBB transporter, which is upregulated in opiate abuse. To compensate this the higher doses of drug are needed to reach the brain.
  • Several other theories of development of tolerance have been proposed among them the protein kinase C and the platelet-derived growth factor receptor-b are the most popular.
45
Q

How are opiates and psychostimulants different in terms of neuroplasticity?

A

Opiates and psychostimulants have opposite effects on brain structural neuroplasticity

46
Q

What are morphological brain changes from chronic opiate use dependent on? How?

A

Morphological changes after chronic opiates are dependent on insulin receptor substrate 2

Chronic opiates induce down-regulation of insulin receptor substrate 2 (IRS2)-Akt pathway. Silencing of IRS2 induces decrease in size of the VTA neurons, which is also observed in chronic opiates. Overexpression of IRS2 prevented morphine-induced decrease in the cell size.

47
Q

How is heroin mediated reward different from cocaine mediated reward? (2)

A

Lesion of the mesolimbic dopamine system decrease cocaine but not heroin self-administration.

Dopamine receptor blocking in low dose increases cocaine administration, and decreases cocaine in high doses. Little effect on heroin self administration.

48
Q

How do opiates interact with the HPA axis? (4_

A
  • Proopiomelanocortin is a precursor of both β-endorphin and ACTH. •
  • Acute opiates suppress HPA activity and opiates withdrawal is
    associated with HPA activation.
  • HPA hypoactivity was found in former heroin addicts.
  • The melanocortin receptor type 2 (MC2R or adrenocorticotropic hormone, ACTH receptor) gene polymorphism can be associated with vulnerability to develop a heroin addiction.
49
Q

Describe some treatments of opiate addiction

A
  • Substitution therapy to prevent withdrawal and relapse (metadon)
  • Opioid receptor antagonist can immediately reverse cardiorespiratory depression from overdose (naloxone)
  • Vaccines can prevent opioids from having an effect. Developing of heroin vaccine is challenging because it is metabolized in the body into compounds that also act on opioid receptor
  • Gene silencing using delivery of gold nanorod-siRNAs
50
Q

Describe opioid addiction treatment with nanorod-siRNA

A

siRNA nanocomplexes are not degraded by nucleases and have ability to cross blood-brain barrier. Gold nanorod-DARPP-32 siRNA complexes in vitro reduced the expression of DARPP-32 and downstream signalling molecules ERK and PP-1 with no observed cytotoxicity.

51
Q

List some therapeutic uses of opiods

A
  • Analgesic and anesthetic
  • Anti-cough
  • Anti-diarrhea for cholera and irritable bowel syndrom
  • Chronic, non-cancer pain
52
Q

List three acute effects of opioids

A

analgesia, inhibition of gastrointestinal transit and respiratory depression.

53
Q

Chronic opiates have what structural changes on neurons in cortical and limbic structures?

A

Chronic opiates reduce dendritic arborisation of neurons in cortical and limbic structures.

54
Q

List the two main opioid actions in reward pathways

A
  • Opioid receptors, especially μ subtype mediate the rewarding properties of non-opioid drugs
  • Signaling via κ receptors provide negative feedback in the reward pathway.
55
Q

Which opioid signaller is important for cytoprotection?

A

δ receptor signalling

Molecular Neuroscience III (8 decks)

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