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PSYC 302 Post midterm 2 > Pain Neurochemistry > Flashcards

Pain Neurochemistry Flashcards

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1
Q

What are the potential targets in the spinal cord to inhibit pain?

A
  • Prevent the release of neurotransmitters in the presynaptic neuron
  • Prevent action potential in postsynaptic neuron (projection or second-order neuron)
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2
Q

What are some potential analgesics that target the spinal cord and how do they work?

A

ACTS ON PRESYNAPTIC CELL

Pregabalin
- Blocks calcium channels in the presynaptic neuron which prevents vesicle release

THC
- Blocks CB1 receptors on presynaptic cell

ACTS ON POSTSYNAPTIC CELL

Ketamine
-NDMA receptor antagonist –> blocks glutamate

Topiramate
- Activates GABA receptors which inhibits neuron

ACTS ON PRE/POSTSYNAPTIC CELL

Duloxetine
- Blocks α2 receptors in presynaptic cell to prevent neurotransmitter release and in postsynaptic cell to prevent action potential

Baclofen
- activate Gaba receptors in pre/post-synaptic cell (inhibitory)

Morphine
- Blocks μ receptors in pre/post synaptic cell

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3
Q

What is off label prescribing?

A

If a drug is approved, then doctors can prescribe it for anything

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4
Q

What were pregabalin and gabapentin originally developed to treat?

A

Epilepsy

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5
Q

How to pregabalin and gabapentin work to reduce pain?

A
  • Binds to calcium channels which blocks calcium entry –> prevents neurotransmitter release
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6
Q

What is the difference between gabapentin and pregabalin?

A
  • Have the same pharmacodynamics (do the same thing to the body)
  • Have different pharmacokinetics –> pregabalin (Lyrica) is much more potent therefore you use much lower doses than gabapentin (Neurontin)
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7
Q

Why do we not target thalamocortical pathways for pain inhibition?

A
  • Theoretically, we CAN target the neurochemistry in the cortex to produce analgesia
  • Problem is that the thalamus and the cortex are MUCH more complicated than the spinal cord
  • The thalamus is also much less studied and is also way less accessible
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8
Q

Have any drugs been approved that target the post-synaptic signal transduction pathways?

A
  • There are MANY analgesia targets but no, none have been developed
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9
Q

What is the difference between opium, opiates, and opioids?

A
  • Opium is the active ingredient found in the poppy plant
  • Opiates are drugs that are synthesized based on the structure of opium (changed with chemistry)
  • Opioids are a broader category which include endogenous drugs –> include drugs which are not derived from natural plant matter
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10
Q

How does Narcan prevent overdoses?

A

Naloxone is a full opioid receptor antagonist –> causes immediate withdrawal

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11
Q

How do opiates act on the body?

A

Full agonists
- Morphine/oxycodone

Partial agonists
- Methadone/ buprenorphine
- Can act as either an agonist or an antagonist depending on the context
- Drug that is typically given to opioid addicts because you don’t go through withdrawal but there’s no chance of overdosing

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12
Q

What’s the difference between a competitive agonist and a non-competitive agonist?

A

Competitive Agonists
- Bind to receptor then leaves

Non-competitive agonists
- Bind to receptor and stay there until it is recycled

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13
Q

What is the difference between potency and efficacy?

A

Efficacy –> does the drug work
Potency –> How much of the drug is needed for it to work

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14
Q

Why is potency important to consider when calculating doses?

A
  • The more potent a drug is, the less of it you need to have an effect, and therefore the easier it is for you to overdose
  • Important because it matters when considering side effects
  • i.e. the bigger the pill, the less potent the drug is
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15
Q

What is the most potent opioid?

A

Carfentanil

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16
Q

What is stimulation produced analgesia? Which areas is the most effective at producing analgesia? How does naloxone effect stimulation produced analgesia?

A
  • Stimulation produced analgesia is when a current is passed through an electrode implanted in the brain and it causes analgesia
  • The area that is most effective at producing analgesia when stimulated is the periaqueductal grey (PAG)
  • You can reverse the analgesia effects of stimulated produced analgesia if you administer naloxone (an opioid antagonist), but ONLY in certain areas of the PAG
  • Naloxone delivered to other areas of the PAG is ineffective

TAKEAWAY: Some forms of stimulation produced analgesia is modulated by opioids BUT there are also non-opioid modulated forms of SPA

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17
Q

In what areas of the descending pain modulatory system does morphine injections and stimulation produce analgesia?

A
  • Periaqueductal grey (PAG)
  • Rostro-ventral medulla (RVM)

Evidence that the descending modulatory pathways of pain are modulated by opioids

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18
Q

Which were discovered first, the opioid receptors of the endogenous opioids that activate them? What is the controversy surrounding it?

A

The opioid receptors were found first

  • Controversy because no one won the Nobel prize because of Pert’s complaints that she wasn’t nominated
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19
Q

What are the 3 opioid receptors?

A
  • Mu (μ)
  • Delta (δ)
  • Kappa (k)

Inhibitory receptors

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20
Q

Which endogenous opioid was the first to be discovered and how?

A
  • Enkephalin
  • By dissecting pig thalamus
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21
Q

Why do we have a descending pain modulatory pathway?

A
  • To inhibit pain during times when your life is at risk
  • AKA stress induced analgesia
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22
Q

Explain the studies that show stress induced analgesia.

A
  • Under the threat of predation (when a cat is in the room), rats will endure higher shock levels before making a tail flick
  • Immediately after SPORT competition, players showed the lowest ratings on a cold pressure test (less painful)
  • After an intruder mouse was bitten by the resident mouse, the intruder will take longer to produce a tail flick –> stress induced analgesia ONLY for the intruder mouse
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23
Q

What is it called when descending modulatory pathways enhance pain?

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A

Stress induced hyperalgesia

24
Q

What determines whether a stressor will cause descending inhibition or facilitation

Study These Flashcards
A
  • The same stressor can cause both SIA and SIH

Will enhance pain (SIH)
- If the stressor is mild
- if the stressor is chronic
- After injury –> if you have inflammation or nerve damage
- AFTER PROLONGUED EXPOSURE TO OPIODS

When there is a threat to survival = analgesia
When threat is not fatal = hyperalgesia

25
How do opioids produce hyperalgesia?
After prolonged use, opioids can actually make the pain worse --> only seems to work for acute pain 4 injections of fentanyl in rats - For 7 hours, rats are analgesic and can withstand more paw pressure - After 7 hours, analgesia wears off and they return to baseline - A day later, in the absence of fentanyl, the rats are hyperalgesia which lasts a week --> can withstand less paw pressure No injury, no drug = control No injury + morphine = hyperalgesia after morphine injection which resolves after 1 week Injury + no drug = allodynic but resolves after 4 weeks Injury + Morphine = allodynic but takes 12 weeks to resolve --> extended the amount of time they were in neuropathic pain
26
What opioid receptor does naloxone block?
- At high enough doses, it will block all 3 - At low doses, it only blocks μ
27
What are side effects of the μ opioids receptor?
- Respiratory depression (why it kills) - Miosis (squinting) - Constipation - Euphoria (why addiction is a problem)
28
Why do we want to develop delta agonists for analgesics? Why do we not see kappa drugs?
- We hope that delta drugs will have less side effects than μ. - We don't develop kappa drugs because they cause dysphoria --> makes us feel like shit so people stop taking them
29
What receptor was originally thought to be an opioid receptor, but isn't?
Nociceptin
30
What receptor does DAMGO activate
μ
31
What is the problem with developing drugs that target opioid receptors?
They are found everywhere in the brain and body!
32
Which side effect would NOT be resolved if we found an opioid receptor drug that only targeted the brain?
Euphoria and dysphoria
33
Why do opioids cause constipation?
Because opioid receptors are found in the intestines
34
What are the 3 genes that produce the endogenous opioids? What receptors do they bind to?
POMC --> b-endorphin --> μ and delta PENK --> enkephalin --> mostly delta, a little μ PDYN --> dynorphin --> only kappa
35
Which peptide/endogenous opioid has no known gene? Which receptor does it bind to? How does it differ from the other peptides?
endomorphin 1/2 -Only binds to μ receptor - Has different amino acid sequencing than the other peptides
36
Why is there so many more proteins than there are genes?
because the same gene can produce many different proteins through alternative splicing
37
What are ON and OFF cells? How do they relate to descending inhibition in the RVM?
- ON cells fire with pain (right before a tail flick) - OFF cells fire when there ISNT pain aka neutral or analgesia (turn off right before tail flick)
38
How does DAMGO affect ON and OFF cell firing in the RVM?
After DAMGO (μ receptor agonist aka an analgesic) - OFF cells will continue firing even when heat lamp is turned on - ON cells will stop firing when heat lamp is turned on
39
How does acupuncture affect pain?
- Acupuncture is clinically effective but not for how they advertise it to work In Mice - Electrical acupuncture in mice causes analgesia that lasts 45 minutes - Effects are removed with naloxone --> proof its mediated by opioids
40
What is the Opioid hypothesis posited by Ji Sheng Han
Electrical acupuncture delivered at different frequency levels rely on different opioid receptors Low frequency = μ dependant Medium Frequency = non specific High frequency = kappa dependent
41
How do antidepressants affect pain?
SSNI --> serotonin noradrenaline reuptake inhibitors - i.e. tricyclic antidepressants like amitriptyline They increase serotonin and noradrenaline which play a role in the descending inhibitory pathways of pain --> inhibits projections neurons from going up
42
Where are cannabinoid receptors found? What are their endogenous ligands? Do cannabinoids work well for chronic pain?
In the CNS --> CB1 In the PNS --> CB2 Ligands: anandamide, 2AG, cannabidiol Evidence that cannabinoids work for chronic pain is WEAK
43
How much of the drug market is for the production of opioids?
35%
44
How long does it normally take for the drug development process to take?
10 years from the beginning of the clinical trial Another 10-ish years in preclinical trials
45
What are the phases of drug development?
Phase 0 (preclinical) - Animal trials - Molecular biology studies Phase 1 - Assess toxicity - Determine safe dosage - Determine administration route - 50 healthy controls Phase 2 - Evaluate effectiveness - Determine side effects - 350 Patients (which the disorder) Phase 3 - Validate effectiveness - 3000 patients (with the disorder) - Most expensive phase FDA or EMA approval --> market introduction
46
What % of drugs successfully complete each phase of the clinical trial. What does that mean for your drug if you successfully beat phase 3.?How many drugs get rejected during the entire clinical trial process?
Phase 1 = 50% success rate Phase 2 = 20% Phase 3 = 12% FDA approved = 11.6% Passing phase 3 basically guarantees FDA approval. 90% of clinical trial drugs get rejected, only 10% get accepted
47
How much does it cost for a drug to get developed on average?
100 million
48
Why do drug companies charge so much for their product?
- Because drug development is extremely costly, NOT the production.
49
Why are generic versions of the drug so much cheaper?
- Because they aren't the ones who developed it.
50
Which class of drugs are the least likely to be approved?
Oncology (cancer drugs)
51
What is the #1 reason why drugs get rejected in clinical trials? What does this tell us about our animal models?
50% rejected drugs are rejected because they didn't beat placebo - This suggests that our animal models aren't good at reflecting human models --> the drugs beat placebo in mice but they fail half the time when they are used for humans
52
Which drugs are the most likely to beat placebo?
Opioids and NSAIDs
53
What is the file drawer problem? What is the proposed solution?
- The truth of success rate in clinical trials is WAY worse than it appears --> they only represent the studies that were published - We used to ONLY publish trials when they worked and if the data didn't look promising, they would never reach the light of day SOLUTION: clinicaltrials.gov -NOW, studies must register their protocol BEFORE the trial even starts --> they must identify their primary outcome (before this, whatever worked would become their primary outcome) - Problem --> if researchers still decide to NOT publish their findings, no one is going to pursue them for it.
54
Explain how NK1 antagonist drugs failed to translate to human models.
NK1 is a receptor for substance P --> blocking this should cause analgesia In animal models - NK1 antagonists worked just as well as morphine and methacin in almost everything - The only it didn't work for was acute pain which they didn't care about because it was supposed to treat chronic pain (tail flick, and paw pressure) BUT in human models - Almost ALL NK1 antagonists failed --> suggests there is something inherently wrong with our animal models
55
Explain what Prialt is, and if it was ever FDA approved
Prialt is snail venom that works by blocking calcium channels - only beats placebo by 0.4 points (not good) - ONLY WORKS in intrathecal infusions - Meaning there is no pill, need to see a doctor to receive it - Therefore, only those whose pain is MAJOR would bother taking it --> basically cancer patients who don't respond to anything else The development process was extremely costly and Elan, the company who developed it ran out of business.
56
Explain what Tanezumab is and if it ever got FDA approved?
Tanezumab is a nerve growth factor inhibitor developed to treat osteoarthritis - In phase 2 trials, a high dose beat placebo by 40 points (which was crazy at the time) - Trials were stopped because a small number of ppl developed rapidly progressing OA --> got much worse - Belief that this worsening was caused because the drug worked so well, that they were overusing their joints to the point of damage --> not true - The actual danger was that tanezumab in combination with NSAID use lead to this OA worsening - Trial 3 resumed but only beat placebo by 1 point (womp womp) - FDA not approved due to the side effect
57
What are Gepants and MABS
MABS (monoclonal antibodies) and Gepants both used to treat migraines by inhibiting CGRP in the dura matter of the brain - MABS work as a preventative treatment and Gepants are for acute pain reduction - MABS work better than placebo but only by 1-2 days

PSYC 302 Post midterm 2 (2 decks)

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