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PSYC 302 > Lecture 6: Pain neurochemistry and pharmacology > Flashcards

Lecture 6: Pain neurochemistry and pharmacology Flashcards

1
Q

What other species than human has been found to use analgesics?

A

Orangutans have discovered analgesic as well

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2
Q

How do humans discover medicinal plants?

A

We do trials with random plants

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3
Q

How would we ideally want to discover analgesics?

A

-neurochemistry–>pharmacololgy–>drug development

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4
Q

Why are drug mostly developed in pharmaceutical companies?

A

The limiting step in drug development is medicinal chemistry, and medicinal chemists are very rare and exist only in pharmaceutical companies.

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5
Q

Where is neurochemistry happening that we should be concerned with?

A
  • nociceptor development and maintenance
  • peripheral algogens
  • transduction
  • propagation
  • spinal cord presynaptic release
  • spinal cord postsynaptic processing
  • supraspinal processing
  • descending modulation
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6
Q

what are peripheral alogens?

A

-compounds in the periphery that cause pain

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7
Q

What do you have to play on in neurochemistry to either block or enhance neurotransmitters ?

A
  • neurotransmitter synthesis
  • neurotransmitter release
  • neurotransmitter degradation
  • neurotransmitter reuptake
  • receptors
  • signal transduction molecules
  • ion channels
  • transcription factors
  • epigenetic processing
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8
Q

What features of “drug targets” are drug companies most interested in?

A
  • “target”: protein that you want to block or enhance
  • some proteins are easier to develop drugs for. ex: g-protein coupled receptors.
  • ion channels are harder, transcription factors are almost impossible
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9
Q

What is a Nerve growth factor (NGF)?

A

-One of many neurotrophins

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10
Q

What are neurotrophins?

A

-Family of proteins that induce the survival, development, and function of neurons

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11
Q

What are the different stages of inflammation?

A
  • rubor, calor: redness, heat
  • tumor: swelling
  • dolor: pain
  • loss of function
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12
Q

What can we say is the main cause of pain aside from nerve damage?

A

inflammation

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13
Q

Why do we say that inflammation is the root of all evil?

A
  • It is the root of many pain syndromes and diseases

- Even if you can’t see it, it doesn’t mean that it isn’t there.

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14
Q

How can bacteria and other pathogens enter the body?

A
  • wound: broken skin. Skin is meant to prevent bacteria from coming in
  • intestines
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15
Q

During the inflammation process, what happens after the bacteria has entered the body?

A

Platelets from blood release blood-clotting proteins at wound site.

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16
Q

What do mast cells do during the inflammation process?

A
  • secrete factors that mediate vasodilation and vascular constriction.
  • delivery of blood, plasma, and cells to injured are increases.
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17
Q

What do neutrophils do during the inflammation process?

A

-secrete factors that kill and degrade pathogens

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18
Q

What do neutrophils and macrophages do during the inflammation process?

A

-remove pathogens by phagocytosis

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19
Q

What do macrophages do during the inflammation process? cytokines

A

-secrete hormones called cytokines that attract immune system cells to the site and activate cells involved in tissue repair.

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20
Q

Does the innate immune system require any prior exposure to start working?

A

-No, it gets right to work.

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21
Q

What works the best to treat inflammation?

A
  • steroids
  • classic one: dexamethasone, can be given orally or injected through the dura (epidural steroid injection)
  • very effective
  • but side effects
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22
Q

What are the main side effects of steroids?

A

blurred vision, weight gain, depression, bloody stool, pancreatitis, low potassium, high blood pressure.

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23
Q

What is the other way we an treat inflammation beside steroids?

A

-NSAIDs: Non-Steroidal Anti-inflammatory drugs

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24
Q

What do broken cells release and they are broke?

A
  • algogens
  • substance that causes pain
  • Ex: H+, adenosine, ATP
  • These bind to receptors for them in the free nerve endings
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25
Q

What does NGF bind to on nociceptors?

A

Track A.

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26
Q

What are the adequate stimulus for pain?

A
  • noxious heat/cold

- mechanical. that damages cells but also doesn’t.

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27
Q

Why does inflammation cause pain?

A
  • cells migrate to area of wound to kill pathogens
  • release chemicals (nTs) to inform brain that smt is happening
  • pain is signal that gets you to notice the wound
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28
Q

What does substance P do?

A

-causes neurogenic inflammation

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29
Q

What is an example of inhibitory system on the membrane of the free nerve ending?

A

endorphins, which act on mu receptors

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30
Q

Which well-known analgesic works entirely on a biological process of the “inflammatory soup”?

A

Ibuprofen which acts on PGE2.

31
Q

what does aspirin come from?

A
  • boiled willow bark
  • known since before the common era
  • mentioned in 80AD
  • probably older
32
Q

What was aspirin turned into later on?

A
  • salicylic acid

- no longer the most common

33
Q

What do COX1 and COX2 enzymes do ?

A
  • They both turn arachidonic acid into PH2, prostaglandin H2.
  • Then it is turned into other prostaglandines
  • They are nt that act on receptors: 4 kinds, IP, TP, EP or FP.
34
Q

What prostaglandin receptors are we concerned with in this course?

A
  • EPs because they are on nociceptors.

- These are the ones that NSAIDS are trying to act on.

35
Q

How do NSAIDs act on enzymes to relieve pain?

A

-Block COX1 and COX2 which in turn blocks cPGES, mPGES and PGE2

36
Q

How efficace are NSAIDs for postoperative dental pain?

A

Half your pain

37
Q

What is the issue with the efficacy of NSAIDs?

A

They have a ceiling effect, they can only kill so much pain.

38
Q

What are the potential side effects of NSAIDs?

A
  • Almost no one gets side effects from using a single dose of NSAIDS.
  • If you use them everyday, you can get gastritis (inflammation of the gastric lining and dyspepsia (gastric reflux)
39
Q

Can side effects of NSAIDs be lethal?

A

Yes (example overdose, don’t forget they are still drugs)

40
Q

What is the specificity of each COX1 and COX2?

A
  • COX1: constitutively expressed enzyme, always there, housekeeping function, plays roles in stomach intestine and kidney.
  • COX2: inducible enzyme, only produced when needed, only in the case of inflammation.
41
Q

what are examples of NSAID that have been created that only block COX2?

A
  • Rofecoxib, Celecoxib

- Would produce the same analgesia as Ibuprofen but without the gastric side effects.

42
Q

What was the reason of the Coxib Controversy?

A
  • Increases the risk heart attack or stroke (called APTC event)
  • The only coxib left on the market is celecoxib.
  • Can’t put drugs on the market that increase the risk of death
43
Q

What is the difference between acetaminophen (paracetamol) and NSAIDs?

A
  • paracetamol is not an NSAID because it is not anti-inflammatory
  • it is also an antipyretic (reduces fever)
44
Q

How do we think paracetamol works?

A
  • Not sure
  • Doesn’t act on COX1 and COX2
  • Probably acts on CB1 cannabinoid receptors in the rostral ventromedial medulla
45
Q

What is sensory transduction?

A

How physical energies and molecules in the world impact us and are turned into a neural code.

46
Q

What types of sensory transduction would he have to understand to understand pain?

A

Sensory transduction of the following stimuli:

  • heat
  • cold
  • touch
  • cell lysis
  • chemical (acid, base, irritants)
47
Q

What will activate the TRPA1 channel?

A

-something colder than 10degrees

48
Q

How does your brain know what temperature a stimuli is?

A

By knowing what TRP channel was activated

49
Q

How is the TRPM8 channel activated?

A

-cool stimuli between 10 and 20

50
Q

How is the TRPV1 channel activated?

A
  • heat stimulus higher than 43 degrees: ex capsaicin which is contained in chili peppers.
  • noxious heat threshold
  • TRPV2 activated at even higher stimuli
51
Q

what is anandamine?

A

endogenous cannabinoid nt

52
Q

What can activate the TRPV1 channel?

A
  • chemical: capsaicin, anandamide
  • heat: 42/43 degrees threshold
  • voltage
  • Other pathways can converge on TRPV1 and activate it
53
Q

What is an antagonist for the activation of TRPV1 channels?

A

resiniferatoxin. Possibly an analgesic?

54
Q

What makes the Ph go down?

A

inflamed tissue because free protons are release from burst cells

55
Q

What would happen if we blocked the TRPV1 channel?

A

-Maybe we would not feel heat

56
Q

What scientist won a Nobel price in 2021 for their research on the TRPV1 channel?

A

David Julius

57
Q

How did the clinical trials of TRPV1 antagonists turn out?

A
  • Most data has never been published

- Might not work

58
Q

What was the main side effect that TRPV1 antagonists gave?

A
  • fever
  • just 1 °or 2 in AVERAGE
  • so some people got like 5 degrees more than 37 normal body temperature, which can be lethal
59
Q

How can capsaicin actually work as an analgesic?

A
  • There is a desensitization period after activation of TRPV1, can last minutes to hours, to forever.
  • Capsaicin is an agonist, used topically, activates channel to create desensitization.
  • Pain gets worse before it gets better.
59
Q

How can capsaicin actually work as an analgesic?

A
  • There is a desensitization period after activation of TRPV1, can last minutes to hours, to forever.
  • Capsaicin is an agonist, used topically, activates channel to create desensitization.
  • Pain gets worse before it gets better.
60
Q

What scientist won a Nobel prize in 2021 for their work on transduction of mechanical pain? (specifically Piezo)

A

-Ardem Patapoutian

61
Q

what can we say about transduction of mechanical pain?

A
  • We don’t know yet how it is transduced
  • We have contenders, but no consensus on what exactly transduces pain.
  • We do know however that Piezo channels (2 of them) transduce touch
62
Q

What would be analgesics in regards to sodium and potassium channels?

A
  • Sodium Na+ channel blocker

- Potassium K+ channel agonist

63
Q

What does Lidocaine do?

A
  • It is a sodium channel blocker

- Local anesthetic: no pain or feeling

64
Q

What is the problem with lidocaine?

A
  • Can’t use that on a regular basis
  • You can target only the sodium channel that are in the PNS, which are Na 1.7, Na 1.8 and Na 1.9
  • trying to come up with that
64
Q

What is the problem with lidocaine?

A
  • Can’t use that on a regular basis
  • You can target only the sodium channel that are in the PNS, which are Na 1.7, Na 1.8 and Na 1.9
  • trying to come up with that
65
Q

What is the problem with lidocaine?

A
  • Can’t use that on a regular basis
  • You can target only the sodium channel that are in the PNS, which are Na 1.7, Na 1.8 and Na 1.9
  • trying to come up with that
66
Q

What is the challenge in trying to target specific sodium channel for lidocaine use?

A

If the drug doesn’t have very good selectivity and it blocks Na 1.5, your heart will stop and you will die.

67
Q

What are some inherited disorders of the SCN9A gene (Na 1.7)?

A
  • HSAN Type V
  • Paroxysmal Extreme Pain Disorder
  • Primary Erythromelalgia
68
Q

What does HSAN Type V do to you?

A
  • aka congenital insensitivity to pain
  • no pain, no other symptoms
  • inability to sweat
  • loss of function mutation
  • most probably no mental issues
69
Q

What does Paroxysmal Extreme Pain Disorder do to you?

A
  • comes and goes, not always there
  • Gain-of-function disorder
  • Hyperactive Nav 1.7 channels
  • Very intense Pain
  • Usually just in babies
  • In and around the rectum
70
Q

What does primary erythromelalgia?

A
  • Gain-of-function disorder
  • Pain and erythema (redness)
  • Hand and feet
  • Cold water seems to help
71
Q

Why does the fact that these diseases sometimes cause pain only in specific places or at specific times doesn’t make sense?

A

-genes are expressed everywhere at all times, so the pain should be everywhere at all times.

PSYC 302 (7 decks)

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