Lecture 6

Question 1

What are neurotrophins?

Answer 1

They are how nociceptors stay alive and are controlled.

Question 2

Who was Rita Levi-Montalcini?

Answer 2

She won the Nobel Prize for an experiment showing that if you take a nerve cell and you add NGF (nerve growth factor), then that neuron starts sending out axons looking for something to bind to, which is how nerves and nociceptors develop.

Question 3

What are the five things inflammation injuries lead to?

Answer 3

Rubor (redness), calor (heat), tumor (swelling), dolor (pain), and loss of function.

Question 4

What causes the redness of a wound?

Answer 4

Vasodilation

Question 5

What do cells release once they are harmed?

Answer 5

Glutamate (the major excitatory transmitter) which binds to glutamate receptors, adenosine which binds to adenosine receptors called 2ATP (energy molecules which bind to P2X receptors), H+ (protons, or acid) which binds to proton receptors called ASICS, and bradykinin.

Question 6

What are algogens?

Answer 6

NGF (nerve growth factor), IL1, bradykinin (which acts on B1 and B2, released PGE2, which binds to EP), histamine, and serotonin. They are all things that cause pain, as when they’re released, they bind to receptors on nociceptors, making the nociceptors fire.

Question 7

What are ion channels?

Answer 7

Ion channels can sometimes be activated directly or indirectly through signal transduction pathways that are themselves activated by the fact that a receptor has been bound by something. Some examples of ion channels are NAV channels and TRPV1.

Question 8

What are some examples of inhibitory receptors?

Answer 8

MU, GABA-A, somatostatin, etc.

Question 9

What is aspirin derived from?

Answer 9

It derives from the bark of a willow tree, which secretes salicylic acid.

Question 10

What is PGE-2?

Answer 10

It is the algogen that causes pain to the extent that it binds to the EP receptor.

Question 11

What is the synthesis pathway to get to PGE-2?

Answer 11

It starts with arachidonic acid, which comes from cholesterol. If the arachidonic acid comes into contact with either COX-1 or COX-2, it will turn into PGH-2. An enzyme called PGES turns PGH-2 into PGE-2.

Question 12

Where are EP receptors found?

Answer 12

EP-1 is found in the kidney, lungs, spleen, muscle, testis, and uterus.
EP-2 is found in the lungs, the placenta, and the heart.
EP-3 and EP-4 are found in the brain (nervous system).

Question 13

What do NSAIDs do?

Answer 13

NSAIDs block COXs’, which means that there is less PGE2, which means that there is less activation at the EP receptors, and therefore less perceived pain.

Question 14

What is the difference between COX-1 and COX-2?

Answer 14

COX-1 is a constitutive enzyme that is always made, always there, and must always be there, because it’s involved in “housekeeping” functions. COX-2 is an inducible enzyme, which means that it is only expressed when it’s needed (inflammation in mast cells).

Question 15

What are the three main drugs created to inhibit COX-2?

Answer 15

Celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra). Celebrex is the only one still on the market.

Question 16

What is the ion channel that fires at noxious heat in your mouth?

Answer 16

TRPV1 fires for things like capsaicin, and TRPV2 fires for things over 52°C.

Question 17

What is the ion channel that fires at noxious cold in your mouth?

Answer 17

TRPA1 fires for things that are under 17°C.

Question 18

Who discovered TRPV1?

Answer 18

David Julius.

Question 19

What are some inherited disorders of the SCN9A gene?

Answer 19

SCN9A is the gene that codes for NAV1.7. It is behind HSAN type V (no pain, no other symptoms, loss-of-function mutation), paroxysmal extreme pain disorder (pain and erythema, rectum and back of thighs, usually only in babies, gain-of-function mutation), and primary erythromelalgia (pain and erythema, hands and feed, gain-of-function mutation).

Question 20

What is an agonist?

Answer 20

A drug that acts like a neurotransmitter, binding to the receptor and activating it.

Question 21

What is an antagonist?

Answer 21

A drug that binds to the receptor and prevents things that could activate the receptor from binding. They can either be competitive (something that goes in and out, and the more it’s in, the less other things can get in), or non-competitive (something that goes in and stays there, doesn’t leave, and takes that receptor out of action until it is recycled.

Question 22

What is a partial agonist?

Answer 22

Something that can be either an agonist or an antagonist, depending on the context and circumstances under which they are used.

Question 23

How was stimulation-produced analgesia (SPA) discovered?

Answer 23

In 1969, a man named David Reynolds did an experiment that was published in ‘Science’. He took a rat and implanted an electrode into a particular part of the rat’s brain. He passed a small electrical current into the brain, just enough to make neurons fire an action potential, and found that the rat had become so analgesic that it didn’t need anesthesia anymore.

Question 24

What is the most reliable area of the brain to get SPA from?

Answer 24

The periaqueductal grey. It also works in the rostroventral medulla (RVM).

Question 25

What are the 3 major types of receptors and who discovered them?

Answer 25

The MU, the delta, and the kappa; they are all inhibitory. Saul Snyder and Candace Pert discovered the receptors in 1973. The opioids corresponding to the receptors were discovered by Hughes and Kosterlitz in 1975.

Question 26

What was the first endogenous opioid to be discovered?

Answer 26

Encephalin

Question 27

When does analgesia become hyperalgesia in stressful situations?

Answer 27

If the stress is due to a threat that is perceived as being life-threatening, it will produce analgesia; if the stress is mild, it will produce hyperalgesia. If the stress is chronic, it is more likely to produce hyperalgesia than acute stress. In the presence of inflammation or nerve damage, the same kind of stress that would produce analgesia will now produce hyperalgesia. After prolonged exposure to opioids, the same kind of stress that would produce analgesia will now produce hyperalgesia.

Question 28

What are the three types of neurons?

Answer 28

There are neutral cells that don't care about whether there is a pain stimulus or not. There are on-cells that are quiet until there is pain, then they turn on. There are off-cells that are firing all the time until there is pain, then they turn off.

Question 29

What is a tricyclic antidepressant?

Answer 29

The first type of antidepressant to be discovered. This includes Amitriptyline.

Question 30

What is the third generation of antidepressants called?

Answer 30

SNRIs (selective norepinephrine reuptake inhibitors). This includes Duloxetine. These antidepressants are better for chronic pain than SSRIs.

Question 31

What is the second generation of antidepressants called?

Answer 31

SSRIs (selective serotonin reuptake inhibitors). This includes Prozac.

Question 32

As of 2009, what was the US market for analgesic drug development?

Answer 32

$27 billion

Question 33

What percentages of different analgesic drug-types made up the US market in 2009?

Answer 33

Opioids made up about 36%, NSAIDs were 28%, anti-convulsants were 13%, antidepressants were 11%, COX-2 inhibitors are 7%, and local anesthetics were 5%.

Question 34

What were the top-selling analgesic drugs of the 2009 US market?

Answer 34

Cymbalta (duloxetine), which was $4 billion; Lyrica (pregabalin), which was almost $4 billion; and Oxycontin, which was almost $3 billion.

Question 35

What are the 5 stages of drug development?

Answer 35

Phase 0 - everything that happens before a clinical trial occurs; based on the strength of the preclinical data, drug company executives will ask for a clinical trial. Phase 1 - this phase is not interested in whether the drugs work for the thing it's designed to work for; it tends not to collect data; this part of the clinical trial is to see if the drug is fatal and to assess the toxicity, the dose, and the route of administration. Phase 2 - looking to see if the drugs beats placebo; evaluating the effectiveness and determining the side effects. Phase 3 - validate the effectiveness of treatment Finally, there is FDA approval and market introduction.

Question 36

How long on average does each part of the drug development process take?

Answer 36

The preclinical part takes about 6-10 years, the clinical trials take about 8.5 years, and FDA approval takes about 1.7 years.

Question 37

What percentages of drugs get FDA approval?

Answer 37

56% of drugs make it past phase 1, 20% make it past phase 2, 12% make it past phase 3, and only 11.6% make it past FDA approval.

Question 38

Why did Prialt fail even though it made it past FDA approval?

Answer 38

They never figured out how to make this drug in oral form, only through intrathecal injection which are too expensive and inconvenient.

Question 39

What are the two types of CGRP drugs?

Answer 39

Monoclonal antibodies, which are administered by injection and are preventative or prophylactic. Gepants, which are pills and are used for acute treatment of migraines.