Pain Quiz 4

Question 1

Common Treatments: which two?

Emerging Treatments: which one?

What is an NSAID? How Do They Work? COX 1 VS 2?

Answer 1

Common Treatments:
- NSAIDs (Non-steroidal anti-inflammatory drugs) first step on analgesic ladder
- Opioids

Emerging Treatments:
- Cannabinoids

What is an NSAID?
– NSAIDs stand for Non-steroidal anti-inflammatory drugs
– They are the first class of drug suggested to treat acute pain - step 1 on ladder
– They are the most commonly used drugs to treat pain – both over the counter and prescribed by physicians - include aspirin, ibuprofen (advil)

How Do They Work?
Tissue injury is cut or burn then phospholipase the convert into A2 arachidonic acid then COX 1,2

Cox 1 - is everywhere all over body mostly cytoprotective properties
Cox 2 - in most tissue but it is induced or has to be turned on and is for inflammation, pain, and fever(temp control)

NSAIDs inhibit COX enzymes

Question 2

NSAIDs Often recommended as the first choice in many patients who can tolerate it and most used

Dosage forms: which two?

Combination with opioids: ?

Combination with acetaminophen:?

Answer 2

Dosage forms:
Gel caps (faster absorption) OR Mucoadhesive patch are time release and localized

Combination with opioids: Different sites of activation and metabolized differently - adjuvant add one drug along another to increase efficacy and decrease dose and or side effects - trying to have synergy

Combination with acetaminophen: Different sites of activation and metabolized differently - adjuvant add one drug along another to increase efficacy and decrease dose and or side effects - trying to have synergy

Question 3

Question: Given the functions of COX-1 predict some potential negative side effects of inhibiting COX-1 activity.

Questions: Given the functions of COX-2 predict some potential negative side effects of inhibiting COX-2 activity.

Answer 3

COX1: Answer - Peptic ulcer, GI bleeding, and water retention

COX2: Answer - Stroke, hypertension, acute kidney injury

Question 4

Opioid Receptors: ?

Types of receptors: which three?

Endogenous Opioids + the receptors they bind to: which three?

Answer 4

Opioid Receptors: differ in cellular distribution, affinity, and effects but all are 7 transmembrane spanning proteins that couple to inhibitory G proteins these are slower acting and bind ligands and have to activate another set relies on second messengers

Affinity refers to the strength or likelihood with which a molecule, such as a drug or ligand, binds to its target, like a receptor.

Types of receptors:
Mu opioid receptor (MOR)
Delta opioid receptor (DOR)
Kappa opioid receptor (KOR)

Endogenous Opioids + the receptors they bind to:
Endomorphin (mu)
Enkephalin and endorphin (delta)
Dynorphin (kappa)

Question 5

Question 1: Which receptor do most prescription opioids bind to?

Question 2: What ion channel(s) have their activity altered following activation of G-proteins bound to mu-opioid receptors? How do you think their activity is altered?

Question 3: Opioid Receptors How do opioids work?

Answer 5

1: The mu opioid receptor and mimic endogenous opioids(traditional)

2. Since second messengers are required like cyclic AMP and ATP maybe then VG Ca
3. Activation by an agonist like endomorphin binds G-protein and activates than once activated by phosphorylation and closes the VG Ca channel inhibiting it and reduces the amount of Ca into the cell and will reduce positive charge causing hypo further away from threshold to send AP so neuron less likely to fire - and opens K channels leaving cell so hypo - decreasing pain sensitive neurons so inhibiting pain sensation sent to brain

Question 6

Side Effects of Opioids besides good analgesic effects: 8?

Answer 6

Side Effects of Opioids besides good analgesic effects:

Sedation - arousal

Constipation - gastric motility

Nausea - increase activation in medulla

Respiratory depression - dose dependent and reduce brain stem activation in pons and medulla

Immunosuppression - immune cells express opioid receptors

Analgesic Tolerance - adaptation people will need to take more drug to get same effect

Itching - pruriceptive circults

Addiction - physical and psychological dependence

Question 7

Definitions Related to the Use of Opioids for the Treatment of Pain - Consensus Document

Addiction:?

Physical dependence:?

Tolerance: ?

Answer 7

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

Physical dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. - withdrawals when stop

Tolerance: is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. - need more drug for same effect
These are hallmark of addiction(physical dependence and tolerance)

Question 8

Opioid Receptors in the Enteric Nervous System(gut) - side effects is constipation:
– Expressed in ?
– Involved in impairment of ?
– Enkephalin is ?
– Loperamide is a ?

Opioid Receptors in the Brainstem - serious side effect is respiratory depression that’s how people overdose:
– High expression of opioid receptors in the ?
– Brainstem nuclei responsible for?
– Rhythm generation is inhibited by?
– Higher opioid doses result in diminished?

Answer 8

Opioid Receptors in the Enteric Nervous System(gut) - side effects is constipation:
– Expressed in motor neurons and interneurons
– Involved in impairment of intestinal transit the opiate-induced - opiates can slow down the movement of food through your intestines
– Enkephalin is co-localized with MOR likely the endogenous ligand regulating motility in GI tract
– Loperamide is a peripherally(one benefit can’t cross BBB inorder to treat diarrhea) restricted opioid that is used to treat diarrhea (Immodium)

Opioid drugs often cause constipation bc in GI tract mu-opioid receptor plays a role in regulating motility by inhibiting NT release and leading to slowed gut movements. mu-opioid receptor is G-protein-coupled receptor and mu-opioid receptor mediate the effects of endogenous(in body) opioid peptides such as enkephalins, as well as exogenous opioids like morphine. Endogenous is naturally produced inside an organism or cell and exogenous originating outside a living organism. Endogenous(in body) opioid peptides such as enkephalins regulate motility in GI by acting on opioid receptors to slow down bowel movements.

Opioid Receptors in the Brainstem - serious side effect is respiratory depression that’s how people overdose:
– High expression of opioid receptors in the Pons (a part of the brainstem - that regulates HR, BP, breathing)
– Brainstem nuclei responsible for keeping us alive – heart rate, breathing, blood pressure
– Rhythm generation is inhibited by opioids; changes in the respiratory pattern are observed at lower opioid doses.
– Higher opioid doses result in diminished tidal volume - reduces sensitivity to C02 so physical ability to breath but also actually drive to breath

Question 9

Cannabinoid Receptors and Ligands

Cannabinoid Receptors: ?

Endogenous ligands: ?

Exogenous ligands: ?

How do cannabinoids work?

CB1 VS CB2?

Cannabis Reduces Pain Scores in Patients in painful HIV-associated sensory neuropathy: ?

Answer 9

Cannabinoid Receptors: CB1 &CB2

Endogenous ligands:
– Called endocannabinoids
– AEA (Anandamide) and 2AG (2-aeachidonoyl glycerol)

Exogenous ligands:
– Plant cannabinoids: cannabis sativa - pot/marjuina
– Synthetic cannabinoids

How do cannabinoids work?
Similar to opioids that are inhibitory for G-proteins and reduce VG Ca entering and increase K leaving both cause hypo so decrease AP which reduces pain perception

CB1: have broad expression in brain liver etc and primary expressed on neurons where most are usually axons

CB2: are immune cells in periphery T and B and monocytes but in CNS microglia also neurons (brainstem, cortex, cerebellum)

Cannabis Reduces Pain Scores in Patients in painful HIV-associated sensory neuropathy: A randomized placebo(hindbrain inhibiting spinal cord neurons)-controlled trial - either gave a cannabis(30% reduction in pain) or regular cig - cannabis treatment for chronic pain

the binding of opioids to G-protein-coupled receptors activates the G-proteins, which then inhibit voltage-gated calcium channels (reducing calcium entry) and activate potassium channels (increasing potassium exit), leading to hyperpolarization and decreased action potential firing, thereby reducing pain perception. G-proteins are normally inactive until a ligand, such as an opioid, binds to the receptor and activates them.

Question 10

Question: One way to reverse an opioid overdose is through administration of fill in the blank , which is an opioid receptor antagonist. It works because it has a higher fill in blank for the receptor than most opioids.

Answer 10

Answer: Naloxone, affinity

Question 11

NSAIDs: Explain the series of steps that occurs following tissue injury, and where in this pathway ?

Opioids: What happens when an opioid binds to its receptor? Is it an ionotropic or metabotropic receptor? Which ion channels are affected? What does this do to membrane potential?

Answer 11

NSAIDs act to reduce pain → stab HTM vs burn TRP V1 + V2 then damage tissue release DAMPS + PAMPS from the phospholipid in the membrane leave to make the conversion into arachidonic acid and NSAIDS act as COX 1 + 2 inhibitors which are enzymes that helps to convert arachidonic acid into prostaglandins. COX 1 constitutional is everywhere always active in every cell and COX 2 inducible in a specific scenario are upregulated when needed in inflammatory conditions.
– Tissue injury is cut or burn then phospholipase A2 and then convert into arachidonic acid then COX 1,2
– Cox 1 - is everywhere all over body mostly cytoprotective properties
– Cox 2 - in most tissue but it is induced or has to be turned on and is for inflammation, pain, and fever(temp control)

G protein metabotropic. Opioid binds to MU opioid activates the G protein and closes Ca extracellular and opens K channel double hit of inhibitory action leading to hyperpolarization further away from threshold. Have a lot of MU opioid receptor in the brainstem and pons which controls breathing

Question 12

COX1:
Functions: 5?
Negative Effects of Inhibiting: 5?

Answer 12

COX1:
Functions:
– Vasodilation of kidneys
– Increase Na and water excertion from kidneys
– Gastric protection: increase mucus secretion, increase bicarbonate, increase mucosal blood flow
– Circulatory system (general) vasoconstriction
– Platelet Aggregation (how well platelets, a part of blood, clump together and cause blood to clot)

Negative Effects of Inhibiting:
– Na and water retention
– Kidney hypertension: high blood pressure caused by the narrowing of your arteries that carry blood to your kidneys
– Hemodynamic(blood flow) acute kidney injury
– Peptic ulcers and GI bleeding
– Increase risk of bleeding (hemo stroke)

Question 13

COX2:
Functions: 4?
Negative Effects of Inhibiting: 6?

Answer 13

COX2:

Functions:
– Vasodilation of kidneys
– Increase Na and water from kidneys
– Circulatory system (general) vasodilation
– Inhibit platelet aggregation

Negative Effects of Inhibiting:
– Na and water retention
– Kidney hypertension
– Hemodynamic acute kidney injury
– stroke ischemic
– High BP
– M.I increase the risk of myocardial infarction - “heart attack,” is caused by decreased or complete cessation of blood flow to a portion of the myocardium

Question 14

QUESTION:
Way to enhance the activity of oxymorphinodole (OMP strong opioid) in order to be able to reduce the dosage to a safer level. In order to do this they tried pairing OMP with Loperamide. Anti diarrhea and stays in the periphery so can not cross BBB. Opioid receptors in the gut which are inhibitory and slows down GI so side effect is constipation

Intrathecally:?

1. What happens to the dose-response curve when loperamide and OMP are given together compared to when they’re given alone? What does the combination do to the tail-flick response?
2. Based on the isobologram, is administering the two drugs additive, synergistic, or antagonistic
   (1+1 get 2 inside of 8 so worse putting together than just grieving separately so they counteract each other) ?
3. What does synergistic mean? What does it mean in terms of how this will alter the dosages? What is Loperamide?
4. What do the results indicate in terms of how effective the combination of Loperamide and OMP were in inhibiting action potentials being sent?
5. In this example, Loperamide was being injected intrathecally. Why is this important to note?
6. What do you predict the results will be once loperamide is given peripherally?
7. What do the above graphs show in terms of effectiveness of loperamide and OMP given together peripherally to reduce pain.
8. Is this a way that we might be able to reduce opioid dosage, by pairing it with loperamide?

Answer 14

Intrathecally: fluid-filled space between the thin layers of tissue that cover the brain and spinal cord and delivered directly into cerebrospinal fluid which bipasses the BBB

1. When given together, shifts to the left. This means that the combo of the two together requires lower doses than when they are alone to achieve better analgesia. It takes longer for the mouse to flick their tail out of the water bath.
2. Synergistic (more effectively improvement)
3. Loperamide is a mu-opioid agonist - it is peripherally restricted at typical doses (cannot cross the blood brain barrier). When two substances are added together, they produce a combined effect greater than the sum of their separate effects. Essentially, instead of 1 + 1 = 2, it is 1 + 1 = 8. Something like that.
   1+1= 2 additive, 1+1=20 synergistic, 1+1 =0.2 is antagonistic
4. The combination was effective at reducing action potential frequency. It took less concentration of both drugs together to achieve greater inhibition. It was synergistic. - drug concentration together is lower and reaches same inhibition effect so give less if you combine them - reduce frequency and intensity of AP - want reducing signaling from nociceptors which is less AP bc less pain is sent bc the drugs reduce pain
5. By injecting it intrathecally, they were bypassing the blood brain barrier. As loperamide is a peripherally restricted opioid, it is important to test it in the periphery to see if it can be synergistic without crossing the BBB. Won’t have much of an effect.
6. Could be any number of things, for example, could have no effect. Could still be synergistic, etc.
7. Even when given peripherally, loperamide and OMP combination was synergistic - effective at inducing analgesia at lower doses. Intraplantar injection - dorsal root gang in periphery have more nociceptors - OMP can cross BBB - peripheral acute allodynia CFA leads to latent
8. Yes! It’s a great way. Also, OMP is a delta-opioid agonist, whereas loperamide is a mu-opioid agonist. Perhaps combining these different pathways is an additional way to reduce negative effects, as the distribution of mu, delta, and kappa opioids differs. Good for acute peripheral injury - reduce likelihood of developing dependence and decrease bad side effects like respiratory depression.
   Intrathecal is more effective but subcutaneous would also work.
   Lower dosage less reward pathway activation so less addiction potential.
   Want to primary effect nociception and not reward pathway can reduce activity.

Question 15

What is Drug Addiction: ?

Risk Factors for Addiction: 4 things?

Answer 15

What is Drug Addiction: Addiction is a chronic, often relapsing brain disease that causes compulsive drug seeking and use, despite harmful consequences to addicted individuals and to those around them. Long-term changes to the brain occur, which can lead to behavioral changes.

Risk Factors for Addiction: There is a complex set of factors that play into whether a person is more or less vulnerable to addiction.
– Biological/Genes: genetics, gender, mental disorders(overlap with mental issue like BD or anxiety or depression)
– Environment: chaotic home/abuse, peer pressure, — poor school achievement, parents use/attitudes
Drugs: smoking or injecting so route of administration increase addiction and binges and effects of the drugs and easily available/affordable
– Number 1 risk factor: using an addictive drug

Question 16

Stages of Drug Use
1-4?

Answer 16

Stage 1: Experimentation OR Prescription of legal drugs: Voluntary use of drugs without experiencing any negative social or legal consequences. - trying out for fun or taking drug told by doctor

Stage 2: Regular Use OR Long-term use of legal prescription: Some people will be able to enter the stage of regular use without developing a dependence or addiction. - chronic condition

Stage 3: Risky Use/Abuse: Defined as continued use of drugs in spite of severe social and legal consequences. - prescribed taking more than you are supposed to

Stage 4: Drug Addiction and Dependency: Characteristics of include withdrawal symptoms and compulsive use of the drug despite severe negative consequences. Hallmarks: withdrawal symptoms and compulsive use of the drug

Stability of Drug Use in the US: ages 18-25, most used is tobacco 1:2, 185 million illicit user world wide

Question 17

What about prescription opioids?

Overdose Deaths:?

Cost of Drug Enforcement:?

What brain areas are involved in addiction:?

Answer 17

— Though the number of prescriptions per 100 Americans has decreased, the prescription rate is still overwhelming
— Much of this was due to misrepresentation of addiction risk and overprescription - used the acute pain numbers and said that was the risk overall instead of looking at chronic numbers so mislead
— More than 17% of Americans had at least one opioid prescription filled, with an average of 3.4 opioid prescriptions dispensed per patient.
— The average number of days per prescription continues to increase, with an average of 18 days in 2017.2 - the longer you take the more likely you will get addicted

Overdose Deaths:
Overdoses have risen in general over the past 5 years
The sharpest increase in overdose deaths has largely been from (mostly inadvertent/accidental) ingestion of Fentanyl (110 times more potent than heroin)

Cost of Drug Enforcement:
The dramatic increases in the cost of drug enforcement has had little effect on drug use.
This has started to change the conversation about the use of harm reduction strategies and legalization

What brain areas are involved in addiction?
Drug use activates a number of areas throughout the brain that serve a variety of functions.
Movemntment, judgment, reward, memory, coordination, vision, and sensations

Question 18

Schematic illustration of the antagonizing effect of naloxone(rescue agent) on μ-opioid receptors:

Naloxone is a short-?

It binds to ?

Naloxone reverses ?

At high doses, naloxone can ?

Bupernorphien is a partial ?

Answer 18

Naloxone is a short-acting, broad opioid receptor antagonist.

It binds to opioid receptors with high affinity and becomes competitive. Antagonist of opioid receptors

Naloxone reverses opioid side effects such as respiratory depression, sedation, and hypotension(low bp)

At high doses, naloxone can block opioid analgesia causing precipitated opioid withdrawal.

Bupernorphien is a partial agonist either alone or pairing with naloxone to help medically assisted withdrawal

Question 19

Drugs Produce Long-Term Changes in the Brain:
– Regardless of the drug, addicts have lower?
– Brain lighting up is ?
– The Damage is?

Answer 19

Drugs Produce Long-Term Changes in the Brain:
– Regardless of the drug, addicts have lower levels of dopamine D2 receptors in the brain
– Brain lighting up is striatum area in BG for reward and motor function and examine dopamine receptor available and regardless of drug they have downregulation of dopamine D2 from drug use
– The Damage is Long-Lasting of D2

Question 20

Role Dopamine - most important NT for drug use

All drugs that people abuse have the common property of activating neurons of ?

Sensitization of dopamine release in ? This is what leads to addiction.

The Drug Addiction Pathway: becomes? plasticity?

Dopamine is produced in the WHAT - dopaminergic cells in midbrain send their projections to axon to the WHAT which is an area important for WHAT and all drugs people abuse have the common property of activating neurons in the WHAT which causes them to release dopamine into WHAT and WHAT send projections and collaterals off to the WHAT cortex where they release WHAT there which is important for decision making and other executive functioning

The WHAT system mediates the stimulating and rewarding properties of nearly all drugs of abuse → involves WHAT neurons in the WHAT, normalling WHAT reduces the amount released in the WHAT so normally there is tonic release of WHAT onto to WHAT to stop its release but however when opioids attach and active the WHAT opioid receptors in the brain on the WHAT ends up reducing the WHAT entering and increasing the WHAT leaving so WHAT becomes WHAT so reducing the amount of WHAT being released so reduced the WHAT and the WHAT will release more dopamine on the WHAT term but on the WHAT term regular use leads to desensitization and down regulation of these receptors and this what withdrawal symptoms are

Answer 20

All drugs that people abuse have the common property of activating neurons of the ventral tegmentum to release dopamine in the nucleus accumbens.

Sensitization of dopamine release in the nucleus accumbens is seen primarily as the neural basis of addiction. This is what leads to addiction.

The Drug Addiction Pathway:
Really the motivation or reward pathway, which after repeated activation by drugs (plasticity) becomes the addiction pathway - drug addiction and reward use the same pathways

Dopamine is produced in the ventral tegmental area (VTA) the dopamine production area in the midbrain - dopaminergic cells in midbrain send their projections to axon to the nucleus accumbens which is an area important for motivation and goal directed behavior and all drugs people abuse have the common property of activating neurons in the VTA which causes them to release dopamine into nucleus accumbens and sem VTA send projections and collaterals off to the prefrontal cortex where they release dopamine there which is important for decision making and other executive functioning

The mesolimbic DA system mediates the stimulating and rewarding properties of nearly all drugs of abuse → involves gaba inhibitory interneurons in the VTA, normalling gaba reduces the amount released in the nucleus accumbens so normally there is tonic release of gaba onto to dopamine to stop its release but however when opioids attach and active the MU opioid receptors in the brain on the gaba ends up reducing the Ca entering and increasing the K leaving so gaba becomes hyperpolarized so reducing the amount of gaba being released so reduced the inhibition and the gaba will release more dopamine on the short term but on the long term regular use leads to desensitization and down regulation of these receptors and this what withdrawal symptoms are

Question 21

Question 1: If you wanted to measure the addictive potential of a drug, which brain area would you most likely try to measure dopamine levels?

Question 2: This is the phenomenon wherein a person addicted to a drug needs to take more of the drug to achieve the same high.

Question 3: What is happening at the level of the synapse?

Answer 21

1: Nucleus accumbens

2: Tolerance

3: VTA terminal and synapse in the NA

Question 22

What is happening physiologically?
There are three primary components to addiction: ?

Answer 22

There are three primary components to addiction: Dependence, Tolerance, and Sensitization

Question 23

Dependence:

Physiological changes occur in the?

When drug use is ceased, withdrawal?

Withdrawal symptoms make it ?

Needs the drug eventually to just ?

Answer 23

Dependence:

Physiological changes occur in the brain that cause dependence (at the molecular level) on the drugs

When drug use is ceased, withdrawal symptoms of variable severity occur

Withdrawal symptoms make it difficult to cease drug use

Needs the drug eventually to just be at baseline so take drugs not even to get high just to not be sick

Question 24

Tolerance:

Repeated?

Essentially the more tolerant to drugs you become, the more of the drug?

Tolerance affects drug potency?

Physiological Tolerance: The liver ?

Cellular Tolerance: Plasticity ?

Morphine Tolerance: A hot light is directed at a rat’s tail and time to flick its tail away from the light is a measure of pain. Morphine ?

Answer 24

Repeated, chronic use of a drug causes physiological tolerance

Essentially the more tolerant to drugs you become, the more of the drug you will need to take to get the desired effect.

Tolerance affects drug potency(how much drug you need to take to get the same high), but many users will compensate by taking a higher dose of their drug of choice.

Physiological Tolerance: The liver gets more efficient at breaking down the drug before it gets to the brain - Amount of drug in blood.

Cellular Tolerance: Plasticity in nerve cells makes them less responsive to drugs.

Morphine Tolerance: A hot light is directed at a rat’s tail and time to flick its tail away from the light is a measure of pain. Morphine decreases pain, but its pain killing action is lost after several days of treatment. The dashed line is the response of rats not given any morphine.

Question 25

Sensitization - only for those who use the drug every once in awhile while tolerance is those using all the time

Sensitization is essentially the opposite of ?

With sensitization, the same dose ?

This refers to drug efficacy ?

If sensitization is part of the motivation to take drugs, continued ?

Amphetamine Sensitization: Amphetamine increases activity (crossovers) in rats. Animals with prior exposure to amphetamine (closed circles) show?

Naturally Rewarding Behaviors Cause Dopamine Release: Binging on sucrose (and not free access to sucrose) produces ?

Answer 25

Sensitization is essentially the opposite of tolerance.

With sensitization, the same dose of drug produces a much stronger action.

This refers to drug efficacy, the magnitude of the drug effect.

If sensitization is part of the motivation to take drugs, continued drug use makes it much more difficult to quit

Amphetamine Sensitization: Amphetamine increases activity (crossovers) in rats. Animals with prior exposure to amphetamine (closed circles) show greater activity to amphetamine than do rats getting amphetamine the first time (open circles).

Naturally Rewarding Behaviors Cause Dopamine Release: Binging on sucrose (and not free access to sucrose) produces a sensitized dopamine response in the nucleus accumbens. A similar effect is seen with the animal’s normal diet. Bigger hit of dopamine release

Question 26

Cellular changes following drug administration: Following systemic cocaine, brains from rats were dissected and stained for cfos, which is a WHAT? The number of cells expressing cfos?

Plasticity of Accumbens Neurons:
– Repeated experience with drugs will increase?
– Increase of number of synapses on NA?
– High frequency sexual activity, violence or cocaine increases ?

Answer 26

Cellular changes following drug administration: Following systemic cocaine, brains from rats were dissected and stained for cfos, which is a measure for cell activation. The number of cells expressing cfos increased in the nucleus accumbens and striatum, two areas involved in addiction

Plasticity of Accumbens Neurons:
– Repeated experience with drugs will increase dendritic spines in the nucleus accumbens. As spines are the site of excitatory synapses, this means the nerve cells are more excitable (sensitization).
– Increase of number of synapses on NA - everyday use down regulation but once in awhile upregulation of sensitization
– High frequency sexual activity, violence or cocaine increase dendritic spines in the same way - increase of number synapse and dendritic spines

Question 27

In Class Question:
Tolerance:

Answer 27

Develops after long term repeated use of a drug, wont have tolerance the first time you use a drug and leads to an increase of tolerance means you need a higher dosage to get the same effects. Two types of tolerance physiological(liver gets more efficient at breaking down drug so upregulates the creation of enzymes to break down the drug) and cellular tolerance (neuron becomes less responses to a drug so internalize receptors and engulf and endocyte the receptors to reduce activity as a protective mechanism so less receptors) - receptor internalization so less numbers of postsynaptic receptors so even same dopamine amount released the receptor are not there for dopamine to elicit a graded potentials that can sum into AP. Can have recovery of the receptor but takes time. System primes you for drug use so if cocaine users and takes cocaine in large party setting and decided one day to take cocaine align in house in setting you don’t do it normally in so you are more likely to overdose in setting because with chronic use your body primes you for the use as a protective mechanism so are less likely to overdose bc you have the environmental cues. Upregulation in liver enzymes is increased with drug and alcohol use.

Question 28

In Class Question:

Sensitization(increase of effect of drug after initial exposure):

Answer 28

Opposite of tolerance so when the same drug dosage creates a stronger effect. This tends to happen early on drug addiction which is why taking something once and then again can hook you because you increase the effect of the drug you have been exposed to before. Can happen after a delay like take it once then take a break and then see sensitization and then develop tolerance but tolerance and sensitization cna have both at the same time. Can develop tolerance without sensitization.

Question 29

In Class Question:
Dependence:

Answer 29

Physiological change in the brian causes the need of drug so causes withdrawal symptoms with cessation of use and caused by molecular changes from long term use. No more euphoria, the allostatic baseline has reduced so no longer taking to get high to taking to get baseline.

Question 30

In Class Question:
Explain the VTA/Nac/PFC Circuit:

Answer 30

Mesolimbic pathway, ventral tegmental area (VTA) which produces dopamine and releases dopamine onto nucleus accumbens and the prefrontal cortex. VTA helps with decision making and what is most valued which changes over time. nucleus accumbens the increase of dopaminergic signaling is the hallmark of addiction. Dopamine is the primary NT released in BG for movement so dopamine is important for different things. All drugs of addiction work in the reward pathway which is VTA and nucleus accumbens. Increase dopaminergic in nucleus accumbens is a hallmark of addiction.

Question 31

In Class Question:
Define plasticity and explain the changes that happen in the brain during addiction:

Answer 31

Plasticity is brain change and adapt with experience. Increase of dendritic spines density in nucleus accumbens so greater number of synapses in nucleus accumbens which causes excitatory synapse response with sensationstion.
The motivation or reward pathway, which after repeated activation by drugs (plasticity) becomes the addiction pathway - drug addiction and reward use the same pathways
Cellular Tolerance: Plasticity in nerve cells makes them less responsive to drugs
Repeated experience with drugs will increase dendritic spines in the nucleus accumbens. As spines are the site of excitatory synapses, this means the nerve cells are more excitable (sensitization)
Increase of number of synapses on NA - everyday use down regulation but once in awhile upregulation of sensitization
High frequency sexual activity, violence or cocaine increase dendritic spines in the same way - increase of number synapse and dendritic spines

Question 32

Clinical Problem:

1. Which curve, A or C, best represents the dose of opiates that your patient will need to treat the pain for their broken leg if they have been taking an opiate elixir as a cough suppressant? What does this shift suggest is happening in the synapse?
2. Your patient explains that their old cough medicine was called Heroin and was marketed as a non -addictive morphine substitute. That proved not to be the case… Research! How is the structure of heroin different from morphine? What drug property does this structural change influence?
3. In 1914 physicians were still allowed to prescribe opiate medications to patients to maintain them if they were addicted, but in 1919 and after court cases in 1920 – the laws changed. When your patient does finally try to quit taking their cough medication, what types of withdrawal symptoms will they have? Why?
4. If you were a doctor in 2015, what drugs might you use to treat your patient if they were addicted to heroin instead? Why?
5. Name a receptor (other than opioid) that may be involved in the development of tolerance to opiates? How? (Hint: google glutamate receptors and opioid tolerance…

Answer 32

1. C because need higher dosage to experience results/effect - shift to right in order to achieve same effect
2. Heroin has two acetyl groups added to the structure of morphine, which makes it more lipid-soluble and allows it to cross the blood-brain barrier faster. Undergoes deacylation to act similar to morphine but when injected can bypass the deacylation. Morphine can also cross BBB but is less fat soluble.
3. Heroin withdrawal symptoms include sweating, goosebumps, nausea, vomiting, diarrhea, muscle and bone pain, sweating, chills, tremors, muscle spasms, runny nose, tearing, anxiety, agitation, and irritability, as the body and brain struggle to readjust to functioning without the drug’s effects.
   The drug suppresses the brain’s natural production of dopamine and endorphins—neurotransmitters responsible for pleasure and pain relief—so when heroin use stops, the body is left in a state of chemical imbalance, causing intense discomfort as it slowly recalibrates.
4. Methadone, buprenorphine, bup + naloxone = suboxone
   methadone was often prescribed to stabilize withdrawal and reduce cravings by fully activating opioid receptors in a controlled way, while buprenorphine, a partial agonist, was used to lower overdose risk by providing milder opioid effects, helping to wean patients off heroin.
   Long lasting and binds to opioid receptors
5. ​​Glutamate receptors are many times linked with opioid receptors, their activity influences one another - G- protein
   The NMDA glutamate receptor contributes to opioid tolerance by promoting cellular changes that reduce opioid efficacy over time, necessitating higher doses for pain relief​