Opioid Analgesics and Antagonists

Question 1

Opioids

Answer 1

all naturally occuring and synthetic substances which bind to opioid receptors in the brain and periphery

Question 2

opiates

Answer 2

drugs derived from opium

Question 3

opium

Answer 3

natural product from poppy plant
greeks and romans used it to produce sleep
chewed or smoked

Question 4

analgesia

Answer 4

absence of the sense of pain without loss of consciousness

Question 5

spinal analgesia

Answer 5

• suppression of pain by analgesic drugs into the space around the spinal cord
• opiates interfere with transmission of pain messages between neurons and prevent them from reaching the brain

Question 6

supraspinal analgesia

Answer 6

• suppression of pain by drugs in the brain itself
• allows a person to know they are experiencing a stimuli that would otherwise be painful
• reduced perception of pain

Question 7

opioid cellular actions

Answer 7

MOR at presynaptic terminal
- stimulated by opioid
- leads to decrease in calcium channels needed to use NT vesicles
- this results in less fusion
- this leads to less firing

MOR at post synaptic neuron
- stimulated by opioids
- increase in K+ channels
- hyperpolarization
- need more to transmit signal
- higher threshold to fire

Question 8

Mu opioid receptors

Answer 8

• located in all pain control areas of the brain and spinal cord (pariaqueductal gray in midbrain, spinal trigeminal nucleus, caudate nucleus, thalamic nucleus)
• located in respiratory control centres and nucleus accumbens

functions
- analgesia (supraspinal and spinal)
- sedation
- inhibition of respiration
- slow GI
modulation of hormone and NT release

respond to
- exogenous opioid drugs
- endogenous opioids: endorphins > enkephalins > dynorphins

Question 9

Kappa opioid receptors

Answer 9

located in
- basal ganglia
- nucleus accumbens
- VTA
- cortex
- hypothalamus
- periiaqueductal grey
- spinal cord

function
- modest analgesia, dysphoria, feelings of depersonalization, disorientation, pupil constriction, mild respiratory depression

responds to
- mixed agonist-antagonist (pentacozine and endogenous dynorphin): dynorphin&raquo_space; endorphins and enkephalins
- mixed ag-ant has affinity for two or more types of opioid receptors and blocks opioid effects on one receptor type while producing opioid effects on a second receptor type

Question 10

Salvinorin A

Answer 10

• pure kappa agonist
• binds only to kaappa opioid receptor

Question 11

delta opioid receptor

Answer 11

found in
-all pain control areas of the brain and spinal cord (pariaqueductal gray in midbrain, spinal trigeminal nucleus, caudate nucleus, thalamic nucleus)
- nucleus accumbens and limbic system

functions
- analgesia (supraspinal and spinal)
- modulation of hormone and NT release

respond to:
- exogenous etorphine
- endogenous enkephanils > endorphins and dynorphins

Question 12

Types of pain neurons

Answer 12

nociceptors - general term for neurons that detect noxious stimuli and carry pain information from skin and muscle to the spinal cord

1. mechanoreceptors
   - respond to pressure
2. capsaicin receptors
   - respond to extreme heat, acid, and inflammation

Question 13

How does the brain interpret pain and send moderating pain signals

Answer 13

• nociceptor neuron releases substance P onto receiving neuron that projects up spinal cord
• inhibitory neurons travel from the brain to the site of entry of nociceptors - act as INTERNEURONS
• when stimulated they release endorphins that bind to the nociceptor neuron to inhibit pain (substance P or any other NT carrying pain information)
• the interneuron can also be stimulated by exogenous opioids

Question 14

3 ways opioids inhibit pain signals

Answer 14

1. inhibiting Ca++ influx into presynaptic nociceptor neuron releasing substance P –> prevents substance P from being released because Ca++ is needed for NT releases
2. hyperpolarizing post synaptic neuron by enhancing K+ outflow of neuron –> makes it more difficult to stimulate –> more difficult to send pain info
3. modearte central perception of pain –> pain is less aversice when perceived

Question 15

Endogenous opioid agonists

Answer 15

endogenous opiate peptides:
enkephalins
endorphins
endomorphins
dynorphin

Question 16

Endorphin as an analgesic

Answer 16

• endogenous opioid peptide
• beta endorphin –> pain
• derived from POMC (pre pro hormone)
• produced by pituitary gland and the hypothalamus and releasd into blood stream from pituitary and into spinal cord and brain from hypothalamus
• highest affinity for mu receptors

Question 17

morphine/codeine

Answer 17

• natural
• derived from opium
• codeine much less potent as analgesic
• same chemical structure as morphine except one carbon and two hydrogen atoms removed
• most analgesic effects are from metabolism to morphine

Question 18

heroin

Answer 18

• natural
• changed chemical structure makes it much faster acting than morphine because it is more fat soluble and easier to transport across membrane of the brain –> more addiction potential

Question 19

methadone

Answer 19

• natural
• more potent than morphine but less sedation
• slow metabolism and very high lipid solubility –> longer lasting than morphine based drugs
• milder withdrawal because of prolonged effects
• cannot be injected
• used as substitute for heroin and other narcotics as treatment

Question 20

dihydrocodeine

Answer 20

synthetic form of codeine

Question 21

fentanyl

Answer 21

• synthetic
• 80x more potent than morphine
• remifentanyl is ultra short acting so it is safer due to less risk of respiratory depression
• active sub 100ug so it is hard to measure

Question 22

hydromorphone –> hydrocodone metabolite

Answer 22

• hydrocodone is the most used opioid
• both analgesics and antitussive effects
• bind to mu opioid receptor

Question 23

meperidine

Answer 23

• synthetic
• short acting
• weak agonist
• muscarinic and mu opioid effects

Question 24

oxycodone/oxycontin

Answer 24

oxycontin is the lost acting form, every 12 hours

Question 25

pentazocine

Answer 25

- mixed agonist antagonist - acts as full agonist receptor at kappa and antagonist at mu - less addiction potential because stimulation of mu is risk in abuve

Question 26

buprenorphine

Answer 26

- synthetic - partial agonist at mu - antagnost at kappa and delta - equal affinity but less intrinsic activity than endogenous opiates - less addiction potential

Question 27

opiate antagonists

Answer 27

- naloxone: opiate OD - nalmefene: opiate OD - naltrexone: alcoholism

Question 28

effects of opiate administration

Answer 28

- brain stem: change automatic body functions, suppress breathing - limbic system: emotions and feelings of pleasure - spinal cord: block pain messages hypothermia hypotension peripheral vasodilation miosis - pupillary constriction drying of secretions constipation respiratory depression

Question 29

effects of opiate administration

Answer 29

- dangerous if alcohol or depressant drugs co present - decrease in sex drive - sedation and anxiolytic effects, relation

Question 30

opiates and the reward system

Answer 30

- opioids inhibit GABA which allows for dopaminergic neurons in the VTA and nAcc to release more DA - increass activity in the reward system

Question 31

physical dependence vs psychological dependence

Answer 31

physical: physilogical state of adaptation in which the body's physiology requires teh drug to work normally, withadrwal symptoms emerge in abstinence psychological: subjective sense of needing or craving positive effects or to avoid negative effects associated with abstinence

Question 32

Is tolerance and dependence with opioids an issue in pain control and recreational drug use?

Answer 32

- less of an issue if for pain - someone who uses opioids recreationally for a long time will become very tolerant - 60mg of morphine are required for respratory depression in non tolerant people and 2000mg in people who are maximally tolerant (have SUD)

Question 33

what are the reasons for opiate withdrawal?

Answer 33

1. opiates inhibit NT release --> body compensates for this by increasing number of receptors --> when opiate is taken away the abundance of receptors leads to a hyperactive state 2. when opiates block enzyme --> the body compensates by increases enzyme production --> opiate removed --> rebound increase in enzyme and its product

Question 34

what are the symptoms of opiate withdrawal?

Answer 34

- serious drug craving - dysphoria - yawning and panting - perspiration, runny nose, teary eyes - pupil dilation - fever and chills - tremors and muscle twitches - severe aching and painful sensation - loss of appetite - diarrhea

Question 35

tail flick test

Answer 35

- rat placed on box with a light source coming from it that is hot - when it is too hot they flick their tail away - can give analgesic and test how long they last - if they don't remove their tail it is evidence of analgesia

Question 36

hot plate test

Answer 36

mice placed on hot plate when it is too hot they lick their paws to cool them down

Question 37

conditioned place preference method

Answer 37

- animals injected w drug of abuse on one side in one session and vehicle on other side in another session - on test day animals are allowed to explore the boxes - animals tend to spend more time on the side that was paired with the rewarding drug

Question 38

locomotor activity test

Answer 38

measuring the horizontal and vertical movement of mice when given drug vs WT

Question 39

tail suspension and forced swim test

Answer 39

- animal hung by tail or forced to swim in water - animal will struggle more and swim more when given antidepressant - does not necessarily mean that the mouse is depressed if it doesn't swim

Question 40

morris water maze

Answer 40

model for alzheimers - tests spatial memory - mouse has to swim in a pool with hidden platform - after training session they ahve to locate the platform - mouse with high tau protein will swim around more and wont remember locaiton - mouse with cleared tau will remember where to go