Opioid Analgesics and Antagonists Flashcards
Opioids
all naturally occuring and synthetic substances which bind to opioid receptors in the brain and periphery
opiates
drugs derived from opium
opium
natural product from poppy plant
greeks and romans used it to produce sleep
chewed or smoked
analgesia
absence of the sense of pain without loss of consciousness
spinal analgesia
- 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
supraspinal analgesia
- 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
opioid cellular actions
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
Mu opioid receptors
- 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
Kappa opioid receptors
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»_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
Salvinorin A
- pure kappa agonist
- binds only to kaappa opioid receptor
delta opioid receptor
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
Types of pain neurons
nociceptors - general term for neurons that detect noxious stimuli and carry pain information from skin and muscle to the spinal cord
- mechanoreceptors
- respond to pressure - capsaicin receptors
- respond to extreme heat, acid, and inflammation
How does the brain interpret pain and send moderating pain signals
- 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
3 ways opioids inhibit pain signals
- inhibiting Ca++ influx into presynaptic nociceptor neuron releasing substance P –> prevents substance P from being released because Ca++ is needed for NT releases
- hyperpolarizing post synaptic neuron by enhancing K+ outflow of neuron –> makes it more difficult to stimulate –> more difficult to send pain info
- modearte central perception of pain –> pain is less aversice when perceived
Endogenous opioid agonists
endogenous opiate peptides:
enkephalins
endorphins
endomorphins
dynorphin
Endorphin as an analgesic
- 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
morphine/codeine
- 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
heroin
- 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
methadone
- 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
dihydrocodeine
synthetic form of codeine
fentanyl
- 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
hydromorphone –> hydrocodone metabolite
- hydrocodone is the most used opioid
- both analgesics and antitussive effects
- bind to mu opioid receptor
meperidine
- synthetic
- short acting
- weak agonist
- muscarinic and mu opioid effects
oxycodone/oxycontin
oxycontin is the lost acting form, every 12 hours
pentazocine
- 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
buprenorphine
- synthetic
- partial agonist at mu
- antagnost at kappa and delta
- equal affinity but less intrinsic activity than endogenous opiates
- less addiction potential
opiate antagonists
- naloxone: opiate OD
- nalmefene: opiate OD
- naltrexone: alcoholism
effects of opiate administration
- 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
effects of opiate administration
- dangerous if alcohol or depressant drugs co present
- decrease in sex drive
- sedation and anxiolytic effects, relation
opiates and the reward system
- opioids inhibit GABA which allows for dopaminergic neurons in the VTA and nAcc to release more DA
- increass activity in the reward system
physical dependence vs psychological dependence
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
Is tolerance and dependence with opioids an issue in pain control and recreational drug use?
- 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)
what are the reasons for opiate withdrawal?
- 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
- when opiates block enzyme –> the body compensates by increases enzyme production –> opiate removed –> rebound increase in enzyme and its product
what are the symptoms of opiate withdrawal?
- 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
tail flick test
- 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
hot plate test
mice placed on hot plate
when it is too hot they lick their paws to cool them down
conditioned place preference method
- 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
locomotor activity test
measuring the horizontal and vertical movement of mice when given drug vs WT
tail suspension and forced swim test
- 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
morris water maze
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
