PHAR 300 Lecture Notes - Lecture 16: Distal Convoluted Tubule, Carfentanil, Psychogenic Pain
7 Jun 2018
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PHAR300
Opioid analgesics
Opioids
-major therapeutic use : relief of pain (very powerful and effective)
-pain is a protective reflex, afferent and efferent pathways control pain
-initial sensation of pain : firing of nociceptors (peripheral nerves, Adelta and C fibers) to spinal
cord (where there is a relay) up towards the brain
-opioids are mainly in the CNS (some action at the periphery also, but it is more non-steroidal
antiinflammatory drugs)
-act on both the ascending pathway (that transmits pain) and descending pathway involved in
pain suppression => dual set of properties
-also act on the areas of the brain responsible for the psychological reaction to pain -> pain is not
only a sensation but also emotional reaction : stressing feeling that we have in reaction to the
pain
-own pain suppression system with our own endogenous opioid peptides
-ingested opioids act through their effect on the pathways normally present to help us relieve
pain
-various other activities can also have effect on the sensation of pain : exercise, placebo,
comforting sensations tend to decrease the sensation of pain
-distribution of our pain suppression chemicals and their receptors : neurons can synthesise
endogenous opioids ; different regions in the brain and in the spinal cord -> presence of innate
opioid transmitters and opioid receptors
-act in the brain, and in the spinal cord (local anaesthetic can act in the periphery and in the spinal
cord if they are injected there, NSAIDS act in the periphery)
Opioids - origin
-all of the drugs/compounds similar to the compounds discovered in the opium poppy -> if they
come directly from the opium puppy => opiates
-opioids : all drugs with opiate-like action including (but not confined to) opiates (e.g. synthetic,
endogenous opioids)
-poppies grow in a warm climate => Pakistan, Middle East, some areas in South America
-poppy plant makes morphine and codeine -> easy to extract them from the plant
-codeine : methylmorphine
-heroin : diacetylmorphine -> very effective when injected IV
-opioids : drugs with morphine-like action
-poppy plant starts with L-Tyrosine and then transforms it to make morphine (and codeine)
Opioids - history
-people were aware of the powerful drug present in the plant since a long time
-seed pod -> we have to get it when it is green enough -> at the right time
-harvesting the white milky material present in the wall of the seed-pod -> make scratches,
they leave it overnight and the white juice leaks out, turning brownish -> scrape the seed-
pods
-hypodermic needle 1860 -> successful relief of pain, but also very powerful addictive agent =>
goes very rapidly to the brain and has powerful effects resulting in a lot of problems
-1975 -> discovered what they were actually doing
-we are able to make endorphins, enkephalins and dynorphins nowadays -> are able to act on
our endogenous opioid receptors
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Morphine
-and codeine = major naturally-occurring alkaloids in the
opium poppy (morphine ~10% of opium by weight ;
codeine ~0.5% of opium)
-used for years (name from Morpheus-> greek goddess of
dreams) ; then used for babies’ growing teeth ; then for
treating cough
-enkephalin (natural ligand) -> common structure to
morphine
-not the most potent opioid but it is the one that we know
all the effects, actions…=> used as a reference to
compare various opioids drugs
-basic structure : 2 hydroxyl, amine, benzene ring, alkene
group => crucially important for the effect of opioids
-codeine : 1/10 potent as morphine ; if we add another
methyl group -> more potent than morphine
-we can make partial agonist / antagonist to opioid
receptor : naloxone ; weak agonists can interact with the
receptor but only partially activate it (some cells/receptors)
: methadone (but it has some very useful clinical properties) -> synthetic opioids
-mu, delta and kappa receptors for the opioids ; mu is the one predominantly involved in the
relief of pain
-sites for affinity and sites for efficacy -> weak agonist : part of the molecule related to the
efficacy is transformed
Pharmacodynamics
-pain transmission system -> production of PG… when injury to cells in the periphery
-relay in the spinal cord to the brain
-relay in the thalamus -> messages goes to the different regions of the brain
-descending pathway : serotonin and noradrenaline are the major transmitters
-primary afferent fiber is activated ; nociceptive neuron releases second neurons in the pathway
-> sends the signal up to the spinal cord
-afferent fibers : opioid receptors on both sides of the synapse : pre-synaptic receptor activated
and decreases the release of the transmitter (G protein coupled receptors ; interfere with the
inrush of calcium) ; post-synaptic receptor : K+ channels -> normally hyperpolarisation of the
2
membrane (also affecting calcium) => opioids
decrease the firing of AP => decrease the impulses
that transmit the pain signal
-descending inhibition coming down from the brain
is also increased -> descending inhibitory neuron
releases an inhibitory transmitter which will affect
the pre-synaptic terminal => opioids decrease this
release ; serotonergic and noradrenergic neurons
normally inhibit the sensation of pain -> descending
inhibitory system is inhibited by GABA control
under normal circumstances (in order to react to a
damaging situation) -> opioids releases the
inhibitory system from the GABA inhibition : opioid
receptors on GABAmenergic neurons so that less
GABA is released on these neurons => serotonergic
and noradrenergic neurons can thus do their job and
inhibit the sensation of pain
-combined result : increase the pain threshold
-receptors in spinal cord, cortex, parts of the brain
involved in responding / relaying the sensation of
pain
-pain : sensation + emotion
-opioids inhibit the transmitter release all over the place
-major action in the spinal cord and in the brain, some on peripheral tissue as well and action
on GABAmenergic neurons
-opioid receptors
-subtypes : mu, delta and kappa
-mu : morphine is located at the active
site, more mu on post-synaptic neurons
-kappa : not self-administered,
psychomimetic and aversive in humans,
seem to have a negative effect
-delta : doesn’t do much
-distribution proportion is different depending
on the subtype ; distributed in the spinal cord,
in the brain stain, thalamus, lymbic system,
cortex
-opioid receptor : G protein coupled
receptor, activating the receptor will affect
ion channels (K+ and Ca2+), adenylyl
cyclase…
-morphine acts on the receptor, decreases
cAMP, calcium entry is blocked => decreased
release of neurotransmitter
-all three receptors decrease calcium
conductance => decrease transmitter release
-receptors can act on their own ; dimers (homo or hetero, or oligomers) => depending on
where they sit on the membrane -> different properties ; different response intensity
depending on the dimerisation of the receptor
-receptor plasticity : opioid agonist acts on the receptor -> then it will be taken into a pit ->
internalised and once inside the cell, it goes to a lysosome where it is broken down or it can
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Document Summary
Major therapeutic use : relief of pain (very powerful and effective) Pain is a protective re ex, afferent and efferent pathways control pain. Initial sensation of pain : ring of nociceptors (peripheral nerves, adelta and c bers) to spinal cord (where there is a relay) up towards the brain. Opioids are mainly in the cns (some action at the periphery also, but it is more non-steroidal antiin ammatory drugs) Act on both the ascending pathway (that transmits pain) and descending pathway involved in pain suppression => dual set of properties. Also act on the areas of the brain responsible for the psychological reaction to pain -> pain is not only a sensation but also emotional reaction : stressing feeling that we have in reaction to the pain. Own pain suppression system with our own endogenous opioid peptides. Ingested opioids act through their effect on the pathways normally present to help us relieve pain.
