Opioids Flashcards
What are opiods
Opioids are analogues to morphine with effects like analgesia, respiratory depression, sedation, euphoria
Full agonist: binds to the receptor- stimulate physiological activity- Morphine, dimorphine (heroin)
partial agonist: bunephorine - binds to the receptor but not produce maximum stimulation
antagonist- binds to the receptor - blocks receptor activity- naloxone
What are the endogenous peptides that bind to the opioid receptors
- The opioid receptors: mu, delta and kappa receptors
Endogenous peptides that bind to opioid receptors. - B-endorphin: bind to MOP, DOP– derived from POMC
-Enkephalins: bind to DOP– derived from proenkephalins
-Dynorphins: bind to KOP– derived form prodynorphins
- Noiceptin/OFQ: NOP receptor
Where are the opioid receptors found & what do they induce
- Mu opioid receptors are most commonly found in the nucleus accumbens (reward), the thalamus (pain), the basolateral amygdala (emotion)
- Opioid receptors have inhibitory effects: cause Activates the Gi/o protien
- Inhibits adenyl cyclase- dec cAMP and dec PKA
- Activates K+ channels- hyperpolarisation – reduces neurone excitability
- Inhibits VGCC- Ca2+ channels –prevents neurotransmitter release
The effects of opioids on the body
Analgesia: mediated mainly by the MOP = opioids with good analgesic effects act
on this receptor
- Respiratory depression: mediated mainly by MOP= opioids desensitise receptors
in centre in the brain that monitors CO 2 levels during respiration = CO 2 increases
without signalling lungs (side-effect) - Reduced gastric motility: mediated mainly by MOP and DOP = opioids induce
constipation = act on opioid receptors in the gut which decreases gastrointestinal
motility - Euphoria: mediated mainly by
MOP = increase dopamine
release in nucleus accumbens
which induces euphoria = may
lead to tolerance and
dependence - Dysphoria: mediated mainly by
KOP - Nausea/Vomiting: acts on MOP
receptors found in
chemoreceptor trigger zone - Tolerance and dependence:
mediated mainly by MOP and
develops for most
pharmacological effects = higher dose needed to exert the same effect
Describe the transmission of pain
- Peripheral Noiceptiors detect stimuli which sends an action potential via the dorsal to the superficial layers.
-this is going to cause the release of substance C and glutamate
-Act on neighbouring neurons to send pain signals from the thalamus to the sensory cortex - as the pain subsides, the activation of the descending inhibitory neurons that project from the brain to the spinal cord- block pain signals
How to opiods block pain signals
opioids are effective analgesics they have receptors in all 3 areas
- afferent neurons (periphery)
- dorsal horn and spinal cord
-Pain regions of the brain
-Opiods bind to the opiod receptors
- opiods activate k+ channels - hyperpolarise the membrane and reduces the excitability of the neurone.
- prevents the release of the neurotransmitter and their action.
- Opioid receptors are found pre synaptically and pos synaptically.
- Opioids result in the activation of neurones in the PAG and NRPG which stimulates the NRM neurones. This is going to result in the release of 5-HT and enkephalins which will reusult in the inhibition of pain signals from the dorsal horn.
- Opiods can also directky act on the dorsal horn and peripheral terminals
What is the opioid disinhibition effect
Dopaminergic neurones project from the ventral
tegmental area (VTA) to the nucleus accumbens
(NAcc)
GABA interneurons release GABA = acts on
dopaminergic neurones = inhibit the release of
dopamine
GABA interneurons have opioid receptors = when
opioids bind, they inhibit the release of GABA =
increases the release of dopamine = DISINHIBITION
what is tolerance- what are the two mechanisms of tolerance
Tolerance = need a higher dosage of the drug to induce the same pharmacological
effect
Tolerance can be caused by two main mechanisms: desensitisation and
internalisation
Receptor desensitisaton
Morphine/heroin (any opioid) acts on MOP = opens potassium channels =
hyperpolarises the neurone = inhibition
2. When the opioid is used for a longer period of time = MOP is bombarded with the
opioid = causes stress on the system
3. Receptor will attempt to oppose the continuous activation by desensitising = opioid
binding will no longer produce a pharmacological response
4. Desensitisation occurs because over time Beta-arrestin (protein) binds to
intracellular domain of MOP
5. There will also be kinases which phosphorylate the receptor = both of these actions
result in the desensitisation of the receptor
6. This shifts the growth response curve to the right = increases
dosage needed for response
All opioids result in desensitisation, but some also cause the
internalisation of receptors
- Morphine doesn’t internalise but methadone does
Receptor Internalisation
Repeated administration causes desensitisation due to phosphorylation and Beta-
arrestin activity
Some receptors will also develop clathrin coated pits = results in the endocytosis of
receptors on the membrane by
engulfing into a vesicle
The vesicle will then be degraded by
lysosomes or recycled back to the
membrane surface
What is the evidence that receptor phosphorylation leads to the development of tolerance
Created knock in mice with a series
of serine and threonine-to-alanine
mutations that render the receptor
unable to phosphorylate
intracellular domain and therefore
recruit Beta-arrestin = led to no desensitisation of MOP receptor
Opioid analgesia was strongly enhanced
Respiratory depression, constipation and opioid withdrawal signs were unchanged
or exacerbated
This shows that phosphorylation is responsible for tolerance but not responsible for
the adverse effects
What are the long term effects of opioids
- Decrease pre frontal cortex activity
- Affect the activity of the HPA axis
