opioid receptors and systems Flashcards
What effects are difficult to directly measure in lab based assays? Why?
- analgesic
- ethical constraints with animals
- human trials confounded by subjectivity
We know opioids are potent modulators of _______________.
GI mobility
Investigators developed a GI based assay to measure ____________.
the potency of opioids
Application of hydraulic pressure stimulates what in an ex vivo preparation of what animal? What does this assess?
- stimulates ileum peristaltic reflex in guinea pig ileum
- assess opioid potencyand endogenous opiod release
Which endogenous opioid reversibly inhibits the ileum peristaltic reflex?
morphine
Which drug rapidly restores ileum peristaltic reflex?
naloxone (opioid antagonist)
Potency in the guinea pig ileum strongly correlates with ___________ in humans.
analgesic potency
How were opioid receptors first identified? What did it reveal about opioid binding?
- radiolabelled naloxone (opioid antagonist)
- opioid binding was reversible, saturable, and high affinity
Opioid receptor binding by the radioligand assay was shown to correlate with __________.
the potency of opioids in the guinea pig ileum bioassay
Demonstration of the binding of radioligands in the _____ brain highlights sites of opioid reeptor. High binding observed in the ________, __________, _______, ___________, and ____________.
rat; striatum, locus coeruleus, thalamus, raphe nuclei, and periaqueductal gray
TRUE or FALSE: opioid receptors are ionotropic
FALSE: G-protein coupled (Gi)
What are the 4 main opioid receptor sybtypes?
δ (delta) – DOR / OP1
κ (kappa) – KOR / OP2
μ (mu) – MOR / OP3
Nociceptin – NOP / OP4
see slide 11 diagram for mu delta and kappa distribution in the brain
go look at it
Answer the following for MOR:
- high affinity for?
- expression in thalamus, PAG, median raphe suggest?
- expression in nucleus accumbens suggest?
- expression in brainstem suggest?
- high affinity for morphine
- analgesia
- reinforcement
- resp depression, cough suppression, vomit reflex
TRUE or FALSE: KOR has similar expression as MOR but more restricted
FALSE: DOR expression similar to MOR but more restricted
TRUE or FALSE: DOR is sensitive to morphine
FALSE: not sensitive
What does DOR have roles in?
olfaction, motor integration, reinforcement, analgesia
Answer the following for KOR:
- what kind of expression pattern?
- high affinity for?
- expressed in?
- regulate what?
- additional roles in?
- distinct expression pattern
- ketocyclazocine
- striatum, amygdala, hypothalamys, pituitary
- pain perception, gut motility, dysphoria
- water balance, feeding, temp control, neuroendocrine function
Where is nociceptin receptor expressed? What are the roles?
- Expressed in amygdala, hippocampus, hypothalamus, and spinal cord
- Roles in anxiety, depression, appetite, and development of tolerance to μ-opioid agonists
ketocyclazocine binds to what receptor? what is it and what does it do?
- Synthetic opioid that is hallucinogenic and induces dysphoria
- binds to KOR
Enkephalins are selective for which receptor? How many subtypes?
- DOR
- 2 subtypes
Dynorphines are selective for which receptor? How many subtypes?
- KOR
- 4 subtypes
Endorphins are selective for which receptor? How many subtypes? What are they contracted from?
- MOR
- 5 subtypes
- contraction from endogenous MORPHINE
Endomorphins are selective for which receptor? How many subtypes? Is the gene or prepeptide identified yet? What is it contracted from?
- extremely high affinity for MOR
- at least 2 subtypes
- not identified yet
- contraction from endogenous morphine
Nociceptins are selective for which receptor? How many subtypes? What is its effect?
- nocicptin receptor
- single species
- anti-analgesic
What are Endorphins, enkephalins, and dynorphins synthesized from?
pre-propeptide genes
Endorphins are expressed from _______, which also gives rise to ______________ and ________________.
POMC; melanocyte stimulating hormones; ACTH
slide 16
Describe postsynaptic inhibition.
result from Gi signalling to adenylate cyclase and G-beta-gamma signalling to hyperpolarize K+ channels (GIRK)
Describe axoaxonal inhibition.
Gi and cAMP signalling to inhibit voltage-gated Ca channels
Describe presynaptic autoreceptors.
inhibit NT release
Opioids are involved in ______________ at both the spinal level and at supraspinal sites.
modulating pain pathways
What are the 2 components of pain perception. Explain.
- early pain - immediate SENSORY component signalling stimulus LOCATION to cause withdrawal or escape from stimulus
- late pain - signals a strong EMOTION component, the unpleasantness of pain sensation – prolongs sensation of pain to focus behaviours to limit further damage and aid recovery
Describe ascending pain pathways. Which fibers signal early pain and where do they project to? late pain?
- sensory neurons in DRG transmit signals in dorsal horn to ascending pathways
- early pain = A-delta fibers to thalamus and somatosensory cortex –> localize info on pain
- late pain = C fibers to thalamus and limbic system (hypothalamus, amygdala, ACC)
review slide 20
go look at it
Describe spinal sites for opioid analgesia.
- opioidergic neurons in descneding modulatory pathways
- opioidergic interneurons release endorphins to inhibit ascending projections neurons
Describe supraspinal sites for opioid analgesia.
opioids function in the limbic system, thalamus , and sensory areas to modulate emotional components of pain
Where do the most important descending pathways of pain originate in? Describe the descending pain modulation pathways.
- most important in PAG
- PAG neurons –> raphe nuclei –> serotonergic projections inhibit input to pain afferents
- PAG –> LC –> noradrenergic projetions incresae firing in respnse to pain
What inhibits noradrenergic cell increased firing in response to pain?
MOR agonists
see slide 23
go look
In PET displacement studies, what do sensory pain scores correlate with?
correlate negatively with opioid release in the nucleus accumbens, amygdala, and thalamus
Affective pain scores correlated _____________ with opioid release in the ______________, _________________, and ________________.
negatively; ACC, thalamus, nucleus accumbens
TRUE or FALSE: endogenous opioids are only involved in early pain
FALSE: both early (acute) and late pain
