Opioid receptors and systems Flashcards
Describe opioid potency
- Analgesic effects are difficult to
directly measure in lab based assays - Human trials can be highly
confounded by subjectivity of pain
measures - Ex vivo preparation of the guinea pig
ileum - Application of hydraulic pressure
stimulates the ileum peristaltic reflex
Describe opioids and peristalsis
- Morphine reversibly inhibits the
ileum peristaltic reflex, the
opioid antagonist naloxone
rapidly restores reflex function.
Describe opioid receptor discovery
- Candace Pert and Soloman Snyder
finally identified the receptor using
radiolabelled naloxone (opioid
antagonist) in 1973
Describe receptor distribution
- High binding observed in the striatum,
locus coeruleus, thalamus, raphe
nuclei, and periaqueductal gray
Describe receptor subtypes
- Opioid receptors are G-protein coupled (to
Gi) - Four main subtypes exist
- δ (delta) – DOR / OP1
- κ (kappa) – KOR / OP2
- μ (mu) – MOR / OP3
Describe MOR expression
μ-opioid receptor (MOR)
* High affinity for morphine
* High expression in thalamus, periaqueductal gray,
median raphe suggests roles in analgesia
* Expression in nucleus accumbens suggests role in
reinforcement
* Expression in brainstem suggests roles in respiratory
depression, cough suppression, and vomit reflex
Describe KOR expression
- Distinct expression pattern
- High affinity for ketocyclazocine
- Synthetic opioid that is hallucinogenic and induces
dysphoria - Expressed in striatum and amygdala, also
hypothalamus and pituitary - Regulation of pain perception, gut motility, and
dysphoria - Additional roles in water balance, feeding,
temperature control, neuroendocrine function
Describe endogenous peptides
- Enkephalins– ‘in brain’
- Selective for δ-receptor
- Two subtypes
- Dynorphins– from Greek dynamis, meaning
power - Selective for the κ-receptor
- Four subtypes
- Endorphins– contraction from
endogenous
morphine - Selective for the μ-receptor
- Five subtypes
- Endomorphins– also a contraction from
endogenous morphine - Selective for the μ-receptor
- Extremely high affinity
- At least two subtypes
- Gene or prepeptide not yet identified
- Nociceptin
- Selective for the nociceptin receptor
- Anti-analgesic
- Single species
Describe endogenous peptide genes and synthesis
- Endorphins are expressed from
POMC, which also gives rise to
melanocyte stimulating
hormones and
adrenocorticotropic hormone
Describe beta endorphin release
POMC is highly expressed in the pituitary –
peptides for both adrenocorticotropic
hormone (ACTH) and β-endorphin.
Co-release of β-endorphin from the pituitary
provides a physiological link between stresses
and pain signalling
Describe endogenous opioid signalling
Postsynaptic inhibition is a result
of Gi signalling to adenylate
cyclase and Gβγ signalling to
hyperpolarizing K+
-channels
(GIRK).
Axoaxonal inhibition can be
elicited through Gi and cAMP
signalling to inhibit voltage gated
Ca2+
-channels
Presynaptic autoreceptors to
inhibit neurotransmitter release.
Describe pain signalling
- Opioids are involved in modulating pain pathways at both the spinal level and at supraspinal sites.
- Pain perception has two components
- Early pain – immediate sensory component signalling stimulus location to cause withdrawal or escape from
stimulus - Late pain – signals a strong emotional component, the unpleasantness of pain sensation – prolongs sensation
of pain to focus behaviours to limit further damage and aid recovery
Describe ascending pain pathways
Early pain is signalled through Aδ fibers
(large, myelinated axons – fast transmission).
Aδ fibers project to the thalamus and
somatosensory cortex to provide location
information on pain.
Late pain is signalled through C fibers (small,
unmyelinated axons – slower transmission).
C fibers project to the thalamus but also
innervate the limbic system (hypothalamus,
amygdala, and anterior cingulate cortex).
Describe early and late pain signal
- In volunteers, early pain (pain
recognition) responses correlate
with somatosensory activation - Late pain (identification of
unpleasantness of pain) correlates
with ACC activation - Both components of pain
bilaterally activate the secondary
somatosensory complex.
Describe sites of opioid analgesia
- Spinal sites
- Opioidergic neurons are involved in
descending modulatory pathways (either
acting directly on projection neurons or on
excitatory interneurons) - Opioidergic interneurons release endorphins to
inhibit ascending projection neurons - Supraspinal sites
- Opioids function in the limbic system, thalamus,
and sensory areas to modulate emotional
components of pain
Describe descending pain modulation pathways
The most important descending pathways
originate in the periaqueductal gray (PAG) in
the midbrain.
PAG neurons project to the raphe nuclei
where seratonergic projections descend to
provide inhibitory input to pain afferents.
Further projections from the PAG terminate in
the locus ceruleus– noradrenergic cells
increase firing in response to pain and are
inhibited by μ-receptor agonists.
- PET scan measuring displacement of a
radiolabelled ligand for the μ-receptor
([11C]carfentanil) by endogenous opioids.
Since the endogenous and exogenous
ligand compete for the same site
decreased signal from the PET ligand is
proportional to increased release of
endogenous opiates.
Describe opioid peptide effects in research
- In PET displacement studies, sensory pain scores correlated
negatively with opioid release in the nucleus accumbens,
amygdala, and thalamus - Affective pain scores correlated negatively with opioid release in
the anterior cingulate cortex, thalamus, and nucleus accumbens
