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
