Opioid Receptors and Systems Flashcards
A great variety of opioids exist
natural and synthetic, owing to
their unsurpassed potency as
analgesics.
Natural narcotics
Opium
morphine, codeine, thebaine
semisynthetic narcotics
Heroin, Hydromorphone, oxycodone, etorphine
totally synthetic narcotics
Pentazocine, meperidine, fentanyl, methadone, LAAM, Propoxyphene
endogenous opioids
endomorphines, enkaphalins, endorphins, dynorphins, Nociceptin
Opioid Potency
Analgesic effects are difficult to
directly measure in lab based assays
* In animal and human trials ethics limit
the types of experimental pain that
can be applied
* Human trials can be highly
confounded by subjectivity of pain
measures
We know opioids are potent
modulators of
GI mobility
Investigators developed a GI based
assay to measure the potency of
opioids
Ex vivo preparation of the
guinea pig
ileum
Application of hydraulic pressure
stimulates the
ileum peristaltic reflex
Morphine reversibly
Inhibits the
ileum peristaltic reflex,
opioid antagonist naloxone
rapidly restores
inhibition of Ileum peristaltic reflex by morphine
Opioid receptor discovery
Candace Pert and Soloman Snyder
finally identified the receptor using
radiolabelled naloxone (opioid
antagonist) in 1973
Opioid binding was demonstrated to
be
reversible, saturable, and of high
affinity.
Opioid receptor
binding and
potency
Opioid receptor binding
by the radioligand assay
was shown to correlate
with the potency of
opioids in the guinea pig
ileum bioassay
Opioid receptor distribution
- High binding observed in the striatum,
locus coeruleus, thalamus, raphe
nuclei, and periaqueductal gray
Receptor subtypes Four main subtypes exist
δ (delta)
κ (kappa)
μ (mu)
Nociceptin
Opioid receptors are
e G-protein coupled (to
Gi)
Putative receptors include
ε (EOR) and ζ
(ZOR) and previously σ
δ (delta) –
DOR / OP1
κ (kappa)
– KOR / OP2
μ (mu)
MOR / OP3
Nociceptin
NOP / OP4
Varied expression of opioid receptors in the rat brain suggest
subtype specific roles.
where are Mu receptors located
Striatum, thalamus, olfactory areas, cortex, Raphe Nuclei, Locus Coeruleus
WHere are delta receptors located
striatum, olfactory areas, cortex
where are Kappa receptors located
Striatum, Cortex, Thalamus, Raphe nuclei, Locus coeruleus
μ-opioid receptor (MOR) High affinity for
morphine
μ-opioid receptor (MOR) High expression in
thalamus, periaqueductal gray,
median raphe suggests roles in analgesia
μ-opioid receptor (MOR) Expression in nucleus accumbens suggests role in
reinforcement
μ-opioid receptor (MOR) Expression in brainstem suggests roles in
n respiratory
depression, cough suppression, and vomit reflex
δ-opioid receptor (DOR) Similar expression to
μ but more restricted
δ-opioid receptor (DOR) Not sensitive to
morphine
δ-opioid receptor (DOR) Roles in
olfaction, motor integration, reinforcement,
and analgesia
κ-opioid receptor (KOR) Distinct
expression pattern
κ-opioid receptor (KOR) High affinity for
ketocyclazocine
κ-opioid receptor (KOR) Expressed in
striatum and amygdala, also
hypothalamus and pituitary
κ-opioid receptor (KOR)Regulation of
pain perception, gut motility, and
dysphoria
κ-opioid receptor (KOR)Additional roles in
water balance, feeding,
temperature control, neuroendocrine function
ketocyclazocine
Synthetic opioid that is hallucinogenic and induces
dysphoria
Nociceptin receptor Expressed in
amygdala, hippocampus, hypothalamus,
and spinal cord
Nociceptin receptor Roles in
anxiety, depression, appetite, and
development of tolerance to μ-opioid agonists
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
Despite dramatic size differences, endogenous peptides show
structural similarity to opiates but are considerably more potent
Endogenous peptide genes and synthesis
Endorphins, enkephalins, and
dynorphins are synthesized
from pre-propeptide genes
- Endorphins are expressed from
POMC, which also gives rise to
melanocyte stimulating
hormones and
adrenocorticotropic hormone
β-endorphin release POMC is highly expressed in the
pituitary
–
peptides for both adrenocorticotropic
hormone (ACTH) and
β-endorphin
ACTH is released in response to
hypothalamic
corticotropin releasing hormone (CRH) and
acts on the adrenal cortex to release
glucocorticoid hormones
Co-release of
β-endorphin from the pituitary
provides a
a physiological link between stresses
and pain signaling
Endogenous opioid signalling is
inhibitory
– this can affect
neurotransmitter release through
a number of different ways.
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
G
i and cAMP
signalling to inhibit voltage gated
Ca2+
-channels
Endogenous opioid signalling is
inhibitory
– this can affect
neurotransmitter release through
a number of different ways Presynaptic autoreceptors to
inhibit neurotransmitter release.
Pain is unique among the senses as it can be induced by a range of factors
mechanical,
chemical, electrical, thermal, and inflammatory stimuli all affect nociceptive neurons.
Opioids are involved in modulating
pain pathways at both the spinal level and at supraspinal sites.
Pain perception has two components
Early pain
late pain
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
arly and late pain are signalled through
distinct neuronal pathways.
Ascending pain
pathways
Sensory neurons in the dorsal root ganglia
transmit signals in the dorsal horn to
ascending pathways.
Early pain is signalled through
A
δ fibers
(large, myelinated axons
– fast transmission).
A
δ 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).
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.
Sites of opioid analgesia
Spinal sites
Supraspinal sites
Opioid receptors are expressed at multiple
steps of pain 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
Descending pain
modulation
pathways The most important descending pathways
originate in the
periaqueductal gray (PAG) in
the midbrain.
periaqueductal gray (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
Sustained pain results in extensive
activation of
endogenous opioid signalling
in limbic structures.
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
r the same site
decreased signal from the PET ligand is
proportional to increased release of
endogenous opiates.
Opioid peptide effects on pain sensation 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
