Topic 17: Opioid Receptors and Systems Flashcards
What is 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
How do morphine and naloxone impact the ileum peristaltic reflex?
morphine reversibly inhibits the ileum peristaltic reflex
the opioid antagonist naloxone rapidly restores reflex function
How were opioid receptors discovered?
opioid receptors were remarkably difficult to identify
opioid binding was demonstrated to be reversible, saturable, and of high affinity
What is 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
What is opioid receptor distribution?
high binding observed in the striatum, locus coeruleus, thalamus, raphe nuclei, and periaqueductal gray
What are opioid receptor subtypes?
opioid receptors are G-protein coupled (to Gi)
four main subtypes exist: delta, kappa, mu, nociceptin
What are mu-opioid receptors?
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
What are delta-opioid receptors?
similar expression to mu but more restricted
not sensitive to morphine
roles in olfaction, motor integration, reinforcement, and analgesia
What are kappa-opioid receptors?
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
What are nociceptin opioid receptors?
expressed in amygdala, hippocampus, hypothalamus, and spinal cord
roles in anxiety, depression, appetite, and development of tolerance to mu-opioid agonists
What are enkepalins?
“in brain”
selective for delta receptor
two subtypes
What are dynorphins?
from Greek dynamis, meaning power
selective for kappa receptor
four subtypes
What are endorphins?
contraction from endogenous morphine
selective for the mu receptor
five subtypes
What are endomorphins?
also a contraction from endogenous morphine
selective for the mu receptor: extremely high affinity
at least two subtypes
gene or prepeptide not yet identified
What is nociceptin?
selective for the nociceptin receptor
anti-analgesic
single species
What are 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
What is beta-endorphin release?
POMC is highly expressed in the pituitary-peptides for both adrenocorticotropic hormone (ACTH) and beta-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 beta-endorphin from the pituitary provides a physiological link between stresses and pain signaling
How is endogenous opioid signaling inhibitory?
endogenous opioid signaling is inhibitory - this can affect neurotransmitter release through a number of different ways
postsynaptic inhibition is a result of Gi signaling to adenylate cyclase by G-beta-y signaling to hyperpolarizing K+-channels (GIRK)
axoaxonal inhibition can be elicited through Gi and cAMP signaling to inhibit voltage gated Ca2+-channels
presynaptic autoreceptors to inhibit neurotransmitter release
What is pain signaling?
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
What are the two components of pain?
early pain: immediate sensory component signaling 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 behaviors to limit further damage and aid recovery
What is the pathway of early pain?
early pain is signaled through A-delta fibers (large, myelinated axons, fast transmission)
A-delta fibers project to the thalamus and somatosensory cortex to provide location information on pain
What is the pathway of late pain?
late pain is signaled 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)
How do early pain and late pain interact?
in volunteers, early pain (pain recognition) responses correlate with somatosensory activation
late pain (identification of unpleasantness of pain) correlates with AAC activation
both components of pain bilaterally activate the secondary somatosensory complex
What are spinal sites of opioid receptors?
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
