Topic 17: Opioid Receptors and Systems

Question 1

What is opioid potency?

Answer 1

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

Question 2

How do morphine and naloxone impact the ileum peristaltic reflex?

Answer 2

morphine reversibly inhibits the ileum peristaltic reflex

the opioid antagonist naloxone rapidly restores reflex function

Question 3

How were opioid receptors discovered?

Answer 3

opioid receptors were remarkably difficult to identify

opioid binding was demonstrated to be reversible, saturable, and of high affinity

Question 4

What is opioid receptor binding and potency?

Answer 4

opioid receptor binding by the radioligand assay was shown to correlate with the potency of opioids in the guinea pig ileum bioassay

Question 5

What is opioid receptor distribution?

Answer 5

high binding observed in the striatum, locus coeruleus, thalamus, raphe nuclei, and periaqueductal gray

Question 6

What are opioid receptor subtypes?

Answer 6

opioid receptors are G-protein coupled (to Gi)

four main subtypes exist: delta, kappa, mu, nociceptin

Question 7

What are mu-opioid receptors?

Answer 7

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

Question 8

What are delta-opioid receptors?

Answer 8

similar expression to mu but more restricted

not sensitive to morphine

roles in olfaction, motor integration, reinforcement, and analgesia

Question 9

What are kappa-opioid receptors?

Answer 9

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

Question 10

What are nociceptin opioid receptors?

Answer 10

expressed in amygdala, hippocampus, hypothalamus, and spinal cord

roles in anxiety, depression, appetite, and development of tolerance to mu-opioid agonists

Question 11

What are enkepalins?

Answer 11

“in brain”

selective for delta receptor

two subtypes

Question 12

What are dynorphins?

Answer 12

from Greek dynamis, meaning power

selective for kappa receptor

four subtypes

Question 13

What are endorphins?

Answer 13

contraction from endogenous morphine

selective for the mu receptor

five subtypes

Question 14

What are endomorphins?

Answer 14

also a contraction from endogenous morphine

selective for the mu receptor: extremely high affinity

at least two subtypes

gene or prepeptide not yet identified

Question 15

What is nociceptin?

Answer 15

selective for the nociceptin receptor

anti-analgesic

single species

Question 16

What are endogenous peptide genes and synthesis?

Answer 16

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

Question 17

What is beta-endorphin release?

Answer 17

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

Question 18

How is endogenous opioid signaling inhibitory?

Answer 18

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

Question 19

What is pain signaling?

Answer 19

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

Question 20

What are the two components of pain?

Answer 20

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

Question 21

What is the pathway of early pain?

Answer 21

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

Question 22

What is the pathway of late pain?

Answer 22

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)

Question 23

How do early pain and late pain interact?

Answer 23

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

Question 24

What are spinal sites of opioid receptors?

Answer 24

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

Question 25

What are the supraspinal sites of opioid receptors?

Answer 25

opioids function in the limbic system, thalamus, and sensory areas to modulate emotional components of pain

Question 26

What are descending pain modulation pathways?

Answer 26

the most important descending pathways originate in the periaqueductal gray (PAG) in the midbrain

PAG neurons project to the raphe nuclei where serotonergic projections descend to provide inhibitory input to pain afferents

further projections from the PAG terminate in the locus coeruleus - noradrenergic cells increase firing in response to pain and are inhibited by mu-receptor agonists

Question 27

How does sustained pain affect opioid signaling?

Answer 27

sustained pain results in extensive activation of endogenous opioid signaling in limbic structures

PET scan measuring displacement of a radiolabeled ligand for the mu-receptor 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

Question 28

What are the effects of opioid peptides on pain sensation?

Answer 28

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

collectively these studies show that endogenous opioids are involved the modulation of both acute pain sensation and the late emotional components of pain sensation