Opioid analgesics and antagonists

Question 1

Synthesis of endogenous opioids

Answer 1

• For brain the peptides are synthesized in the pituitary gland and hypothalamus
• They are cleaved from large precursor proteins, starting w/ POMC (for endorphins), pre-proenkephalin, and pre-prodynorphin
• beta-endorphin is the most potent endogenous opioid

Question 2

Distribution of beta-endorphin

Answer 2

• Synthesized from POMC in 2 locations: arcuate nucleus of hypothalamus and nucleus tractus solitarius (NTS)
• Opioid neurons of the arcuate nucleus project to the limbic forebrain and brainstem areas: nuc accumbens, amygdala, other nuc of hypothalamus
• Other projections: periaqueductal gray (serotonin), VTA (DA), and locus ceruleus (NE)
• Opiod neurons in NTS project to brainstem pathways that modulate ANS

Question 3

Opioid receptors

Answer 3

• 3 kinds: mu, kappa, and delta
• They are all GPCR that inhibit AC, decrease cAMP, inhibit presynaptic voltage-gated Ca channels and increase the efflux of K from the postsynaptic cell
• Overall this reduces NT release from presynaptic cell and decreases excitability of the postsynaptic cell
• Thus opioids exert different effects depending on the pre or postsynaptic distribution of the receptors

Question 4

Opioids and pain modulation in spinal cord 1

Answer 4

• Descending pathways (NE and 5HT) from brainstem synapse on enkephalin interneurons near nucleus proprius in the dorsal horn
• The opioid receptors are found on dendrites of presynaptic nociception neurons and dorsal horn projection neurons, both part of the STT pathway
• Activation of the nociception neurons causes their release of Glu and substance P on the dorsal horn neurons, which convey pain signals to the thalamus via STT

Question 5

Opioids and pain modulation in spinal cord 2

Answer 5

• However if the NE/5HT neurons in brainstem are activated, they will activate the opioid neurons to release enkephalin onto the nociception and dorsal horn neurons
• The enkephalins bind to their opioid receptors on the pre and postsynaptic cells and decrease the cells’ firing rates
• This reduces the pain signals to the thalamus

Question 6

Opioid disinhibition of DA transmission

Answer 6

• In the VTA activation of opioid receptors on GABA neurons stimulates the disinhibition of DA projection neurons
• The GABA neurons normally inhibit DA release to the striatum from the VTA
• Opioids bind to the GABA neurons and remove this inhibition, thus causing an increase in DA firing in the striatum and reinforcing the activity
• Key mechanism in drug addiction

Question 7

Natural and synthetic opioids

Answer 7

• Natural: morphine and codeine
• Morphine relieves pain by raising the pain threshold in the spinal cords and by altering the brain’s perception of pain
• Morphine reduces the firing of nociception neurons and STT neurons in the SC by preventing presynaptic release of glutamate and sub P, and preventing postsynaptic depolarization
• Pain is there but not viewed as unpleasant
• The main receptor is mu, and upon activation it causes: analgesia, euphoria, and respiratory depression

Question 8

Effects of opioids on physiologic functions 1

Answer 8

• CNS: analgesia (dull pain blocked more), sedation, suppression of cough (antitussive), dysphoria, euphoria (disinhibition of DA release from VTA), addiction
• Respiration: depresses by reducing sensitivity of respiratory center neurons to CO2 levels, both pointing and medullar centers affected too (most common cause of death)
• Miosis: pinpoint pupil due to activation of EW nucleus and enhanced para stimulation of eye

Question 9

Effects of opioids on physiologic functions 2

Answer 9

• Emesis: directly stimulates chemoreceptors in area postrema of medulla to cause nausea/vomiting
• Renal system: depressed renal function, elevated ADH and urinary retention
• GI: constipation, decreases peristalsis, delayed gastric emptying and gastric acid secretion
• CV: little effect on HR or BP in supine, orthostatic hypotension in standing

Question 10

Metabolism, excretion, and absorption

Answer 10

• Metabolized in liver (duration 4-5 hrs), elderly are more sensitive
• There is significant first pass metabolism, so parentally is best way to administer
• Different opiates have different time to peak effect and durations

Question 11

Distribution of opiates

Answer 11

• Heroin and codeine pass thru the BBB more easily than morphine
• Fentanyl has short duration of action b/c it rapidly redistributes from brain to peripheral tissues
• Morphine is used for severe pain and has relatively long duration of action
• Fentanyl is used for fast induction and emergence of analgesia

Question 12

Narcotic antagonists

Answer 12

• Bind to opioid receptors but have no significant effect on normal pts
• In patients w/ opioids in system these will rapidly reverse the effects of the opioids and precipitate the symptoms of withdrawal
• Used to Rx acute opioid overdose
• Naloxone is used to reverse the coma and respiratory depression of opioid overdose (w/in 30 sec of IV injection). Highest affinity for mu receptor
• All narcotic antagonists are metabolized in liver
• Tolerance does not develop to these and no withdrawal symptoms following chronic use