narcotic analgesics part 1

Question 1

the EOPs (endogenous opiod peptides, previously known as “the endorphins”) are products of 3 separate genes which are?

Answer 1

1. Pro-opiomelanocortin produces ß-endorphin as well as ACTH and melanocyte stimulating hormone.
2. Pro-enkephalin produces met-enkephalin and leu-enkephalin (enkephalins).
3. Pro-dynorphin produces dynorphin.

Question 2

how does the pain sensory system work?

Answer 2

In the dorsal horn of the spinal cord, primary pain sensory afferent fibers release excitatory neurotransmitters such as glutamate and Substance P

This stimulates neurons that project up to the thalamus, or to the reticular activating system, or to midbrain areas

These then project to the hypothalamus and limbic system, or directly to the hypothalamus and the cortex.

Question 3

how does the descending system work?

Answer 3

Descending pain-inhibitory systems originate in the periaqueductal gray region of the midbrain and from several nuclei of the upper anterior medulla oblongata and project downward to the dorsal horn.

The descending systems → norepinephrine (NE), 5-HT, other neurotransmitters → inhibit activity of the ascending pain pathways
- by direct synaptic contacts

• indirectly by activating inhibitory interneurons
  (Enkephalin)

Question 4

what do endogenous opiod peptides do?

Answer 4

Endogenous opioid peptides modulate pain sensory transmission in the spinal cord, in limbic structures, in the hypothalamus, and in the medial thalamus.

Endogenous opioid peptides also modulate gastrointestinal function.
Stimulation of opioid receptors on the intestine, increases random contractions of the circular muscles.
This disrupts sequential segmental contractions and blocks the propulsive transport of lumen contents.
The result is constipation.

The longer the food is in the GI the more water that is taken up and the stool is harder so this creates constipation.

Question 5

what are the 3 classes of EOPs?

Answer 5

• 3 classes of receptors: µ (mu), (kappa) and  (delta)
• Each with several subtypes: mu1 and 2
  kappa1, 2 and 3
  delta1 and 2
• Linked to G proteins, regulate ion channels and cellular
  metabolism. Generally inhibit adenylyl cyclase

Question 6

where are these opiod receptors in the CNS?

Answer 6

Delta and kappa more in the spinal cord while mew is more widespread

Question 7

what does each receptor have affinity for?

Answer 7

mu receptors have the highest affinity for ß- endorphin (now just called “endorphin”)

• kappa receptors have the highest affinity for dynorphin
• delta receptors have the highest affinity for
  met-enkephalin and leu-enkephalin.

Question 8

where are the receptors located?

Answer 8

Mu, kappa and delta receptors are on the presynaptic terminals of neurons, which release other neurotransmitters such as noradrenaline, serotonin, acetylcholine, glutamate, substance P, etc.

These receptors close calcium channels and this reduces or prevents the release of the other neurotransmitters

Question 9

what are the opioid synaptic receptor actions?

Answer 9

Opioid Synaptic Receptors-Actions
- mu and delta receptors
open potassium channels → hyperpolarization of the
postsynaptic membrane → reduces or prevents the
propagation of action potentialsin the postsynaptic neuron.

Question 10

how do G-protein coupled opioid receptors work?

Answer 10

Coupled negatively to adenylyl cyclase (AC) by G-proteins (Gi).
Activation ↓ activity of adenylyl cyclase → ↓ production of cAMP
This → ↑ efflux of K+ and cellular hyperpolarization
↓ influx of Ca++ and lower intracellular concentrations of free Ca++
→↓ release of neurotransmitters.

Question 11

how do mu receptor stimulation work?

Answer 11

• In the spinal cord and in the brain produces analgesia
• In the brain stem, suppresses pCO2 sensors produces respiratory depression
• Suppresses cough in brain stem
• In the GI tract they block propulsive motility producing
  constipation
• In the limbic system and related brain areas produces
  euphoria (main reason for abuse)

Question 12

how does kappa receptor stimulation work?

Answer 12

• In the spinal cord and in the brain produces analgesia, less euphoria

Selective kappa agonists such as Butorphanol
Affinity for opioid receptors in vitro of 1:4:25 (mu:delta:kappa)
produce less euphoria
act as “less-addictive” analgesics

Question 13

how does delta receptor stimulation work?

Answer 13

• In the spinal cord and in the brain produces analgesia