Opioids

Question 1

What are opioid drugs?

Answer 1

narcotic analgesics (reducing pain without loss of consciousness)

Some Molecules: morphine, codeine, thepaine, narcotine)

Question 2

What is morphine the main active ingredient in?

Answer 2

Main active ingredient in opium (isolated in 1800s)

Question 3

What is opium?

Answer 3

Opium is poppy plant extract. Used in 1700s in wine stuff (laudanum + paregoric)

Question 4

How is heroin made?

Answer 4

Semi-synthetic: increases bioavailability. Adding 2 acetyl groups to morphine making it more lipid solute: reach brain faster, more potent, but once its in brain, the molecule that acts on things is morphine.

Question 5

Where do opioid drugs bind?

Answer 5

Receptors in brain (using radioligand binding assays) and in the gut.

Question 6

What are the different opioid receptor subtypes?

Answer 6

All metabotropic
Mu
delta
kappa
NoP-R

Question 7

Describe Mu.

Answer 7

High affinity for morphine (area shows effects)

• medial thalamus, PAG, raphe, locus coeruleus, spinal chord = ANALGESIA
• brainstem= CARDIOVASCULAR, RESPIRATOR CONTROL, COUGH, NAUSEAU/VOMIT
• Thalamus, striatum= SEMSORIMOTOR INTEGRATION
• NAc FEEDING, POS REINFORCEMENT
• thought to mediate pleasureable aspects of fatty foods and orgasms

Question 8

Describe the delta receptor?

Answer 8

Forebrain structures. overlap with mu receptors.

• olfaction, motor integration, reinforcement, cognitive function
• modulation of analgesia because of overlap with mu.

Question 9

Describe the kappa receptor

Answer 9

striatum, amgydala, hypothalamus

• makes you feel BAD
• pain perception, gut motility and dysphoria
• identified by binding ketocyclazocine which is an opioid that produces halluciations and dysphoria. bad cousin of mu

Question 10

Describe the Nociceptin/Orphanin FQ receptors.

Answer 10

Wide distribution (cortex, limbic, thalamus, raphe, spinal chord)

• does not bind opiod drugs
• lowers pain threshold, opposite to mu and delta
• feeding, learning motor function and neuroendocrine regulation

Question 11

What are endogenous opiods?

Answer 11

Found out that PEPTIDE TRANSMITTERS bind to opioid receptors in 1970s
- Enkephalin (in the brain)

Multiple peptides discovered = ENDORPHINS (endogenous morphine)

Question 12

How are endogenous opioids made?

Answer 12

In cell body, pro peptides are made with active parts within them that are cut up in the terminal into peptide transmitters. The propeptides have endogenous opiates and other transmitters in them.

Different variations exist. Co localized with other neurotransmitters in nerve terminals.

POMC: b-endorphine
PROENKEPHALIN: met ENK and leu-ENK
Dynorphin A and B

Question 13

What are the preferences of endogenous opioids?

Answer 13

Not selective, but preferential.

Mu: endorphins and a bit of endomorphins (no propeptide for endomorphins yet)

Delta: enkephalins and endorphins

kappa: dynorphins

Question 14

How do opioids inhibit neural activity?

Answer 14

1. Postsynaptic inhibition: G protein that opens K + channels to hyperpolarize
2. Axoaxonic inhibition heteroreceptors: activate G proteins to close Ca2+ channels reducing transmitter release (but net effect CAN be disinhibitory depending on circuitry)
3. Presynaptic autoreceptors
   - reduce release of neurotransmitter.

All inhibit adenylyl cyclase c-AMP

Question 15

What are some natural narcotics?

Answer 15

Opium

• Codeine
• Morphine
• thebaine

Question 16

What are some semisynthetic narcotics?

Answer 16

FROM MORPHINE
- heroin and hydromorphone (dilaudid)

FROM THEBAINE

• oxycodone (percodan)
• Etorphine

Many activate Mu receptors.

Question 17

What are some totally synthetic narcotics?

Answer 17

Pentazocine (Talwin) 
Meperdine (Demerol) 
Fentanyl (Sublimaze) 
Methadone -opioid replacement strategy (Dolophine) 
LAAm 
Propoxyphene (Darvon)

Question 18

What are some endogenous opiods?

Answer 18

Enkephalins, Endorphins, Dynorphins, Endomorphins

Question 19

What is an example of a partial agonist for opiod receptors?

Answer 19

Buprenorphine: less potent than morhpine but less respiratory depression and dependence.

Question 20

What are some antagonists of opioids?

Answer 20

Naloxone and Naltrexone: no efficacy. Prevent or reverse the effect of opioids.

Question 21

What are the 3 ways that opiods can inhibit pain signals within the spinal cord?

Answer 21

Prevent signal transduciton.

1. Directly activate opiod receptors in neurons in spinal cells. Inhibitory interneurons.
2. Descending pathway to effect neural activity, Opiates in the brain cause it to send an inhibitory signal to inhibiti pain projections.
3. Descending pathway to inhibit excitatory interneuron that synapse on pain projection cells

The desce

Question 22

How do descending pain signals get activated?

Answer 22

Opiods activate 2 descending pain inhibiting pathways from PAG.

• rich with opiod peptides and receptors.
• stimulation makes analgesia (stopped with antagonists) this is shown in rats that self administer.
• projections from PAG DISINHIBIT raphe (5ht) and locus coruleus (NE) descending projections that suppress pain signals in spinal cord.

Question 23

What does opioid activity in supraspinal locations do?

Answer 23

In areas like sensory, limbic, or hypothalamic areas, it mediates emotional, autonomic, and neuroendocrine components of pain. So a combo of spinal and supra spinal can reduce conduciton and blunt emotional response.

Question 24

How does acupuncture decrease pain

Answer 24

Activate endogenous opioid system:
PROVEN
1) given nalaxone reduces effect
2) FMRI showed activity in PAG

Question 25

What are the effects of opioids at low and high doese? Therapeutic vs recreational?

Answer 25

Therapeutic: intramuscuarly or orally, slower, no euphoria REcreationally: IV, inhalation, snorting, subcutaneous) more rapid Low dose: pain relief, constricted pupils, drowsiness, no concentration, dreamy sleep High dose: euphoria! Highest dose: sedative effects lead to unconciousness and death - suppress brainstem respiratory center

Question 26

What are the aversive effects of opioids?

Answer 26

Not everyone reacts the same way. dysphoria, restlessness, anxiety, nausea. - reduces gastro motility (constipation is a common side effect, reducing smooth muscle contraction) - used to treat diarrhea (and the dehydration that comes with it) for things like stomach parasites tho. - if you give a receptor antagonist that doesn't cross the BBB you can get the analgesic effects without the gastro effects. IV administration risks - infection, collapsed veins, liver damage, kidney damage, but compared to other drugs the toxic effects aren't that bad (except for overdose) -new studies show cognitive deficits, PFC functions, permeant changes.

Question 27

How are opioids reinforcing?

Answer 27

animals and humans readily self administer. (Mu receptor stimulation, kappa is bad) Opiods activate mesolimbic dopamine path! (rewards) 1. Mu activation in VTA inhibit GABA neurons, disinhibiting DA = more DA release in NAc 2. Kappa activation on DA terminals in NAc reduces DA release with presynaptic inhibition. (maybe its why they're so aversive?)

Question 28

Describe opioid tolerance.

Answer 28

Tolerance develops at different rates. - analgesia/pleasure is fast - constibuation, pupillary dilation and respiratory depression is slow Tolerance is mostly pharmacodynamic (changes at cellular level to compensate) Cross tolerance occurs (morphine - fentanyl)

Question 29

Describe opioid withdrawal.

Answer 29

opioids depress CNS function, withdrawl activates it so much. - unpleasant, not deadly. (pain, dysphoria) - worst on 2nd or 3rd day, done in a week Severity depends on dype of drug (morphine, heroin is severe, methadone and buprenophine is less sever) Precipitated by opioid antagonists (Naloxone)

Question 30

How do opioid antagonists precipitate withdrawal symptoms

Answer 30

Systemically or certain nuclei. Systemically: quick and intense withdrawl. Distinct nuclei: show that different regios do different things. LOcus or PAG: opioid antagonists trigger physical symptoms of withdrawal (so if you reduce locus activity you reduce the severity of the withdrawal, or give NE also reduce) Other regions like NAc and amygdala are in charge of emotionally aversive effects. If you administer antagonists, you get emotional effects. If you re-administer, (with same or different drug, remember cross dependent) you reduce or eliminate withdrawal symptoms.

Question 31

How does tolerance withdrawal operate at a single cell level?

Answer 31

Morphine inhibits syntehsis of cAMP, but with repeated treatment cells adapt to produce more camp, but if you remove morphine or add naloxone you get increased camp levels. IN locus coeruleus, morphine reduces firing rate, but adapt over time. If you give naltrexone or withdrawl, you get increase locus firing above normal levels.

Question 32

How do you initially treat opiod addiction.

Answer 32

Detoxification, can be assisted with drugs. Reducing locus coeruleus activity with alpha 2 adrenergic agonists (clonidine) can make NE more normal, but doesn't relieve all symptoms and has other side effects.

Question 33

what are maintenance and replacement treatments for opioid addiciton?

Answer 33

Methadone: Opioid agonist, less potent when given orally (high if injected so you have to watch ppl), prevents severe withdrawal and reduces cravings. cross tolerance develops so euphoric effect of heroin are reduced, reducing liklihood of relapse. Opioid antagonist: naltrexone (longer lasting than naloxine, orally active) - for motivated ppl - must take it every day. doesn't stop craving, only stops effects.