Opiates

Question 1

History

Answer 1

use may predate written history of man, but the use of opiates goes back at least 7000 years.

early Arabic/Roman/Greek cultures prized the opiates…they have many useful effects:

opiate receptors first discovered by Snyder and Pert in 1972, labeled morphine w/ radioactivity and exposed it to brain tissue.

Question 2

Effects

Answer 2

Analgesic:
Antitussive:
Sedative:
Gastro-intestinal muscle relaxant:

Narcotic: classic term for the opiates and opiate-like drugs; comes from Greek word Narcotikos = to make sleep or to numb.

Question 3

Drug Examples

Answer 3

Morphine

Codeine

Heroin

Naxolone

Question 4

morphine can be altered to produce

Answer 4

Heroin

Question 5

Why is heroin more potent than morphine?

Answer 5

crosses the blood-brain-barrier more easily.

Question 6

Heroin is a ______ type of opiate.

Answer 6

semi-synthetic opiate

Question 7

Synthetic opiates

Answer 7

very powerful

Example: fentanyl, a true synthetic opiate that is about 100X as powerful as morphine.

Question 8

Naloxone/naltrexone:

Answer 8

Synthetic opiates

critical drugs: synthetically developed, direct antagonists for opiate receptors.

Allows blockade of all of opiate effects…including
reward/analgesia/respiratory depression (used in “EMT cocktail).

Question 9

administration of opiates varies with their…..

Answer 9

fat solubility:

Question 10

Morphine

Answer 10

can be administered orally, by inhalation, or by injection (usually IV),

though slow absorption means that injection is fastest means to an intense drug effect.

w/ morphine or heroin, the half life is about 4 hr

Question 11

Heroin

Answer 11

usually smoked or injected; better absorbed than morphine due to increased lipid solubility.

Once it is in the brain, however, it is converted to morphine to exert its effects on behavior.

w/ morphine or heroin, the half life is about 4 hr

Question 12

Codeine

Answer 12

converted to morphine in CNS (10%);

on its own has little effect except on cough centers in the brainstem.

Question 13

Fentanyl

Answer 13

a true synthetic opiate that is about 100X as powerful as morphine.

very easily absorbed; can be administered via mucosal membranes or even by a dermal patch.

They are also most potent when injected…can lead
to overdose problems.

half-life of about 30 min

Question 14

General pharmacokinetic Properties

Answer 14

all opiates are metabolized by liver and excreted by the kidney in urine

half-life varies from very short (e.g., fentanyl, with a half-life of about 30 min) to reasonably long (e.g., LAAM, a synthetic opiate, with a half life of about 24 hr).

w/ morphine or heroin, the half life is about 4 hr

Question 15

General properties Pharmacodynamics

Answer 15

all opiates are direct agonists that work at a group of receptors in the brain called opiate receptors…

Postsynaptic inhibition: open K+ channels
Axoaxonic inhibition: close Ca2+ channels
Presynaptic Autoreceptors: Reduce NT release

three main kinds.

all are indirect gating; mediate changes in ion conductances that decrease excitability (K+) or synaptic transmission (Ca2+).

Question 16

Brain Areas

Answer 16

Found high binding in areas like hypothalamus; spinal cord; and brainstem.

Question 17

μ receptor

Answer 17

most sensitive to morphine and heroin

widespread distribution

underlie euphoric, brain & spinal analgesic, sedative; GI motility effects.

Question 18

Δ receptor

Answer 18

more sensitive to enkephalins, one of the endogenous opiates

involved in spinal mechanisms of analgesia

Question 19

κ receptor

Answer 19

most sensitive to dynorphin
(endogenous)

mostly in spinal cord and brainstem

involved in spinal analgesia and sedation; significantly, has these effects without rewarding properties of mu opiates

also high in thalamus, locus coeruleus, and raphe nucleus… possible accounting for the hallucinatory effects of drugs like Salvia divinorum

Question 20

What is the 4th type of opiate receptor

Answer 20

NOP-R

sensitive to nocicepten/orphanin FQ/ pronocicepten

cortex, amygdala, hypothalamus, hippocampus, preiaqueductal gray, thalamus, sub. nigra, brainstem and spinal cord

Spinal analgesia, supraspinal pronociception, neuroendocrine, feeding, learning, motor

Question 21

endogenous opiates example of and history

Answer 21

classic examples of a peptide neurotransmitter

independent discovery of endogenous opiates by Kosterlitz and Hughes in 1975

isolated what they called ENKEPHALINS, meaning from the head…this term was eventually changed to the ENDORPHINS, meaning a naturally occurring
substance that acts like morphine

Question 22

Endogenous Opiates properties

Answer 22

role in normal stress response; released during times of pain (e.g., childbirth), fear (e.g., a fight)…and during very strenuous exercise (e.g., long-distance running).

begin as proopiomelanocortin, prodynorphin, and proenkephalin; are “cleaved” by enzymes into different types of chemical messengers.

much more potent that morphine/heroin/most exogenous opiates.

Question 23

Behavioral Effects:

Answer 23

in general, sedative-hypnotic like effects but not considered classical sedative hypnotics because they have many other effects at lower doses.

Question 24

Order of type of opiate used

Treatment of Chronic (not acute) Pain:

Antianxiety Effects:

Euphoric Effects:

Cough Suppressant:

Antidiarrheatic:

Sensory-motor integration:

Feeding:

Answer 24

Treatment of Chronic Pain: μ > δ > κ > NOP-R (spinal)

Antianxiety Effects: μ > δ > κ

Euphoric Effects: μ > δ > κ (dysphoric) and NOP-R

Cough Suppressant: μ > κ > δ

Antidiarrheatic: μ > κ > δ

Sensory-motor integration: μ & δ > κ

Feeding: κ & NOP-R > μ & δ

Question 25

Why should there be opiate receptors in your brain?

Answer 25

Because your brain makes endogenous opiates.

Question 26

pain pathways from the periphery

Answer 26

pain pathways from the periphery

1) decussate in the spinal cord;
2) ascend to synapse in the RAS, the PAG, and various places in the thalamus.

Question 27

supraspinal control of pain

Answer 27

1) begins in frontal lobes and hypothalamus;
2) pathways descend to brainstem to PAG;
3) PAG excites cells in LC (NE) and raphe nuclei (5-HT);
4) axons from these nuclei descend into spinal cord to synapse in dorsal horns

Question 28

opiates can reduce pain in the spinal cord

Answer 28

a) inhibiting projection neurons;
b) inhibiting interneurons that activate projection neurons;

and/or

c) exciting interneurons that inhibit projection neurons

Question 29

Opiate tolerance

Answer 29

develops to most effects; reason why dose must be increased to maintain an analgesic or reinforcing effect of the drug.

requires frequent administration.

involve enhanced activity of second messengers associated with the opiate receptors.

can be learned; tolerance is only expressed in drug-predictive environments (conditioned tolerance)
and
only develops to effects that
are expressed (contingent tolerance)

can be reduced by concurrent administration of NMDA antagonists

Question 30

Opiate Addiction and Withdrawal

Both types

Answer 30

not as severe as popular press makes out; for example, you cannot die during withdrawal for opiates, and at worst is seems like a bad case of the flu.

PHYSICAL: appear w/in hours; symptoms include drug craving; anxiety; runny nose; nausea; fever; muscle aches; diarrhea. Can be alleviated by further administration of opiate; can be precipitated by administration of an antagonist.

PSYCHOLOGICAL: fueled by both negative reinforcement (avoidance of withdrawal symptoms) and positive reinforcement (seeking euphoria/rewarding effects). Can also be conditioned (e.g, needle freaks; increased likelihood of relapse if social change not part of treatment).