EXAM 2 Opioid analgesics and antagonists Dr. Pond

Question 1

Which opioid receptors are primarily found in the area of nociception and reward?

Answer 1

Mu (μ) receptors
analgesia, reward (euphoria)!!!, sedation, respiratory
depression, miosis, inhibition of GI motility, modulation of hormone release

Delta (δ) receptors
-> Mediate analgesia and modulation of hormone release

Question 2

How are Kappa (κ) receptors different from the others?

Answer 2

-Unique anatomical distribution and unique pattern of physiologic action

-produces dysphoria (opposite of mu receptor)
-Increase psychotomimesis (hallucinations, delusions)
-also causes sedation, and slow GI transition

Question 3

Target of endogenous opioid peptides

Answer 3

endorphins (large peptide) -> mu receptors
enkephalins (5 AS) -> delta receptors
dynoprhines (dynorphin A and B) -> kappa receptors

but all peptides bind to all receptors with some affinity

Question 4

What are the differences between the enkephalins?

Answer 4

Tyr-Gly-Gly-Phe-…

5-AS-peptide
Met-enkephalin
Leu-enkephalin

Question 5

What is the name of the newly discovered opioid peptide?

Answer 5

Orphanin FQ or nociceptin
-> binding ORL1

Question 6

What is the propeptide from which endorphins are derived?

Answer 6

Pro-opiumelanocortin -> ß endorphin

-> also contains ACTH: adrenocorticotropic hormone (stimulates the release of cortisol)

Question 7

What type of receptors are opioid receptors?
Metabotropic or ionotropic?

Answer 7

Metabotropic -> interacts with ion channels and changes the memrabne potential
->interact with enzymes (adenylate cyclase)

Question 8

What are the effects of opioid receptors?

Answer 8

-inhibit adenylate cyclase (blocks: ATP -> cAMP conversion)
-activation of K+ channels (IPSP) on postsynaptic neuron
-inactivation of voltage-gated Ca2+-channels axoaxonic (blocking NT release)

-> inhibitory effect

Question 9

Where in the path of pain transmission are opioid receptors located?

Answer 9

-Primary nociceptors
-Secondary afferent neurons within the dorsal horn of the spinal cord
-Tertiary afferent neurons of the thalamus
-Cerebral cortex (target of thalamic neurons)

Question 10

Locations of opioid receptors in the brain

Answer 10

Reward:
-Cerebral cortex
-VTA
-nucleus accumbens

Pain:
-Cerebral cortex
-Thalamus
-brain stem
-spinal cord

Question 11

How do opioids work on the descending pathway?

Answer 11

it inhibits the inhibitor (GABA) of the descending (inhibitory) pathway

GABA would inhibit the descending pathway -> but it blocked by opioids

opioids blocks voltage gated Ca2+channels and prevents GABA release

-> increasing INHIBITORY effect of the descending neuron

Question 12

What is the primary REWARD pathway in the brain?

Answer 12

mesolimbic dopamine pathway

VTA (reward) projects and releases dopamine to nucleus accumbens (reward)

Question 13

What are the functions of endogenous opioids?

Answer 13

-mediate stress-induced analgesia (ACTH is produced together with ß-endorphin)

-may contribute to the regulation of appetite drives (for food, water, or sex), endocrine function, and perhaps memory

Question 14

What is the role of ß-arrestin in the opioid pathway?

Answer 14

-respiratory repression
-N/V
-desensistization of neurons -> tolerance???

Question 15

How does the drug Oliceridine work?

Answer 15

G protein-pathway selective (µ-GPS) modulator

-it modulates the mu-receptor in a way that the conformational change prevents the interaction with ß-arrestin

-> directs the opioid effect towards the G-protein pathway

-ß-arrestin causes N/V, respiratory depression, and inhibits the analgesic effect of the G-protein pathway
-G-protein also causes N/V, and respiratory depression but less

Question 16

Which opioids are used for severe pain?

Answer 16

Strong agonists

-Morphine
-Oxymorphone

-Methadone (long-acting)
-Meperidine (short-acting)

-Fentanyl (short-acting)
-Sufentanil (short-acting) - 5-7x more potent than fentanyl

Question 17

Which opioids have activity on the kappa receptor?

Answer 17

Morphine +κ
Sufentanil +κ (also +δ)

Pentazocine +κ
Butorphanol +++κ

-> stimulates dysphoria and psychotomimesis

Question 18

ADE of Meripidine

Answer 18

-antimuscarinic effects
-negative inotropic action on the heart
-potential for producing seizures

Question 19

Opioid used for the treatment of addiction

Answer 19

Methadone
-when orally taken it has a slow absorption -> prevents euphoria, at the same time suppresses withdrawal

mu-agonist only
NMDA-antagonist -> reduces opioid tolerance

Question 20

Opioids for moderate pain

Answer 20

-Oxycodone (++mu -> moderate agonist)

-Codeine and Hydrocodoen (+/- mu partial agonist
-> ceiling effect)

-Tramadol (+ mu weak mu agonist, SERT/NET inhibitor (reuptake transporter of Serotonin/NE)

Question 21

What effect does SERT/NET inhibitor have on nociceptic neurons?

Answer 21

inhibitory

prevenitng Serotonin and NE reuptake -> higher concentration of Serotonin and NE -> they bind to alpha-2 receptor (adrenergic) and close voltage-gated Ca2+ channels

Question 22

Which opioids are thought to benefit from the SERT/NET contribution in pain relief?

Answer 22

Tramadol (SERT/NET inhibitor + weak mu agonist)
Tapentadol (NET inhibitor + mu agonist)

Question 23

Which opioids are used for diarrhea?

Answer 23

Mild to moderate agonists

-Diphenoxylate (and its metabolite difenoxin)

-Loperamide (Imodium) (limited brain access)

->limited access to brain bc more hydrophilic

Question 24

Opioids with mixed receptor actions

Answer 24

-Nalbuphine (IV): kappa agonist, mu antagonist

-Buprenorphine: partial mu agonist, kappa antagonist

-Butorphanol: Kappa agonist, partial mu agonist
->analgesia with more sedation

-Pentazocine: Kappa agonist and partial mu agonist

REMEMBER: kappa agonists are more likely to cause psychotomimesis (hallucinations, delusions)

Question 25

Naloxone (IV, intranasal)

Answer 25

Naloxone (IV, intranasal): short duration of action of 1-2h -> so if a patient overdoses on methadone (long-halflife) consider that they can turn back to respiratory repression when using a short half-life antagonist

Naltrexone (oral)

Question 26

How are opioid antagonists used to prevent abuse of SUD drugs?

Answer 26

in Suboxone: Naloxone doesnt really work orally, but when trying to abuse with IV it gets activated and prevents the “high

Question 27

Abuse deterrent formulations

Answer 27

Troxyca: Oxycodone + Naltrexone
-> Naltrexone is embedded in the core and will not be released when taken as directed, Oxycodone is released and will help with withdrawal symptoms

Suboxone: Bupenorphine + Naloxone
(sublingual or tablet)

Question 28

How are opioids involved in the euphoria and reward pathways in the CNS?

Answer 28

Opioids -> increases dopamine
VTA projects to nucleus accumbens and releases dopamine

GABA is released by another neuron and inhibits dopamine release from the VTA nerve (balance mechanism?)

-> opioids bind to opioid receptors on the GABA neuron and block voltage-gated Ca2+channels -> thereby preventing GABA release, thus preventing the inhibitory effect to the VTA nerve -> more dopamine release to the nucleus accumbens

Question 29

Which area in the brain confers sedation, respiratory repression, and Miosis?

Answer 29

Locus coerulus (LC)
(key nucleus in the brain stem for NE)
normally NE in that area will make us alert, awake, attentive

Question 30

Temperature abnormalities mu and kappa

Answer 30

mu: hyperthermia

kappa: hypothermia

Question 31

Peripheral effects

Answer 31

Cardiovascular -> bradycardia
GI -> constipation
biliary tract -> contraction of biliary sphincter
-renal function is depressed (less blood flow)
-contraction of bladder sphincter -> urinary retention

-reduces the uterine tone (weaker contraction, help with pain, but may also impairs labor)

-neuroendocrine -> stimulates release of ADH (antidiuretic hormone - retention of body fluid), prolactin, and GH, inhibits LH (may decrease fertility)

-Pruritus -> flushing, warming of the skin, sweating, itching

Question 32

Possible mechanism thought to be involved in tolerance?

Answer 32

not fully understood

-Upregulation of the cAMP system (
-Effects on mu receptor recycling
-Receptor uncoupling

-Delta receptors involved?
-NMDA receptor involved?
Ketamine and Methadone blocks tolerance development

Question 33

Which effects of opioids are not affected by tolerance?

Answer 33

moderate: bradycardia

little to none:
Convulsion
Constipation
Miosis

Question 34

Which drug can be used for opioid induced constipation?

Answer 34

-Methylnaltrexone bromide (Relistor)
->antagonsist that is only active in the periphery

-Naloxegol (Movantik)

Question 35

Physically dependence on opioids

Answer 35

when stopping taking it -> WITHDRAWAL

-opioids cause constipation -> in withdrawal diarrhea
-opioids cause relaxed and chill mood -> in withdrawal anxiety
-runny nose, lacrimation, chills
-hyperventilation, hyperthermia
-pupil dilation
-muscle aches
-hyperalagesia (increased sensation of pain)

Question 36

Withdrawal symptoms in the brain

Answer 36

no inhibition of the inhibitor (GABA)
-> less dopamine to the nucleus accumbes and prefrontal cortex -> feeling down

-NE pathways that were inhibited by opioids become active -> more alert, anxious

Question 37

How does Lofexidine work?

Answer 37

for opioid withdrawal
-alpha-2-receptor agonist

REMEMBER: Noradrenergic receptors
-alpha-2 receptors are found presynaptic and are inhibitory autoreceptors -> normally NE will bind and cause closing of voltage-gated Ca2+ channels (negative feedback for NE release?)

ADE: hypotension, bradyarryhtmia, dry mouth, somnolence, dizziness