EXAM 2 Opioid analgesics and antagonists Dr. Pond Flashcards
Which opioid receptors are primarily found in the area of nociception and reward?
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
How are Kappa (κ) receptors different from the others?
-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
Target of endogenous opioid peptides
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
What are the differences between the enkephalins?
Tyr-Gly-Gly-Phe-…
5-AS-peptide
Met-enkephalin
Leu-enkephalin
What is the name of the newly discovered opioid peptide?
Orphanin FQ or nociceptin
-> binding ORL1
What is the propeptide from which endorphins are derived?
Pro-opiumelanocortin -> ß endorphin
-> also contains ACTH: adrenocorticotropic hormone (stimulates the release of cortisol)
What type of receptors are opioid receptors?
Metabotropic or ionotropic?
Metabotropic -> interacts with ion channels and changes the memrabne potential
->interact with enzymes (adenylate cyclase)
What are the effects of opioid receptors?
-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
Where in the path of pain transmission are opioid receptors located?
-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)
Locations of opioid receptors in the brain
Reward:
-Cerebral cortex
-VTA
-nucleus accumbens
Pain:
-Cerebral cortex
-Thalamus
-brain stem
-spinal cord
How do opioids work on the descending pathway?
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
What is the primary REWARD pathway in the brain?
mesolimbic dopamine pathway
VTA (reward) projects and releases dopamine to nucleus accumbens (reward)
What are the functions of endogenous opioids?
-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
What is the role of ß-arrestin in the opioid pathway?
-respiratory repression
-N/V
-desensistization of neurons -> tolerance???
How does the drug Oliceridine work?
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
Which opioids are used for severe pain?
Strong agonists
-Morphine
-Oxymorphone
-Methadone (long-acting)
-Meperidine (short-acting)
-Fentanyl (short-acting)
-Sufentanil (short-acting) - 5-7x more potent than fentanyl
Which opioids have activity on the kappa receptor?
Morphine +κ
Sufentanil +κ (also +δ)
Pentazocine +κ
Butorphanol +++κ
-> stimulates dysphoria and psychotomimesis
ADE of Meripidine
-antimuscarinic effects
-negative inotropic action on the heart
-potential for producing seizures
Opioid used for the treatment of addiction
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
Opioids for moderate pain
-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)
What effect does SERT/NET inhibitor have on nociceptic neurons?
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
Which opioids are thought to benefit from the SERT/NET contribution in pain relief?
Tramadol (SERT/NET inhibitor + weak mu agonist)
Tapentadol (NET inhibitor + mu agonist)
Which opioids are used for diarrhea?
Mild to moderate agonists
-Diphenoxylate (and its metabolite difenoxin)
-Loperamide (Imodium) (limited brain access)
->limited access to brain bc more hydrophilic
Opioids with mixed receptor actions
-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)
Naloxone (IV, intranasal)
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)
How are opioid antagonists used to prevent abuse of SUD drugs?
in Suboxone: Naloxone doesnt really work orally, but when trying to abuse with IV it gets activated and prevents the “high
Abuse deterrent formulations
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)
How are opioids involved in the euphoria and reward pathways in the CNS?
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
Which area in the brain confers sedation, respiratory repression, and Miosis?
Locus coerulus (LC)
(key nucleus in the brain stem for NE)
normally NE in that area will make us alert, awake, attentive
Temperature abnormalities mu and kappa
mu: hyperthermia
kappa: hypothermia
Peripheral effects
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
Possible mechanism thought to be involved in tolerance?
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
Which effects of opioids are not affected by tolerance?
moderate: bradycardia
little to none:
Convulsion
Constipation
Miosis
Which drug can be used for opioid induced constipation?
-Methylnaltrexone bromide (Relistor)
->antagonsist that is only active in the periphery
-Naloxegol (Movantik)
Physically dependence on opioids
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)
Withdrawal symptoms in the brain
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
How does Lofexidine work?
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
