Lecture 43: Neuropharmacology of Opioids (and Alcohol Addiction) Flashcards by Hao-Hua Wu

What is an opioid?

Any chemical compound with pharmacologic actions similar to those of morphine
“narcotic analgesic”
Morphine is the prototype drug

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What are morphine and codeine?

Alkaloids of the poppy plant

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What is Naltrexone?

ORALLY active antagonist of opium

-used in alcohol addiction treatment

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What is Naloxone?

PARENTERALLY (not oral) antagonist of opiate receptor

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What are the two approaches to pain pharmacotherapy?

Local anesthetic
- it doesn’t hurt anymore. It’s numb
Opioid analgesic
- it HURTS but who cares?

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What is opioid’s effect on the body?

Makes you not care about pain…you feel pain but don’t care about it
-acts at the THALAMIC and CORTICAL (post central gyrus) levels to decrease pain sensation

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What is the purpose of mu opioid receptors? Location?

They mediate both spinal (DRG) and supra spinal analgesia 
Location:
	-in periaqueductal gray
	-thalamus
	-sensory cortex

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What is the purpose of delta receptors?

Mediate spinal analgesia for pain C fibers in spinothalamic tracts
Location: dorsal horn of the spinal cord

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What are the ascending tracts of opioids?

spinothalamic

2. spinoreticular

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Where is the euphoria of opioid coming from?

VTA dopaminergic neurons project to nucleus and medial prefrontal cortex

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Where is the nausea of opioids mediated by?

Kappa receptors of area postrema

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What is the Area Postrema?

Located in the MEDULLA
Controls vomiting
Area Postrema connects to the solitary nucleus and is excited by impulses from GI tract

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How do opioids cause respiratory depression?

Produced in brainstem
Decreases neuronal sensitivity to PCO2
Cause of death in overdose

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How do opioids cause antitussive activity?

Produced in brainstem

D-isomers of opioid lack euphoria but retains anti-tussive action

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What does antitussive mean?

Capable of relieving or suppressing coughing

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What are the actions of opioids?

Euphoria
Nausea
Respiratory Depression
Antitussive
Constipation
Constriction of the pupil
Peripheral vasodilation (DMX)
THINK PARASYMPATHETIC except for constipation lol

What is the cause of death in opioid overdose?

Respiratory depression

What are the 3 main endogenous opioid receptor ligands in the CNS?

endorphin
Enkephalin
Dynorphin

What is endorphin?

An endogenous opioid receptor LIGAND

-binds to mu and delta opioid receptors

What is enkephalin?

An endogenous opioid receptor LIGAND

-binds to mu and delta opioid receptors

What is dynorphin?

An endogenous opioid receptor LIGAND

binds to kappa opioid receptors
causes the DYSPHORIC effects of opioids

What is the ACUTE cellular response to morphine?

Decreased levels of cAMP
Decreased levels of CREB phosphorylation
Opens K+ channels and HYPERPOLARIZES GABA releasing neurons
Less GABA release; decrease in firing

What are the mechanisms of opioid tolerance?

mu receptor phosphorylation by src kinases at 2nd intracellular loop
- leads to INCREASE of cAMP
- switches from an inhibitory to stimulatory cAMP signal (switch from Gi to Gs)
mu receptor phosphorylation by G protein kinases at 2nd intracellular loop
-uncouples G-protein from Mu opioid receptor
-leads to DECREASE of mu receptors due to increase of mu receptor internalization
-mediated by Beta-Arrestin
Receptor downregulation alters RATIO of high affinity vs low affinity receptor forms

What is the CHRONIC cellular response to morphine?

DECREASED levels of Gi proteins
cAMP no longer inhibited…cAMP is upregulated
because cAMP is upregulated, CREB and PKA is upregulated as well
PKA = opens Na channels, DEPOLARIZATION
Depolarization leads to INCREASE neurotransmitter release

What does beta-arrestin-2 do?

Mediates Mu opioid receptor (MOR) internalization

What does Filamin A (FILA) do?

Links the Mu opioid receptor to the C-terminus of actin | No FILA = no internalization

What are the symptoms of opioid withdrawal?

12 hours after last dose of morphine Physical symtpoms are mild (wont kill you but sucks) and are OPPOSITE of morphine actions 1. Anxiety 2. Agitation 3. Diarrhea 4. Pupillary Dilation 5. Craving for opioid (can be cued by drug-related perceptions Sympathetic response except for the diarrhea lol

What is the epidemiology of opioid addiction?

~1 million opioid addicts in the US 50% of risk of opioid addiction is inherited 85% relapse in 1 year Relapse is initiated by carving … the gordian knot of opioid addiction

How do we treat opioid addiction?

1. Methadone maintenance - if an addict injects heroin under methadone treatment, euphoria is markedly attenuated 2. Buprenorphine-Naloxone 3. Naltrexone

What are advantages of methadone treatment?

1. lowers rates of HIV & hepatitis 2. Lowers rate of re-arrest 3. Increases employment rates

What is heroin?

An opioid analgesic

What is buprenorphine-nalozone (Suboxone)?

Buprenorphine is an orally-active partial mu agonist that dissociates slowly from MOR -causes less severe withdrawal symptoms Also blocks euphoria if heroine is concomitantly injected

What are the significant genetic variations of MOR?

Single Nucleotide Polymorphism in MOR…changes A to a G allele Those who are AA for N40D polymorphism are less susceptible to alcohol abuse Those who are AG are much more susceptible to alcohol abuse because self-reported stimulation is seen as greater

The more G allele in N40D in MOR means?

More dopamine release in striatum with ingestion of alcohol | -can be blocked by Naltrexone

OPRM1 (opioid mu receptor) AA homozygotes have what disadvantages?

Cannot be blocked by Naltrexone so it doesn’t work as a treatment

What is the significance of Naltrexone?

Because it REDUCES the euphoria associated with ethanol…but only with people G alleles in the opioid receptr Can also be used as opioid addiction treatment

What do opioids do acutely?

Decrease cAMP activity

What happens when you get tolerance of opioid activity?

cAMP is UPREGULATED so you no longer have the same effect as before Gi is replaced by Gs subunit