Barker lecture 2 Flashcards
Benzylisoquinolines
Noscapine (6%)
Papaverine (1%)
Phenanthrenes
Morphine (10%)
Codeine (0.5%)
Thebaine (0.2%)
Non-phenanthrenes
Tramadol
Meperidine
Fentanyl
Human genome contains several genes encoding endogenous opioids
Peptides active endogenously
Large precursor proteins are cleaved into more opioid subtype selective peptides
Degree of redundancy
Proopiomelanocortin (POMC)
B-endorphin–>mu opioid
Preproenkephalin
Leu-enkephalin–> delta opioid
Met-enkephalin–>mu and delta
Preprodynorphin
Dynorphin–>kappa opioid
Nociceptin/Orphanin FQ
G protein coupled receptor
Family A–peptide receptors
Gi/o coupled (inhibition of cAMP production)
Open GIRK(beta gamma) potassium channels–>hyperpolarized
Close calcium channels
Mu
Morphine
Endogenous opioid=endorphin
Kappa
ketocyclazocine
Endogenous opioid=dynorphin
Delta
deferens–> where identified
endogenous opioid=enkephalin
Opioid receptor for signal transduction
Presynaptic: inhibit calcium channel (Gi) decrease neurotransmitter release
Postsynaptic: activate GIRK channel (GBy) Efflux of K=hyperpolarization making it more negative and making it more difficult to reach
Mu opioid receptor
Beta-endorphins (endogenous morphine)
Pro-opiomelanocortin
Component of runners high
Analgesia
Not as effective for chronic pain
Cancer pain, palliative, PCA
Sedation
Antitussive
Suppression of cough center in the medulla oblongata
Opioid induced side effects are mostly on-target effects
Respiratory depression
Constipation
Itch
Addiction
Urinary retention: opioid-induced ADH release
N/V
Miosis: oculomotor nerve
not meperidine
Kappa opioid receptor
Dynorphins natural ligand: preprodynorphin
Activation is dysphoric aversive
Potential use for treatment of addiction: reduce DA release
Counterbalance mu opioid receptor effects
Delta opioid receptors
Enkephalins are natural ligand
Preproenkephalin
More dynamic expression
Role in hypoxia/ischemia/stroke
Hibernation release of enkephalin like opioid
Reduce anxiety
Reduce depression
Treat alcoholism
Relief hyperplasia;chronic pain
SE: SEIZURES
NO FDA APPROVED DELTA OPIOIDS
Opioid site of action
nucleus accumbens
VTA
important for reward
almost all known substance uses have connections in these circuits
Depressants can cause dopamine release just like stimulants
- opioids bind mu receptor
- Gi signaling inhibits neurotransmitter release
- Less GABA to activate GABAa
- Less inhibition of dopamine neuron activity
- increase dopamine release
- increased activation of dopamine receptors
