Download Opiate receptors, endogenous opioid systems in brain, Analgesia

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Pharmaceutical industry wikipedia , lookup

Prescription costs wikipedia , lookup

Medication wikipedia , lookup

Stimulant wikipedia , lookup

Nicotinic agonist wikipedia , lookup

Drug interaction wikipedia , lookup

NK1 receptor antagonist wikipedia , lookup

Cannabinoid receptor antagonist wikipedia , lookup

Drug design wikipedia , lookup

Pharmacokinetics wikipedia , lookup

Theralizumab wikipedia , lookup

Dextropropoxyphene wikipedia , lookup

Drug discovery wikipedia , lookup

Pharmacogenomics wikipedia , lookup

Polysubstance dependence wikipedia , lookup

Psychopharmacology wikipedia , lookup

Neuropsychopharmacology wikipedia , lookup

Neuropharmacology wikipedia , lookup

Transcript
NeuroPharmacology (NB404):
Dr. Charles Chavkin
Professor of Pharmacology
D425 HSB
NeuroPharmacology (NB404):
• How drugs interact with their targets.
• How pharmacology can be used to discover
new medicines.
• How pharmacology can be used to increase our
understanding of healthy and pathological brain
functioning.
Opiate receptors, endogenous opioid systems in brain,
Analgesia, stress adaptation, drug addiction
Natural opium alkaloids
Morphine - gold standard
Codeine
Thebaine - (non-analgesic)
Opiate chemical structures
CH2=CH Naloxone
CH3C=0
Heroin
CH3C=0
Endogenous Opioid Agonists:
enkephalin - 2 pentapeptides
b-endorphin - POMC, ACTH
dynorphin - endog kappa agonist
NH2-Tyr-Gly-Gly-Phe-Leu-COOH
Opioids
NSAIDS
SynapticArrangement of Dorsal Horn
Descending Projections from R aphe' N.
To Reticular Formation,
Thalam us
Dorsal Root Ganglion
Excitatory
Synapses
Serotonin
Serotonin
From
Nociceceptors
Inhibitory
Synapses
Enkephalin
Substance Pand
other transmitters
Dynorphin or GABA
Types of Pain
Nociceptive pain mechanical, thermal, chemical activation of nociceptors
somatic pain: response to tissue injury
inflammatory mediators: prostaglandins, substance P,
bradykinin
Neuropathic pain damage to nerves (trigeminal neuralgia, postherpetic
pain, diabetic neuropathy)
Actions of Opiates:
analgesia
anxiolytic
sedation
euphoria
gut hypomotility (constipation)
cough suppression
respiratory depression
pupillary constriction
nausea and vomiting
endocrine suppression
itching (specifically morphine)
Endogenous opioid peptides (enkephalins and b-endorphin)
have Morphine-like effects
Analgesia
Euphoria
Antidepressant
Reduction in anxiety
Endogenous
opioids form
important stress
regulating systems
in brain
Endogenous dynorphin opioid peptides
Analgesia
Dysphoria
Depressant ?
Increase in anxiety ?
Stress-induced analgesia
Stress-induced dysphoria
Stress-induced priming of relapse?
QuickTime™ and a
Motion JPEG OpenDML decompressor
are needed to see this picture.
Forced swim stress-induced analgesia is blocked by
prodynorphin gene disruption
Day 1
Day 2
Dyn KO mice generated by Hochgeschwender; see Sharifi et al., 1998
QuickTime™ and a
YUV420 codec decompressor
are needed to see this picture.
Mechanisms of opiate actions:
Activate mu (m) delta (d), or kappa (k) opioid receptors
principal therapeutic opiates are selective for mu receptors
Opioid receptors are members of the 7TM, G proteincoupled receptor superfamily (>1,000 members)
Activation of opioid receptors inhibits neuronal activity
increases potassium conductance
decreases calcium conductance
inhibits neurotransmitter release
how do opiates act at a molecular level?
GDP
GTP
PO4
GDP
GDP
GTP
K+
Activated arrestin
G-Receptor Kinase
tolerance
opioid dose
Opiate Tolerance
receptor desensitization
compensatory adaptations in neuronal circuit
learning mechanisms
Physical Dependence
compensatory adaptations in neuronal circuit
Drug Withdrawal
removal of opiate unmasks compensatory
adaptations
Drug Addiction (extremely rare during treatment of pain)
b-arrestin produces GPCR tolerance in a series of resolvable steps
• GPCR-PO4 activates b-arrestin
• Newly exposed b-arr domain
binds GPCR
• GPCR- b-arr prevents Gprotein association
G Protein receptor kinase
b-arrestin
• GPCR- b-arr complex is
internalized by a dynamin
and clathrin dependent
mechanism
Acutely, morphine inhibits LC firing - sedation
Neuron hyperpolarized and
NE release inhibited
R
K+
mOR
Opiates inhibit
Noradrenergic neuron in the locus ceruleus
Chronically, this causes a compensatory increase in LC activation
decreased auto-inhibition, increased excitatory drive
R
R
Tolerance
Receptor desensitization
mOR
R
Excitatory drive
Normal
Excitability
restored
Noradrenergic neuron in the locus ceruleus
Opioid withdrawal - abstinence syndrome
Severity depends on dose used and rate of elimination.
Rhinorrhea
Lacrimation
Chills
Goose flesh - ‘cold turkey’
Muscle aches
Diarrhea
Yawning
Anxiety
Hostility
Hyperalgesia
Precipitated withdrawal by a partial agonist or antagonist administration
Withdrawal
R
R
Clonidine, an 2-adrenergic
receptor agonist, is effective at
reducing the sympathetic nervous
system hyperactivity associated
with acute opiate withdrawal.
Opiate gone
mOR
R
Hyper-Excitability
state
Excitatory drive
Noradrenergic neuron in the locus ceruleus
What is drug addiction? Correct use of prescribed medications for pain,
anxiety and hypertension produce tolerance and physical dependence.
Addiction is:
compulsive drug use,
obsessive thoughts about drug,
use despite objective evidence of harm,
loss of control of drug use,
high risk of relapse once abstinent.
Commonly Abused Prescription Opiates
Buprenorphine (Buprenex, Subutex, Suboxone)
Codeine
Fentanyl (Actiq, Sublimaze, Duragesic)
Hydrocodone (Vicodin, Vicoprofen)
Hydromorphone (Dilaudid)
Meperidine (Demerol)
Methadone (Methadose, Dolophine)
Morphine (MS Contin, Avinza, Oramorph SR)
Oxycodone (OxyContin, Percocet, Percodan)
Propoxyphene (Darvon)
“Molecular Basis of Addiction”
• Voluntary intake
tolerance
readily reversible
physical dependence
sensitization
• Involuntary - compulsive intake
cravings, obsession, self-destructive behavior
Addiction - high relapse risk
Progression to Addiction
challenges at the molecular front:
identify molecular and cellular changes in the addicted brain
genes controlling risk of addiction
molecular events controlling relapse risk
Conditioned place preference measures the
rewarding properties of drugs
• assess drug craving
Day: 1
2
3
4
5
6
Difference in time spent on
drug-paired side (sec)
Free Run, 30 min
Forced swim stress exposure
Cocaine, box 2, 30 min
Vehicle, box 1, 30 min
*
1200
Untreated mice, no stress
Vehicle-treated FST mice
nor-BNI treated FST mice
1000
800
600
*
*
400
200
0
-200
Baseline
Day 5 results
Drug consumption
Stress-induced priming of relapse?
crash
relapse
time
Heroin
Cocaine
Ethanol
Nicotine
stress
Working Model - (wild speculation)
Stress induces release of endogenous opioids in key brain
regions (nAc and VTA).
This results in ‘priming’ of the circuit - manifests as craving
Activation of the endogenous kappa opioid system during the
stress response elicits dysphoria, anxiety depression.
Drug self-administration self medicates the depression.
Kappa antagonists may be effective in treating this form of
depression.
SUMMARY:
Opiates are important therapeutic tools
Endogenous opioids have important role in mediating the
adaptive response to stress
Opiates can induce addiction - a compulsive use of drug
despite adverse consequence