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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.

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slide1

NeuroPharmacology (NB404):

Dr. Charles Chavkin

Professor of Pharmacology

D425 HSB

slide2

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

slide3

Natural opium alkaloids

  • Morphine -gold standard
  • Codeine
  • Thebaine - (non-analgesic)
slide4

Opiate chemical structures

CH2=CH Naloxone

CH3C=0

Heroin CH3C=0

slide5

Endogenous Opioid Agonists:

enkephalin - 2 pentapeptides

b-endorphin - POMC, ACTH

dynorphin - endog kappa agonist

NH2-Tyr-Gly-Gly-Phe-Leu-COOH

opioids

Opioids

NSAIDS

slide8

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)

slide9

Actions of Opiates:

analgesia

anxiolytic

sedation

euphoria

gut hypomotility (constipation)

cough suppression

respiratory depression

pupillary constriction

nausea and vomiting

endocrine suppression

itching (specifically morphine)

slide10

Endogenous opioid peptides (enkephalins and b-endorphin) have Morphine-like effects

Analgesia

Euphoria

Antidepressant

Reduction in anxiety

Endogenous dynorphin opioid peptides

Analgesia

Dysphoria

Depressant ?

Increase in anxiety ?

Endogenous opioids form important stress regulating systems in brain

Stress-induced analgesia

Stress-induced dysphoria

Stress-induced priming of relapse?

slide12

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

slide14

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 protein-

coupled receptor superfamily (>1,000 members)

Activation of opioid receptors inhibits neuronal activity

increases potassium conductance

decreases calcium conductance

inhibits neurotransmitter release

slide15

how do opiates act at a molecular level?

GDP

GTP

GDP

GDP

GTP

PO4

K+

Activated arrestin

response

G-Receptor Kinase

tolerance

opioid dose

slide16

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)

slide17

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 G-

protein association

• GPCR- b-arr complex is

internalized by a dynamin

and clathrin dependent

mechanism

G Protein receptor kinase

-arrestin

slide18

Acutely, morphine inhibits LC firing - sedation

Neuron hyperpolarized and NE release inhibited

R

OR

K+

Opiates inhibit

Noradrenergic neuron in the locus ceruleus

slide19

Chronically, this causes a compensatory increase in LC activation

decreased auto-inhibition, increased excitatory drive

R

R

Tolerance

Receptor desensitization

OR

R

Normal Excitability restored

Excitatory drive

Noradrenergic neuron in the locus ceruleus

slide20

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
slide21

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

OR

R

Hyper-Excitability state

Excitatory drive

Noradrenergic neuron in the locus ceruleus

slide22

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)

slide23

“Molecular Basis of Addiction”

• Voluntary intake

tolerance

readily reversible

physical dependence

sensitization

• Involuntary - compulsive intake

cravings, obsession, self-destructive behavior

Addiction

- high relapse risk

slide24

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

Untreated mice, no stress

nor-BNI treated FST mice

Day: 1

2

3

4

5

6

Free Run, 30 min

Forced swim stress exposure

Cocaine, box 2, 30 min

Vehicle, box 1, 30 min

*

1200

Vehicle-treated FST mice

1000

800

600

*

*

Difference in time spent on

drug-paired side (sec)

400

200

0

-200

Baseline

Day 5 results

Conditioned place preference measures the rewarding properties of drugs

• assess drug craving

slide26

Stress-induced priming of relapse?

Drug consumption

escalation

crash

relapse

time

stress

Heroin

Cocaine

Ethanol

Nicotine

slide27

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.

slide28

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