Opioid Analgesics:Pathways to Addiction.

Chris Evans, PhDNIDA Center for the Study of Opioid

Receptors and Drugs of Abuse (CSORDA),UCLA, California

One side of the story- Pain of all types is undertreated in our society. The pediatric and geriatric populationsare especially at risk for undertreatment. Physicians’ fears of using opioid therapy, and the fears of other healthprofessionals, contribute to this problem.

- Opioid analgesics are generally safe medications when prescribed withappropriate monitoring. There is very little if any evidence of organ damage from the long termtherapeutic use of opioids. With appropriate titration and stable dosing, tolerance develops to most of the side effectsof opioid therapy, including cognitive impairment. Constipation is the most common persistent side effect and should bemanaged prophylactically.

Use of opioid analgesics for the treatment of chronic noncancer pain - A consensusstatement and guidelines from the Canadian Pain Society 1998

John Liebeskind 1935-1997

1) New Nonmedical Prescription Pain Reliever users Outnumbered New Marijuana Users (2002-2004)

2) 2.7% of the population 12 and older in 03 used prescription psychotherapeutic medications

nonmedically in the month prior to surveyed. This included 4.7 million using pain relievers (compares to

166,000 Heroin users).

3) Estimated 415,000 Americans received treatment for pain reliever abuse in the past year.

4) Past year abuse of Vicodin 3.0% among 8th-graders, 7.0 % among 10th-graders, and 9.7% among

12th-graders in 2006, (stable since ‘02). Despite a drop in past year abuse of OxyContin among

12th-graders in ‘06, abuse among 8th-graders nearly doubled since 2002 (1.3% in ‘02 - 2.6 % in ‘06)Data from the 2002, 2003 and 2004 National Surveys on Drug Use and Health

Past Year Nonmedical Use of PainRelievers (% use 12 or Older, 02-04)

Nonmedical New Usersof Psychotheraputics

% US Population5.68-7.003.78-5.672.61-3.75

The Other Side

3 million

2 million

1million

0

MORPHINE, FENTANYL, ETORPHINE, HYDROCODONE, OXYCODONE,CODEINE, BUPRENORPHINE, HEROIN, METHADONE

(RARELY RECEPTOR SPECIFIC - Drugs are dirty)

ACTH, MSH

POMC PROENKEPHALIN PRODYNORPHIN

Prohormone Convertases (PC’s)CPE and PAM

ENDOMORPHINS?MORPHINE?

PROORPHANIN-FQ

δ κ µ ORL-1

NCCH2CH3CH2CH2N

Fentanyl (epidural, Moscow Siege Gas)

O

N-CH3

OH

OH

O

Morphine (surgery)

HO-C-CH3

N-CH2

C (CH3)3

OH

O

CH3O

Buprenorphine (addicts) Methadone (addicts)

CH3

CH3-N-CH3CH3O

Oxy/hydrocodone (pain)

Opioid Receptor selectivityAgonist/Partial AgonistsActivity at other receptors (NMDA)Rate of onset/duration*Route of AdministrationDependency/toleranceActivity at mu opioid receptors

OXY (X=OH)HYDRO (X=H)CODONE

NCH3

O

CH3O

XO

PERCOSETPERCODAN OXYCODONE OXYCONTINVICODIN HYDROCODONE

MuAgonists: analgesia, constipation, reward, nausea,respiratory depression - gender specificAntagonists: aversive*, prevent reward

DeltaAgonists: not-rewarding, weak analgesia,seizure-inducingAntagonists: no obvious effects

KappaAgonists: aversive, hallucinogenic, analgesiaAntagonists: potential antidepressants/relapseORL-1Agonists: Hyperalgesia* and block opioid analgesiaAntagonists: no obvious effects

Homologousrecombination

Mu KO mice have no classical morphine effects (analgesia, respiratorydepression, reward, immune modulation). No longer are alcohol, nicotine orTHC rewarding! Reviews by Kieffer’s group Curr Opin Neurobiology, 2004

BUPRENORPHINE (κ antagonist, µ/δ /ORL-1 partial agonist)HAS NO ANALGESIC EFFICACY IN MU RECEPTOR KO MICE

0

3

6

9

12

15

Baseline 0.1 mg/kg0.3 mg/kg 1 mg/kg 3 mg/kg

Buprenorphine (s.c.)

Tail

flick

late

ncy

(sec

)

WTMuKO

0

3

6

9

12

Cut off

Baseline 0.1 0.3 1 3Bup. (mg/kg s.c.)

WTORL-1KO

Bup. (0.3mg/kg s.c.)Baseline Cont.

0

3

6

9

12

WTORL-1KO

+J-113397

BUPRENORPHINE HAS INCREASED ANALGESIC EFFICACYIN ORL-1 RECEPTOR KO MICE

ORL-1 Receptor KO Mice Courtesy of Hiroshi Takeshima, J-113397 Ivy Carroll

Tail

flick

late

ncy

(sec

)

ACUTE OPIOID EFFECTSAnalgesia, AntitussiveConstipation, Euphoria,

Nausea*, Calming*Decreased Respiration

WITHDRAWAL

oxycontin, vicodin

heroin, morphine

Hyperalgesia, Dysphoria, Anxiety,Sweating, Runny nose, Chills,

Diarrhea, Nausea

CHRONIC OPIOID EFFECTSTolerance to acute effects,normalization of physiology &psychology in presence of drug

molecular

, cellula

r

and be

haviora

l

adapta

tions

relapse?

?

drug/actionassociations

LikingTaking the drug feels good

- is rewarding and/orsatisfies the reasons for

taking the drug.

WantingThe drug is desired for its

remembered effects (analgesia,rewarding, calming, combating

withdrawal, physiologic effect).In extreme cases this can

become craving

HabitTaking the drug as a result of

automatic response to a stimulus -after eating - smoke

Stressed or anxious - drink ortake a vicodin

REWARD(CPP)

Activation of Mesolimbic Dopamine system

CB-1 and NK-1receptor activation by

endogenous ligands

THCNicotineAlcohol

Mu receptoractivation by

endogenous opioids

Morphine/HeroinCB-1AChGABA/NMDA Mu Opioid

Receptors

Kappareceptoractivation

AVERSION

AntagonismNaloxone

SYSTEM INTERDEPENDANCE FOR REWARD

Methadone Maintained Patients are Hyperalgesicin Cold Pressor Test.

0

10

20

30

40

50

60

70

Control

MM

*

***

***

Detection Tolerance Detection Tolerance

0 HOURS 3 HOURS

•••

•••

COLD PRESSOR TEST

••• p<0.0001

***p<0.0001

*p=0.023

T

i

m

e

(

s

e

c

o

n

d

s

)

Tim

e in

ice-

cold

wat

er (s

econ

ds)

Slide kindly provided by Walter Ling, UCLA

3hr after Methadone

PainDetection

PainTolerance

PainDetection

PainTolerance

Control

MethadoneMaintained

0

1

2

3

4

5

salinecontrol

chronic morphine

base

line

tail

with

draw

alLa

tenc

y (s

)

hot p

late

late

ncy

(s)

0

5

10

15

20

25

30

salinecontrol

chronic morphine

150’ post-morphine

A B

Hyperalgesia Following Chronic Morphine (TAD)- Pain Paradigm Specific

48ºC

**

*

[cAM

P ] % C

HANGE

FORSKOLIN-STIMULATED cAMP ACCUMULATION FOLLOWING ACUTEAND CHRONIC OPIOID TREATMENT - CYCLASE SUPERSENSITIVITY

RTI-1d

0

100

[DAMGO]

Control

Acute:opiod +forskolin

400

200

300

Chronic: 24hopioid thenwash out+forskolin

0.1nM 1nM 10nM 100nM

100+proteins100+proteins

MU OPIOID RECEPTOR COMPLEX (diversity)

SIGNALING8+proteins

100+proteins

COMPLEX DETERMINATION

1. Cellular Proteome2. Mu receptor alternative splicing3. Cellular Compartment4. Oligomerization (Hetro/Homo)5. The Receptor Activation State6. History of Receptor/Environment

Arrestins/G-proteins/GRK’s/Src’s/RGS’s

TRAFFICKING2+proteins

REGULATION5+proteins

FLAG & MOR-C12 STAINING OF 293-CELLSTRANSFECTED WITH MU RECEPTORS

CONTROL ETORPHINE DAMGO ETOR/NALOX MORPHINE

(100nM) (100nM) (100nM/10µM) (20µM)

Agonist Binding

P P

Beta-arrestin 1-2 (cSrc)

DesensitizedReceptor

Severing of CCV byDynamin

Recruitment ofClathrin

EndosomeP

Recycling (µ)

Uncoating ofCCV and Fusionwith Endosome

Dephosphorylation

LysosomesDownregulation (δ)

P P

GRK 2 (1-6)Phosphorylation

P

P

P

Re-sensitizedReceptor

Signaling Signaling Signaling

4 hr

0 min

µ α2A Merged

DAMGO

4 hr+PD16

Tracy Xie CSORDA Lab 2006, submitted

µ α2A Merged

Mouse Dorsal Root Ganglion CellsExpress mu and alpha2A receptors

Opioid Pretreatment Time

Calcium C

urre

nt I

nhib

ition(

%)

DAMGOMorphine

0

10

20

30

40

50

60

*

#

**

9711 211914

4 hr + PD164 hr0 hr

0 min

30 min

4 hr

µ α2A Merged

Morphine

Morphine(No internalization)

DAMGO(Internalization)

-Blocking internalization with the P38 inhibitorPD169316 blocks calcium signalingdesensitization via DAMGO but not morphine- The alpha 2A receptor internalizes withDAMGO treatment - blocked by PD169316

4 hr

0 min

µ α2A Merged

DAMGO

0 min

µ α2A Merged

4 hr

Clonidine

Clonidine and DAMGO but not morphine induce both mu andalpha2A internalization and desensitization.

0

10

20

30

40

#

*

76120 hr 4 hr 4 hr+CT

Clonidine Challenge

0 hr 4 hr

Morphine Pretreated

1112

DAMGO Pretreated

Calcium C

urre

nt I

nhib

ition(

%)

0

10

20

30

40

50

60#

**

81862

4 hr0 hr 4 hr +Yoh4 hr +Yoh4 hr0 hr

Morphine testDAMGO test

#

*

7910

DAMGO Challenge

MorphineChallenge

Clonidine Pretreated

Calcium C

urre

nt I

nhib

ition(

%)

4 hr Clonidine Treatment + P38 inhibitor PD169316

µ α2A Merged

P38 inhibition blocks mu internalization but not Clonidine-inducedalpha2A internalization and desensitization.

0

20

40

60#

**

CloPD16

CloNonePretreat

101862

DAMGO Challenge

Calcium C

urre

nt I

nhib

ition(

%)

0

5

10

15

20

25

##

**

DPD16

17

PretreatDNone

812

Clonidine Challenge

Calcium C

urre

nt I

nhib

ition(

%)

0

10

20

****

Clonidine Pretreatment

Clonidine test

0 hr 4hr 4 hr+PD16

141421

Summary

-Functional implications of mu and Alpha2Aadrenergic association in endogenouslyexpressing nociceptive neurons-Mu agonist specific cross-desensitizationof Alpha2A adrenergic signaling

Calcium C

urre

nt I

nhib

ition(

%)

?Sugar Sugar

Sugar

noyes noyesSugar Sugar

Sugar

Mu opiate receptor knockout mice.- Lack reward-directed behaviors to many rewarding drugs- Phenotype of sibling response to mother absence

Sugar

15 20 25 30 35 40 45 500

2

4

6

8

10

12

14

1 2 3 4 5 6 7 8 9 10

1st 10 rewards Blocks of 5 rewards

MU -/-WT

Leve

r pre

ss p

er m

in

Acquisition

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0NonDEV

MOR WT

Leve

r pre

sses

per

min

0

1

2

3

4

5

6

7

1 2 3 4 5

4-min bins

devnon

devnon

MOR

WT

DevaluationExtinction Punishment

Maidment and Balleine Labs CSORDA 2006

Role of Opioid System in Habit and Goal-Directed Behaviors

grain

graingrain

grain

grain

grain

grain

Enkephalin knockout mice.

sugar grainsugar

? SugarSugar

Sugar piles upin food tray inEnk-KO trials

grain grain sugar

1h 10’ 10’

No food

Sugar SugarSugar

noyes noyesSugar Sugar

grain

graingrain

grain

grain

grain

grain

Summary

100

Dev

alua

tion

% to

tal r

espo

ndin

g

Retrieved value: Extinction

0

20

40

60

80

10

30

50

70

90DevaluedValued

D V

WT

D V

pENK

D V

Mu

0

20

40

60

80

10

30

50

70

90

DevaluedValued

D V

WT

D V

pENK

D V

Mu

Punishment

Mu -/- appear to have a problem with retrieving reward value:They are sensitive to changes in value but are unable to retrieve changes in a test of free recallbut can when the outcome is delivered.

pENK -/- are unable to control their actions when faced with lack of salience. They appear tohave a specific problem with goal-directed actions. Performance is likely controlled by a stimulus-response process and is habitual.

100

�

WITHDRAWALSymptom alleviation NK-1antagonist hyperalgesia

REWARD/ANALGESIAKappa antagonists?(JD-Tic)

� PLASTICITYENVIRONMENTDRUG ACCESS�

�

Adaptive Changes. Tolerance.Salience for rewards likelydisruptedPartial Agonists?Mu-agonists that show selectivesignaling and trafficking

�

1) +NK-1/CB-1 antagonist2) Slow on and off rate +/-3) Partial agonist - safety

RELAPSE

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