OPIO

IDS

ALK

ALO

IDS IN

OPIU

M

10%0,5%

0,2 %

1 %6 %

% percentage in the opium

juice

Heroin 2 -C

OC

H3

PHARMACO

LOG

ICAL ACTIONS O

F MO

RPHINE

Central Nervous System Analgesia Euphoria Sedation (D

ysphoria and hallucinations) Pupillary constriction N

ausea and vomiting

Respiratory depression D

epression of cough reflex Tolerance and dependence

Gastrointestinal tract

Reduced motility and increased

tone with:

Constipation

Contraction of biliary sphincter

Other actions

Histam

ine release with:

Urticaria and itching

Bronco constriction H

ypotension and bradycardia

Imm

unosuppressant effects

In the 1950s: proposal of the presence of specific receptors for opioids

In the 1970s: P

roposal of the presence of three different receptors: •

mu receptors (from

Morphine) M

OR

•

kappa receptors (from K

etocyclazocine) KO

R

•delta receptors (from

Deferent vessels) D

OR

Isolation and characterization of endogenous ligands (endorphins): •

Beta-endorphins

•D

ynorphins •

Enkephalins

In the 1990s: •

Cloning of M

OR

, DO

R and K

OR

GP

CR

s •

Identification of Orphanin FQ

/ nociceptin receptor (no affinity tow

ards naloxone)

OPO

IDS R

ECEPTO

RS A

ND

THEIR

LIGA

ND

S

OPPIO

IDI EN

DO

GEN

I

END

OG

ENO

US O

PIOID

PEPTIDES

END

OG

ENO

US O

PIOID

PEPTIDES: SYN

THESIS

Beta-endorphin

Met/Leu-enkephalin

Leu-enkephalin

Dynorphin

Orphanin FQ

/ nociceptin

META

BO

LISM O

F END

OG

ENO

US PEPTID

ES

neprilysin (N

EP) am

ino peptidase N

(A

PN)

MO

PDO

PKO

PNO

PEN

DO

GEN

OU

S OPIO

IDS

Beta-endorphin

Leu-enkephalin M

et-enkephalin D

ynorphin O

rphanin FQ/nociceptin

+++ (++) ++ + -

+++ +++ +++ + -

+ + + +++ -

- - - - +++ R

ECEPTO

R SELEC

TIVE DR

UG

SA

gonistsD

AM

GO

D

PD

PE

E

nadoline R

o64-6198

+++ - - - -

- ++ - - -

- - +++ - -

- - - +++ -

Antagonists

CTO

P N

altrindole N

or-binaltorphimine

SB

612111

+++ - + - -

- +++ + - -

- + +++ - -

- - - +++ -

Dietis N

et al. Br. J. A

naesth. 2011;107:8-18

AGO

NISTSPARTIAL AG

ONISTS

ANTAGO

NISTS

Morphine (T1/2 = 2 h)

Meperidine

Levorphanol Fentanyl M

ethadone (T1/2 = 14-40 h)

BuprenorphinN

albuphine N

alorphine

NaloxoneN

altrexone

MO

P RECEPTORS

MEC

HA

NISM

OF A

CTIO

N

•All four types of opioid receptors are G

i/o-protein coupled receptors

1. Adenynyl cyclase inhibition

2. N and P

/Q voltage-dependent calcium

channel inhibition

3. Activation of G

IRK

(G protein-inhibited rectifying K

+ channels)

4. Activation of M

AP kinase pathw

ay

Pharmacological classification of the opioid receptor fam

ily.

Dietis N

et al. Br. J. A

naesth. 2011;107:8-18

© The A

uthor [2011]. Published by O

xford University P

ress on behalf of the British Journal of

Anaesthesia. A

ll rights reserved. For Perm

issions, please email:

journals.permissions@

oup.com

CLA

SSIFICATIO

N O

F THE O

PIOID

REC

EPTOR

FAM

ILY

THE OPIO

ID SYSTEM PARADO

X?

A large number of endogenous ligands (at least 11) converge on only a

small num

ber of opioid receptors (4 genes) E

ndogenous ligands display poor selectivity towards opioid receptors

(with the exception of D

ynorphin A for KO

R)

Several pharm

acological evidence suggest the existence of multiple

receptor subtypes M

OP antagonists (e.g. N

aloxonazine) block morphine-induced

analgesia but not alter respiratory depression, constipation or itching O

n the other hand, knockout of MO

P receptor inhibits all the MO

P receptor associated activities

© The A

uthor [2011]. Published by O

xford University P

ress on behalf of the British Journal of

Anaesthesia. A

ll rights reserved. For Perm

issions, please email:

journals.permissions@

oup.com

PHA

RM

AC

OLO

GIC

AL C

LASSIFIC

ATION

OF

THE O

PIOID

REC

EPTOR

FAM

ILY

DO

OPIO

ID

REC

EPTOR

SU

BTYPES EXIST?

Three alternative possible mechanism

s:

•A

lternate splicing of a comm

on gene product

•Functional selectivity (biased agonism

)

•O

mo - and/or hetero-dim

erization

1. ALTER

NATIVE SPLIC

ING

Exon 1 is necessary

for the analgesic activity of m

orphine P

RO

TEIN

ISO

FOR

MS

Exon 2 is necessary

for the analgesic activity of fentanyl

Different ligands influences w

hich G protein associates w

ith the receptor thus prom

oting distinct coupling efficiencies (distinct intracellular pathw

ays)

2. FUN

CTIO

NA

L SELECTIVITY

(ligand-selective efficacy)

Adaptor protein-2 (AP-2)

Role of G

-protein coupled receptor kinase (GR

K) and arrestins

DE

SE

NS

ITIZATION

of GP

CR

s: m

olecular mechanism

s

Receptor desensitization is a reduced response of a receptor

that follows a prolonged exposure to an agonist and it is due to

uncoupling of a receptor from G

proteins

Desensitization also results from

receptor internalization, the rem

oval of receptors from a plasm

a mem

brane by endocytosis (dow

nregulation)

Internalization can be followed by receptor recycling

(resensitization) or lysosomal degradation

Desensitizantion can cause (pharm

ocodinamic) tolerance, the

need to increase the drug dose to obtain the required effect

Turning off the signal: desensitization of G

PC

Rs function

FUN

CTIO

NA

L SELECTIVITY

Selective ligands of opioid receptors can direct the receptor

to favore one or more signaling events

PKC

DAMG

OM

orphine

GRK

Morphine does not prom

ote MO

P receptor internalization and causes tolerance at high degree

In contrast, DA

MG

O causes

robust internalization and low

tolerance degree

Dim

erization affects signal transm

ission and desensitization

and can explain the differences in efficacy and in abuse potential of different ligands

3. GPC

R D

IMER

IZATION

Potential G

PC

R dim

er interfaces C

ontact dimers D

omain dim

er interfaces

No response:

Agonists stim

ulation causes the dim

er dissociation

Strong response: R

educed internalization

MO

RDO

R

Different signal properties: in

DO

R absence, M

OR

dependent tolerance and dependence are reduced

OM

O- and H

ETERO

-DIM

ERIZATIO

N betw

een Opioid receptor subtypes

MO

RNK1

MO

RCB1

Alfa2M

OR

OM

O- and H

ETERO

-DIM

ERIZATIO

N betw

een GPC

R

Enhances the potency of m

orphinePotentiated phosphorylation

of MA

PK induced by

morphine

SubP causes internalization

MO

PDO

PKO

PNO

P

Analgesia

supraspinal spinal peripheral R

espiratory depression P

upil constriction R

educed gastrointestinal motility

Euphoria

Dysphoria and allucinations

Sedation

Tolerance and dependence

+++ ++ ++ +++ ++ ++ +++ - ++ +++

- ++ - ++ - ++ - - - -

- + ++ - + + - +++ ++ -

antag++ - - - - - - - -

FUN

CTIO

NA

L EFFECTS A

SSOC

IATED W

ITH

THE M

AIN

TYPES OF O

PIOID

REC

EPTOR

PAIN

PATHW

AYS

Afferent nerves

stimulated by noxiuos

stimula (1)

activate spinal neurones (2)

that take the inform

ations to the sovraspinal centers (3)

The SN

C m

odulates the overall response through efferent control system

s (4)

• Pain: a sensorial and

emotional experience

due to a real or potential tissue dam

age, associated w

ith somatic and

emotional com

ponents1.

Acute: useful, triggers appropriate

protective responses 2.

Chronic: unuseful, w

ith adaptive and em

otional mechanism

s that can increase pain perception

1st OR

DER

NEU

RO

NS

C fibers - slow

conductance speed: sm

all amyelinated

sensitive to thermal changes, chem

icals, pressure diffuse and strong pain

Aδ fibers - fast

conductance speed: sm

all myelinated

sensitive to mechanical

noxiuos stimuli

localized pain

Prim

ary sensory nerves N

ociceptors

1st OR

DER

NEU

RO

NS

Nociceptors are

activated also by m

ediators released after tissue injury

PAIN

PATHW

AYS

: 1st and 2nd order neurons

3th OR

DER

NEU

RO

N

2nd OR

DER

NEU

RO

N

1st OR

DER

NEU

RO

N

THE

TOP

-DO

WN

PATHW

AY: the efferent control system

s

anterior cingulate cortex (AC

C)

hypothalamus (H

) thalam

us (T) periaqueductal grey (PA

G)

rostral ventromedial m

edulla (RV

M)

inhibitory (OFF cells, green)

serotonergic (yellow)

No pain....

facilitatory (ON

cells, red) Yes, pain!

W

ithin the RVM

MO

R agonists produce anti-nociceptive effects by inhibiting on cells and disinhibiting off cells O

RL1 (NO

P) and KOR agonists can block analgesia by inhibiting

off cells or block hyperalgesia by inhibiting on cells

Yes, pain!N

o pain....

thalamus

DescendingInhibitoryPathw

ays

SG

GS substantia gelatinosa

Spinothalamic

pathway

Nociceptive afferents

(C, A delta fibers)

Mechanoreceptors (A beta fibers)

GATE

CO

NTR

OL

SYSTEM

dorsal horn

Pain pathw

ays: an overview

THE MESO

LIMBIC DO

PAMINE PATHW

AY:THE REW

ARD CIRCUIT AND THE BASIS FOR DRUG

ABUSE

VTA ventral tegm

ental area

Nacc nucleus accum

bens

PFC

prefrontal cortex

VTA

PFC

Nacc

The dopaminergic neurons activity in the V

TA is negatively controlled by the basal activity of G

AB

Aergic neurones

Drugs that cause disinhibition of dopam

inergic neurons are potentially drug of abuse (e.g.: benzodiazepines)

THE MESO

LIMBIC DO

PAMINE PATHW

AY:THE REW

ARD CIRCUIT AND THE BASIS FOR DRUG

ABUSE

Disinhibition m

echanism of dopam

inergic neurons in the V

TA by benzodiazepines

1

2

DA

DA

Disinhibition of dopam

inergic neurons (left) in the VTA by

opioid (1) and cannabinoid (2) receptors expressed on G

AB

Aergic neurons (right)

CB

1R