Effects of morphine and met-enkephalin analogue on gastric lesions induced by indomethacin

Pharmacological

Research Communications,

223

Vol. 19, No. 3. 1987

ANALOGUE

EFFECTS OF MORPHINE AND MET-ENKEPHALIN LESIONS

ON

GASTRIC

INDUCED BY INDOMETHACIN R. Arrigo-Reina

C. Spadaro, Institute Catania,

of Vl.

and G.M.

Pharmacology A. Doria 6,

Scoto

and Pharmacognosy , University 95125 Catania (Italy)

of

Received in final form 20 February 1987

SUMMARY The effects analogue

morphine

CD-Ala2,MePhe4

gastric of

of

damage

(lmg/kg

both

of

by indomethacin. (2mg/kg

i.p.).

duction

of

metidine i.p.)

the This

(25mg/kg not

and

secretion i.p.)

been

investigated. HCl

of

was reversed effect since

prevent

lesions

induced

related

HCl

to

damage

a

re-

drug

bromide

mucosal

)

significant

antisecretory

and methscopolamine

i.p.

by naloxone

was not the

Rats

(lOmg/kg

a statistically intensity

protection

significantly

experimental

same

number

on

administration

morphine

showed

The protective gastric

did

) have with

i.p.)

(FK 33-824)

intraperitoneal

i.p.

pretreated

and FK 33-824 reduction

by the

( lOmg/kg

intraperitoneally

met-enkephalin

,Met(0)501-lenkephalin

produced

indomethacin

HCl and a synthetic

ci-

( lOmg/kg under

the

conditions.

INTRODUCTION Several operate ganism tence gether

reports

suggest

homeostatically undergoing of

with

their

in

stressful1

endogenous

opioids receptors

0031-6989/87/030223-08/$03.00/O

that the

endogenous adaptive

stimuli. in

the

(Linnoila

opioid responses

In

addition

gastrointestinal et

a1.,1978;

peptides

may

the

of the

or-

exis-

tract,toOrwall

and

0 1987 The Italian Pharmacological

Society

224

Pharmacological

Kenda11,1980; could

Snyder

play

scribed

a part

the

to

gut

in

a multiple

mucosa In

of

(Ferri the

protect

against

stress

procedure

study

opioids,

that

that

they

a previous

study

wede-

synthetic

caused

et

in

the

a1.,1984;

prostaglandin

met-

rat

(Arrigo-Reina

by

an

and Ferri,

Candeletti

bothmorphineandFK

we extended

at

gastric

gastric

a nonsteroidal

(Ferri

Vol. 7 9, No. 3, 1987

suggested

morphine,and/or

damage

showed

Communications,

et

33-824induced

content

in

gastric

a1.,1983).

present

of

In

gastric

endogenous et

effects

of

agents

We also

an increase

physiology.

effect

and necrotizing 1984).

al.,

in

analogue

exposure 1980)

and Simantov,l977)

protective

enkephalin

Research

our

to

level,

mucosal

investigations

lesions

antiinflammatory

find

out

induced

the

on whether

they

by indomethacin,

compound.

MATERIAL AND METHODS Animals tween

and drugs.

200 and

trolled

220 g,were

environment

The animals

were

and water

for

24 h prior

to

(10 animals Chemical pH 8.4 chloride

with

Sprague

housed

an

artificial

weighing

scheduleof

experiments.

drugs

were

1N NaOH, at

on an ad libitum

to

in

the

5% sodium

administered

con-

Rats

were

18.00h). food

fasted

for

giventodifferentgroupsofrats

following:

a dosage

be-

light

maintained

dissolved

(C.Erba)

in

rats,

andoffat

treatment.The each)

Dawley

(switchedoneachdayat0.600

1 week prior

in

Co)

Male

of

Indomethacin

bicarbonate lOmg/kg

30 min before

( Sigma

and adjusted i.p.;

at

Morphinehydro-

indomethacin

,

at

Pharmacological

lOmg/kg

i-p.;

a stable min

Research Communications,

/_'D-Ala2,MePhe4,Met(0)501-~enkephalin

analogue

before

Zmg/kg

of

of

, given

PGE2 (kindly

indomethacin,at

lmg/kg

made up in

0.9% w/v

and injected

(Sigma

Chemical

Co),a

60 min

before

bromide

drugs

were

Gastric methacin

within

treatment

ministration

of Fig.

the

dicated

in

itoneal

administration

treatment

groups

removed

immediately,

for ly

microscopic described

in

where

It

examination by Arrigo-Reina

);

and

g b-w. known

30 or

that

indo-

ulcerations following

60 min

drugs

rats

the of

their

greater

curvature of

lesions

(1980).

before

and doses

after

rapidly,

and Ferri

All

(Robert,l976;Whittle,

hours

scoring

admin-

i.p..

animals

indomethacin,lO

the

was

anticholinep

These

agent,with

along

before

i.p.;Methscopol-

well

i.p.)

Three

at

Cimetidine

antagonist,

rats.

began

Lab),

-5OC

lOmg/kg

is

(lOmg/kg

30

followingevaporation

starved

decapitated cut

methanol

25mg/kg

in

the

2.

30 min

solution:0.lm1/100

ulcerogenic

of

in

Co)

injected

opioids,

Ingelheim),an

treatment

1 and Fig.

the

indomethacin,at

indomethacin

Pharmacological

before

H2 receptor

ulcers

6 hr

(HC1,Endo

immediately

by indomethacin.

2 to

with

i.p.

a saline

gastric

Naloxone

solution

,Boehringer

in

produces

develop

1977).

dissolved damage

NaCl

before

Co)

by Upjohn

indomethacin,at

30 min

(FK 33-824)

Chemical

stored

histamine

(Buscopane

gic~drug,given

20 min

i.p.(PGE2

methanol

amine

i.p.;

supplied

the

istered

(Sigma

lmg/kg

antagonist

i.p.;

freshly

enkephalin

indomethacin,at

a narcotic

225

Vol. 19. No. 3, 1987

adin-

intraperdifferent stomach

was

andopened as previous-

Pharmacological

226

Statistical

Research Communications,

The occurrence

analysis.

was expressed

by means

of

analyzed

with

a non-parametric

Whitney

U-test

(Siege1,1956).

of

histograms

(fig.

a specific 1,2

statistical

Vol. 19. No. 3, 1987

lesion were

) . Data

procedure,the

Mann-

RESULTS The intraperitoneal severe

gastric

peared

in

elongate while

damage

the

corpus

or

punctate

lesions

were

Haemorrhagic phine

administration

of

served

for

with

in

almost

the

naloxone.

The PGE2 intraperitoneally

formation

in

as shown

The antisecretory amine

bromide

lesions

did

induced

This

not

in

the

As seen

in

Fig.l,mor-

antrum.

gastricdamage

duplicated

of

syn-

the effectsob-

protection

was preventedby blockedulcer

(1976).

as cimetidine

significantly

edges,

and

administered

agents,such

and

administration

by Robert

ap-

demarcated

prevented

33-824

2).

The lesions

forestomach present.

caused

as petechiae

sharply

The peripheral

(fig.

animals

animals.

completely

analogue,FK

morphine

indomethacin

stomach,mainly

was often

by indomethacin. enkephalin

control

the

absent

material

thetic

all

erosions

hydrochloride

induced

in

of

prevent

and methscopolthe

developmentof

by indomethacin.

DISCUSSION These thetic

results analogue,FK

age caused

indicate

that

33-824,are

by indomethacin

morphine capable

as well

and met-enkephalin of

impeding

as those

obtained

mucosal

syndam-

indiffer-

Pharmacological

ent et

Research Communications,

experimental

conditions

1984;Candeletti

al.,

the

mechanisms

the

cellular

provided

of

non has

already

seminal

vescicles

al.,

1979).

sis

and release

In

order

the

of

opioids

in

been

an

described

al.,

(1979,1981)

mechanism,since

gastrointestinal

tract

cologically,i.e

.,after

exogenous

important duced But

in

the

role

by morphine the

lated

to

the

previous between

inhibition

of

cytoprotective administration,but can

This

be

suggests

that

the

gastric

a1.,1983). et

acid In

a1.(1984)

effect output,since

pharma-

the

allow

and an indirect antisecretory

by

effects

intract.

seem to

secretion,in fact

phys-

PG may playan

do not

of

is

stimulated

opioids

acid

PGcontent

also

gastrointestinal

antiulcer

gas-

only

the

et

synthe-

the

in

by Ferri

of

depletion

and FK 33-824

of

(Scotoet

local

protective

(Ferri

a direct

that

the

inhibition

suchas

and placenta

of

effects

findings

tissues

mechanism

protective

and FK 33-824

the

a1.,1983).

other

phenome-

an important,natural

biosynthesis

et

This

not

are

(Ferri

intraperitoneal

indomethacin,

Therefore,PG

their

endogenous

by inhibitors,like

ulcerogenic.

iologically,since

evidence,

of

a1.,1983).

demonstrated is

maintaining

the

after

1974)

prostaglandin

cytoprotective

opioids

et

understand

in

increase

regarding

et

to

also

mucosa

(Ferri

(Collier

of

relevant

gastric

morphine

Robert

action

study,for

content

and Ferri,lgEO:Ferri

a1.,1984).

seems

a previous

administration

of

et

underlying

prostaglandin

tric

(Arrigo-Reina

integrity,it in

227

Vol. 19, No. 3, 7987

be re-

morphine

presentdataand a

dissociation effect agents,

due to such

228

Pharmacological

Research Communications,

Vol. 19, No. 3. 1987

ci

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Pharmacological

Research Communications,

229

Vol. 19, No. 3. 1987

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uorsa1

aqi

JO a3uaxxn330

0

Pharmacological

230

as cimetidine vent

the

and methscopolamine

development

In

conclusion,

in

different

1980; idea

sponses that

these

et

1984;

Candeletti

of

noxious

gut

to

H2-receptors

are

caused

et

not

by

involved

pre-

indomethacin

other

dataobtained and

Ferrj

al.,1984

) support

the

role

adaptative

re-

conditions, mechanisms

Vol. 19, No. 3. 1987

markedly

( Arrigo-Reina

peptide

(muscarinic)

do not

with

conditions

opioid

the

damage together

an endogenous

cholinergic

histamine

results,

al.,

bromide,

gastric

experimental

Ferri of

of

Research Communications,

in and

also

and those in

this

suggest

related

to

process.

REFERENCES (1980) Eur.J.Pharmacol. fi,85-88. Arrigo-Reina,R. and Ferri,S. Candeletti,S.,Cavicchini,E.,Ferri,S.,Romualdi,P.,Spadaro,C.and Speroni,E. (1984) Farmaci e Terapia 1,3-5. Collier,H.O.J.,McDonald-Gibson,W.J. and Saad,S.A. (1974)Nature =,56-58. .,Arrigo-Reina,R.,Candeletti,S.,Costa,G.,Murari,G.,SpeFerri,S and Scoto G.M. (1983) Pharm.Res.Commun.g,409-418. roni,E. Ferri,S., Candeletti,S.,Cavicchini,E.,Romualdi,P.,Spadaro,C.,Speand Spampinato,S. (1984) In: Central and Peripheral roni,E. Endorphins:Basic and Clinical Aspects.Miiller E.E.and Genazzani A.R.eds. New York,Raven Press,pp.217-227. .,Miller,R.J.,Chang,K.J. and CuaLinnoila,R.I .,DiAugustine,R.P trecasas,P. (1978) Neuroscience 3,1187-1196. and Kendal1,J.W. (1980) Endocrinology x,438-442. Orwal1,E.S. Robert,A. (1976) In: Advances in Prostaglandin and Tromboxane Research,vol.2,Samuelsson B. and Paoletti R. eds. New York, Raven Press,pp.507-520. Robert,A. (1979) Gastroenterology z,761-767. (1981) Scand.J.Gastroent.supp1.67,16,223-227. Robert,A. Arrigo-Reina,R.and Ferri,S. Scoto,G.M.,Spadaro,C.,Spampinato,S., (1979) Arch.Toxicol. supp1.2,375-380. Siegel,S. (1965) Non-parametric statistics for the behavioural Sciences,McGraw-Hill,London. and Simantov,R. (1977) Neurochemistry 28,13-19. Snyder,S.H. Whittle,B.J.R. (1977) Br.J.Pharmacol. =,455-460.