Naloxone-induced increase in blood and brain ethanol concentrations in rats

Pharmacological

Research

Communications,

NALOXONE-INDUCED

Vol. 79, No.

723

IO, 1987

INCREASE IN BLOOD AND BRAIN ETHANOL

CONCENTRATIONS IN RATS. Benitez,

M.,

Boada,

Departamento Universidad

J.,

Diaz,

E.,

Feria,

M. and Prunell,

M.

de Farmacologia. Facultad de Medicina. de La Laguna. La Laguna. Tenerife. Espaiia.

Received

in final form

9 September

1987

SUMMARY Although a reduction in blood ethanol concentration has been proposed to mediate the ethanol antagonist activity of naloxone observed in clinical and experimental situations, an increase in this variable as well as in brain ethanol concentration has been found in rats treated with naloxone i-p.1 ten min after intragastric (0.5 and 2.0 mg/kg, administration of ethanol (1 and 2 g/kg). This effect disappeared either when naloxone was administered 50 min after ethanol or when ethanol was given intraperitoneally. naloxone induced a slight but significant On the other hand, slowing in intestinal transit rate. These results suggest that naloxone may facilitate gastrointestinal absorption of ethanol when administered soon after an oral load of this drug. Therefore, mechanisms other than a pharmacokinetic interaction appear to be involved in the antagonist action of naloxone. KEY WORDS Blood

ethanol

concentration,

naloxone,

interaction.

INTRODUCTION A series naltrexone and

1983;

et

have al.,

Castellano

hypothetical

0031-6989/87/l

reports

inhibited

animals

Nelson

of

indicating several

been

1981;

00723-7/$03.00/O

ethanol

published Boada

and Pavone, antagonism

that

et

naloxone (EtOH)

(Sorensen al., 1984).

on opioid

1981;

effects

in

man

and Mattison, Kiianmaa

Alternatively peptides,

and

(Nx)

Badawy

1978;

et

al.,

to

an

et

al.

Ol987The Italian PharmacologicalSociety

724

Pharmacological

(1981a,

1981b,

1985)

to

effect

by lowering

this

through

an enhancement

a generalisation the

fact

an early

et

stage

1981).

In

concentration 10

of

MATERIAL Male

the

present were

The animals

were

and water,

except

to

the

administration

of

any drug

treatment

at

of

as

considered

more

of

2.0

receptor induced 1979).

In

action

Nx

once

whether

when

or

administered under

EtOH antagonism

BEC and brain in

rats

of

EtOH.

(Boada

EtOH

treated

with

this

weighing

200-250

g,

housed

and had

free

a period

drugs.

(from

of

a 15% v/v

Nx

way,

blocking by a higher

et

low

effect dose

(less

BEC was determined

used.

access

hours

prior

received

EtOH was given solution)

al.,

by of

since

route,

induced of

it

was

specific)

dose

by gas liquid

at

10 min

by a specific

Nx was compared

intra-

intra-

Nx was administered

by intraperitoneal the

were

animals

instead

Badawy

'physiological'.

six

withdrawn.

was preferred

case

mg/kg

of

Once the

was also

route the

in

for

2 g/kg

This

route.

and

water

1 and

peritoneal,

EtOH.

dose

by

a circumstance

induce

studied

individually

food

0.5

an effect

work,

rats,

to

gastric

However,

AND METHODS. Sprague-Ddwley

doses

to

an intragastric

(BEC)

to determine

such

found

rise

EtOH administration.

EtOH intoxication,

(BrEC)

after

min

the

from

interest

been

give

made difficult

studied

elapsed

to produce

Nx has also

al.,

of

Vol. 19, No.

oxidation. is

only

had

could

Nx

EtOH hepatic

authors

Communications,

EtOH concentration

hypothesis

(90 min)

Nx continued

which

of

considered

that

prOpOSed

blood

this

these

time

was thus

not at

of

that

a certain It

have

Research

with

(Sawynock chromatography

doses

after

opioid that et

al., at

5,

10. 1987

Pharmacological

Research

Communications,

20 and 50 min after

Basically,

the

was followed. brain

one half

Once blood

samples

removed

being

(334

4QC for

presence

fuged

at

10000

supernatant also

fluid

of

the

results

ments

were

marginally 60 min

5,

50 min after

route

Lastly,

mined.

8 ml/kg

resin

was given

group

received

The second by i.p. after

either

removed. the

head,

orally

to

third

three

by i-p. groups

the

or

Nx

abdomen

rate

run

of

the

which

series

other

was

giving

opened

animals and

by charcoal

expressed

20 min after rate

suspension

in

of

was deter2.5% Accacia

rats.

The first

10 min after 0.5

charcoal.

and 2 mg/kg charcoal.

were the

i.p.)

(2 mg/kg

Nx

measured

10 min after the

(2 mg/kg

EtOH by intra-

transit

received

experi-

and BEC measured hand,

groups

of

Nx

p.o.1

route

respectively, saline

added

was centri-

Firstly,

BEC being

a 10% charcoal

The distance transit

out.

on intestinal

saline

and

route,

on the

of

rotative

was then

short

10 min after

Nx action

was

chromatography.

On the

(2 g/kg),

halves,

acid

a Selecta

EtOH analysis,

obtained,

Nx.

two

4QC, an alliquot

EtOH (2 g/kg

was administered

peritoneal

and

after

(1980) whole

perchloric

The homogenate

carried

was given

Nx.

The sample

acid

for

by gas liquid

view

i-p.1

used

the into

2-3 ml of

10 min at

after

obtained,

processed.

of

puncture.

and Hoover

and sectioned

10 ml.

being

In

20 and

of

rpm for

performed

were

More perchloric

volume

by heart

by Brien

10 min by means of

homogenator.

up to a final

obtained

subsequently

the

725

10, 1987

5, 20 and 50 min

reported

in

tissue

at

procedure

homogenated mM) at

samples

measured

was immediately

only

Nx.

in

Nx

BrEC was paralelly

Vol. 19, No.

killed

small

was then

as a percentage

of

Nx

20 min by a blow

intestine measured of

the

whole

726

Pharmacological

length

in

Communications,

Vol. 19, No.

30 min.

Statistical

calculations.

determine between

Research

the

Student's

statistical

t test

significance

was used

of

to

differences

means.

RESULTS The administration of

EtOH gave

as shown

in

rise Figure

of to

Nx 10 min after

a consistent

1. This

3.5 I

effect

increase was clearer

3.5 *wE2+N2

2.5

intragastric in

doses

BEC and BrEC, in

the

case

** P+

E2+N2

2.5 * E2+N0.5 E2

1.5 -I

1.5

cl.5

0.5

l-

L-7-7 20

f 05

I 50 min

i i5

20

50

min

Figure 1. Effects of Nx on BEC (blood ethanol concentration) and BrEC (brain ethanol concentration). Each point represents the mean of seven measurements + SE. E=Ethanol. N=Naloxone. Figures following E express doses in g/kg p-0. Figures following N express doses in mg/kg i-p. *=p 0.05, at least, as compared with El. *=p 0.05, at least, as compared with E2.

10, 1987

Pharmacological

of

the

with

Research

higher

the On the

rate of

doses

lower

of

hand,

60 min

727

10, 1987

Nx and EtOH,

but

no significant after

intraperitoneally was slightly

Nx (Table

Vol. 19, No.

was also

noticeable

ones.

other

Nx was given given

Communications,

EtOH (Table (Table

but

changes

2).

found

1) or when

Lastly,

significantly

were

slowed

EtOH was

intestinal by

when

the

transit two

doses

3). TABLE 1

Blood ethanol concentration following Nx administration 60 to the mean of min after EtOH p-0. Each value corresponds seven measurements + SE. 65 min

80 min

110 min

EtOH 2 g/kg

l-14+0.16

1.11+0.18

l-20+0.15

EtOH 2 g/kg plus Nx 2 mg/kg

1.24+0.19

1.15+0.13

l-04+0.12

Figures

express

mg/ml

of

EtOH.

TABLE 2 Blood ethanol concentration determined after giving EtOH by i.p route. Nx was administered 10 min after ethanol. Each value corresponds to the mean of six measurements +SE. 2.30+0.11

EtOH 2 g/kg

Figures

EtOH 2 g/kg plus Nx 2 mg/kg indicate mg/ml of

2.56+0.13 EtOH.

TABLE 3 Effect of Nx on charcoal intestinal represent percentage of the whole charcoal in 30 min (mean -+ SE) Control Nx 0.5 Nx 2.0 l ) p (0.05

mg/kg mg/kg

as compared

with

transit intestinal

61.3+2.41 51.3+1.87* 53.1+2.56* control.

rate. Figures length run by (n=13) (n=7) (n=9)

728

Pharmacological

Research

Communications,

Vol. 19, No.

DISCUSSION The results

obtained

Nx administered causes

this

the

10 min after

a consistent

hand,

in

study

demonstrate

an intragastric

increase

effect

present

in

disappeared

dose

BEC and BrEC.

either

when

that

of

EtOH

On the

other

Nx was administered

60 min after

EtOH or when

route.

as a whole,

these

findings

al.

(1981a,

1981b,

1985)

effects

on EtOH pharmacokinetics,

both

Nx and the

route

Taken

by Badawy et rise

to

variable

administration

timing

EtOH being found.

apparently

Therefore,

to

accept

for

the

cannot

Although

in

the

bowel

could

given

at

presumably

slowing to

the

enhance necessary

the

low

it

for

must

a more

Nx action. dose one,

it

of

the of

modification

is

difficult

responsible mechanisms

is,

the

rate

In

any case,

this

context,

Nx produceda

higher

seems unlikely

that

the

such

of

an effect studies

this

as the increase an action

Nx-induced

and unrelated

further

assessment

when

EtOH had been

was slight that

the

EtOH intragastric

although

be recognized

from

effect of

after

at increase

EtOH absorption

60 min

transit

precise

unexpected

proportion

hand,

In

be given

Nx lacked

other

EtOH absorption.

unexplored specific)

in

a high

that

intestinal

dose,

of it

cannot

mediating

Indeed,

which

On the

in

type

as mainly

explanation

absorbed,

administration.

Nx gives

out.

a facilitation

in

that

Neuropharmacological

be considered.

a time

the

mechanism

process

BEC and BrEC,

reported

administration

circumstances

a definitive

as to

those

indicate

these

EtOH antagonism. ruled

and

of

under

be thus

by intraperitoneal

determinant

a pharmacokinetic Nx-

present

of

EtOH was given

could are

hitherto high

(less

in

BEC that

on opioid

70, 1987

Pharmacological

Research

receptors

is

Finally, either

Communications,

basically

the

presence

not

the

aim of

the

the

EtOH antagonist to changes

70, 1987

responsible

BEC time-course

in

related

Vol. 19, No.

paralleled

or

the

present

absence

study,

effect in

for

of

phenomenon.

with

that

of

this

Nx.

not

of

BrEC

Although

result

Nx does

blood/brain

this

it

was

indicates

appear

to

that be

EtOH distribution.

Ackowledgements. This work was supported Direction of Universities The Canary Islands.

by a grant and Research

from the General of the Government

of

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S.W.

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