Interactions between the Discriminative Stimulus

0022.3565/91/2581-0149$O3.OO/0 THE JOURNAL OF PHARMACOLOGY Copyright © 1991 by The American

AND

EXPERIMENTAL

Society

Vol. 256, No. 1 Printed in U.S.A.

THsaaPEuiics

for Pharmacology

and

Experimental

Therapeutics

Interactions between the Discriminative Stimulus Effects of Mu and Kappa Opioid Agonists in the Squirrel Monkey1 S. STEVENS

NEGUS,2

MITCHELL

of Psychology,

Department

for publication

Accepted

J. PICKER

University September

of North

and

LINDA

Caroilna,

Chapel

A. DYKSTRA3 Hill, North Carolina

20, 1990

ABSTRACT of mu

U50,488, pendent

and

kappa

were

opiold

evaluated

bremazocine and

agonists

Fentanyl

varying degrees and antagonist effects in squirrel monkeys trained to discriminate either the selective mu agonist fentanyl or the selective kappa agonist U50,488 from water. In the fentanyl-trained monkeys, fentanyl, as well as the less selective mu agonists buprenorphine and (-)metazocine, produced dose-dependent and complete substitution for the training stimulus. U50,488 produced neither agonist nor antagonist effects in the fentanyl-trained monkeys, but the less selective kappa agonists bremazocine and tifluadom generally produced either agonist or antagonist effects, depending on the monkey tested. In the U50,488-trained monkeys,

of selectivity

and tifluadom

complete

with

for their agonist

all produced for

substitution

the

receptors

stimulus.

tional

pendency

ies

opioid that subtype

between

demonstrating

opioid

receptor

other

opioid

et at.,

1985;

These

receptor

Negus

opioid

ity, is

Most subtype

than

the

for

for

work

to

have

publication

was

supported

(e.g.,

affinity

its

a higher other

March

by U.S.

for

other

subtypes,

types

for and

one thereby

ABBREVIATION5:

of

receptor

display

Public

Health

Service

Grants and and

from

and

Endocrinology, Research Foun-

the

National

to mu,

the

of

drugs

of receptor

opioids

will

bind

or detta

kappa is specific

to more

selectivity

of intrinsic

of a drug’s response,

and

than

opioid

a given

one

to

and

a drug’s range

full-agonist

to

have

high

produce

antagonist

efficacy.

Intermediate

some assays, or as partial

Intrinsic

activate

receptor

as

efficacy

whereas drugs

from

(Kenakin, several

that

act

in other assays they act either agonists that produce submaximal

and

alone Because

receptor

subtypes,

a

partially

drug’s

reverse

intrinsic

a given

opioid

generally

may

effects can

produce

vary

agonist

via a receptor subtype at which it has high efficacy, and taneously produce antagonist effects via another receptor type plifies with

at

which this

more

it has capacity

than

little of

one

or no efficacy. some

receptor

opioids type

Buprenorphine to

(Cowan

or no

agonists

in

as antagonists effects when

the

efficacy

drug’s

little

full

as

but

agonists.

the

to have

may

a

1987). Drugs assays are con-

drugs

considered

are

initiate

is theoretically

it is inferred

efficacy,

addi-

is a mea-

and

efficacy

of assays effects across

effects

by the

efficacy

a receptor

intrinsic

inasmuch

produce

is complicated

efficacy.

ability

a wide

across

administered

some

DA02749

issue

sidered

receptors.

opioid

variable

effects

13, 1990.

Department of Basic and Clinical Research, Scripps Clinic dation, 10666 North Torrey Pines Rd., La Jolla, CA 92037. S Recipient of Research Scientist Award K05DA00033

on Drug

of

opioid

of many

Interactions

buprenorphine and (--)agonists bremazocine on the basis of the low receptor

binding

none

assay-independent

Holaday

in figure la. Receptor affinity for one type

affinity

However,

biologic

that

DA05355 from the National Institute on Drug Abuse. 2Present address: Division of Preclinical Neuroscience

Institute

sure

result from two general a lack of receptor selectiv-

is illustrated of a drug’s

of one another.

mu agonists selective kappa

in their

selectivity

The

to

mechanism,

effects in the and (-)-metazo-

subtype.

interde-

1983a;

Leander,

appear

and

relative

opioids

Some

dose

in press).

is a measure

Received

1This

et at.,

drug-dependent

selectivity receptor

subtypes

first

effects.

independently

the less selective

receptors.

receptors has been suggested by studopioids apparently selective for one can interact with opioids selective for

interactions The

mechanisms.

respective

nor antagonist

but buprenorphine

metazocine, or the less and tifluadom, can be explained selectivity of these drugs.

pendently

their

function

involving

receptor

producing

agonist

the discriminative stimulus effects of U50,488. The inability of the selective mu agonist fentanyl and the selective kappa agonist U50,488 to antagonize each other’s discriminative stimulus effects suggests that the stimulus effects mediated by mu and kappa opioid receptors in squirrel monkeys do not interact with a common biologic substrate. Rather, these results suggest that the stimulus effects mediated by mu and kappa

Opioids produce their principal effects by binding to at least three different types of receptors, the mu, kappa and detta opioid receptors (Martin et at., 1976; Lord et at., 1977; Howard et at., 1986; Mansour et aL, 1988). However, less is known about the degree to which these opioid receptor subtypes act indein

neither

monkeys,

cine antagonized

a dose-de-

training

produced

U50,488-trained

bind et at.,

to

of full across effects

simulsubexem-

and 1977;

interact Wood

et

Abuse.

FR, fixed ratio; DAR,

drug-appropriate

responding;

ARL, average response

latency. 149

Downloaded from jpet.aspetjournals.org at ASPET Journals on August 30, 2016

A series

150 at.,

at al

Negus 1981;

Leander,

binds with its intrinsic

acts

1987;

Negus

et at.,

high affinity to both efficacy varies such

as an agonist

kappa The

Vol. 256

at mu

in press).

mu that

Buprenorphine

and kappa buprenorphine but

receptors,

as

Massie,

an

antagonist

phine

at

receptors.

second

opioids,

mechanism,

effects

Specifically,

this

between

level,

receptors

can

(Leander,

1983a;

many

effects on

Mucha

1988). Such potentiation

ent

opioid

produce

antidiuretic

Parada,

as

Sadee,

the

bremazocine such (Leander,

as

The

kappa

1985).

agonists in the rat urination a blockade of kappa opioid 1985).

Rather,

agonists mental

these

produce endpoint

Kappa

and

in the

drug

used

extensively

opioids

data

opioid to

1980;

man,

discriminate and the

Picker

for

agonists

and

one

kappa

also

the

produce

distinct that

Dykstra,

1987;

receptor

Picker

the

nation.

In humans, that have

effects

opposing

agonists produce mon et at., 1986; have

on

subjective Pfeiffer that

suggested

effects

effects

opioid

of mu

for example, been described

mu

and

mu

(see

whereas

kappa

as

and

systems

kappa

study

and

less

U50,488

Massie, 1985)

and

Kosterlitz, for kappa and

selective

1988), brema-

1986).

over

Of mu

bremazocine

Goldstein, 1984; Doty et at., 1989; hypothesized that, if interactions were of the training drugs with the less and

then the sufficient

However,

is

nonse-

et at., in press).

and Kelly,

less

Berzetei-

included

Dykstra

low to

if antagonist

receptor explain

selectivity of these these interactions

interactions

a)

Drug A

been

extended

to

Drug B

111

of

can Effect

from

No Effect

the

on

b)

Drug A

Drug B

un-

subjective

whereas

kappa

as dysphonic (KuPfeiffer et at. (1986)

opioids

affecting

the

Negus

for

mu

1990)

agonists

euphoric,

Hayes

tifluadom

agonists, would be

drug vehicle, by opioids

produce

effects described et at., 1986), and

1984;

(James

la).

in 1983;

1985).

is

1989a; is virtually

1987;

et at., 1980; Corbett and has the highest selectivity

(Romer

fig.

et at.,

buprenorphine

aL,

Dykstra,

in its affinity and Cuatrecasas,

(-)-metazocine

Negus

Leander,

used et

U50,488

et at., 1986; and Holtz-

differ

agonists

agonists

nonselective

and

et at., 1981;

(Leander,

discriminative stimulus effects produced by nonopioids or opioids selective for the other opioid receptor subtype. Furthermore, it has been suggested that the discriminative stimulus effects of mu and kappa opioid agonists not only differ, but are also diametrically opposed to one another in a manner not unlike

1990)

whereas

1982;

buprenor-

effects

et at.,

typically

subtype

Lowe,

kappa

1982),

and

1977;

selectivity (Chang

receptors

et at.,

(VonVoightlander

mu

effects

agonists from effects produced

(Wood

et at.,

(-)-

included

1986)

experi-

has

receptor-mediated

kappa opioid stimulus

and

lective

due to Sadee,

the

a procedure

Gurski

selective drugs be

and

on

et

(Magnan

study

et aL,

and Richof

agonists

effects

at.,

Magnan

Craft et at., 1989). We restricted to combinations

can

not and

1985). Both humans (Kumor and laboratory animals (Teal

mu and discriminative

selective

that

1981;

is

kappa

effects

are probably (Richards

interacting

study

of

tifluadom

antagonist

procedure,

(Holtzman, et at., 1986)

Pfeiffer

and

receptors

suggest

discrimination

effects

morphine, t-methadone 1983a; Leander, 1984;

procedure

distinct but of urination. mu

diuretic

Cowan

receptors,

agonists

et at.,

in the

Slifer

highest

these,

whereas mu agonists 1983b; Huidobro-Toro

used

1970; 1976;

zocine

of physioby differ-

agonists

has the kappa

tifluadom

Imper-

kappa

example,

(Leander,

U50,488,

opioid

and

(Martin

The a

endpoint

Di Chiara

in rats,

me-

mu

Of these, fentanyl mu receptors over selective

in at

different

experimental

For

Moreover,

blocked by mu agonists low doses of etorphine

that,

1985;

effects

effects

1985).

effects

raises the possibility of effects mediated

subtypes.

diuretic

such

single

Herz,

cases

the by

drug lb.

the (Villarneal,

produce

emotional

and

kappa

agonists

[e!Pto

opposing perceptual

experience.

In view

ence

of the

potential

other’s

effects

each

via

either

to

determine

of the the the

antagonize

the

other

degrees with the

bination

discriminate kappa addition

the

agonist

to

mu

the

and drug

two mechanisms ability of agonists discriminative

receptor

of varying

for in

subtype.

of selectivity training drug mu

agonist

described at one

stimulus To

this

end,

fentanyl

above, receptor and

we sought subtype to

of agonists kappa

alone monkeys

(0.017

Effect

influ-

procedure

effects mu

were tested in squirrel

U50,488 (0.75 or fentanyl (Zimmerman

to

discrimination

and

mg/kg)

at

agonists

drug

in comtrained to or

1.7 mg/kg) from water. et at., 1987; Dykstra

the In and

No Effect

Fig. 1. Mechanisms by which drugs characterized as mu or kappa agonists could interact. a) A lack of receptor selectivity. A drug (Drug A) having low receptor selectivity could produce agonist effects by binding to one subtype of opioid receptor (Receptor A) at which it has high intrinsic efficacy, and simultaneously antagonize the effects of a second (Drug

B) by binding to a second subtype

of receptor

(Receptor

B)

at which Drug A has low efficacy and Drug B has high efficacy. b) A biologic interaction. A drug (Drug A) could bind to one subtype of opioid receptor (Receptor A) at which it has high efficacy and activate the receptor to initiate a set of effects that, among other things, prevents the expression of effects produced by a second drug (Drug B) via a second type of opiold receptor (Receptor B).

Downloaded from jpet.aspetjournals.org at ASPET Journals on August 30, 2016

produce

a

and

which in figure

It is known

mediated

convergence or antagonism

receptor

typically

and

receptors.

converge

logic

ards

those

interaction

opioid

between

in

is a biologic

by different

agonists

interaction system illustrated describes

there

and

biologic

biologic and is

mechanism

diated postreceptor

the

second

which

ato,

a

is dependent on are being evaluated

1988),

metazocine

receptors, but generally

Interactions

1991 combinations

of

U50,488

with

evidence

for

agonists

(see

in

fig.

a

the

the

highly

selective

each other, then biologic interaction squirrel

monkey

agonists

this drug

could between

fentanyl be

and

considered mu and

discrimination

as kappa

procedure

lb).

Subjects.

was

used.

lights

initiated.

At was lights remained duration: 1 sec) was

component

the

conclusion

At the

were

beginning

illuminated,

of each and

a 5-sec

session,

the

avoidance

house

light

component

the end of the 5-sec avoidance component, an escape initiated, during which the house light and stimulus on, and a series of 15 shocks (intensity: 3.0 mA; was administered, with 1 sec between each shock. At

of the

escape

component,

there

was

a 30-sec

Responses

programmed

on

the

other

consequences.

were recorded but monkeys reliably terminated pniate lever during either period

discrimination

During

training

was

lever

were

recorded

but

initially

had

no

Similarly, responses during the time-out had no programmed consequences. Once all 20 trials by responding on the approthe avoidance or escape component, drug initiated.

drug discrimination training, both stimulus lights were illuand an autotermination criteria was introduced such that failure by the monkey to terminate three consecutive trials automatically terminated the session. Monkeys in one group (N = 3) received i.m. injections of either distilled water or 0.017 mg/kg of fentanyl 15 mm before the start of the session. A random sequence was used to determine which injection was administered, with the restriction that minated,

left

lever

was

designated

as

the

fentanyl-appropniate

lever

was the fentanyl-appropniate lever for the third monkey. Beginning at this stage of training, each response on the inappropriate lever initiated a 3-sec changeover delay, during which responses on the injection-appropriate lever were recorded but had no programmed consequences (e.g., did not terminate the trial). Trials during which the first response was emitted on the ofthe

monkeys,

and

injection-appropriate

during priate

the first

lever,

the

lever

which

right

were

designated

response

or during

which

lever

as

was emitted no response

correct,

on the

was

All

conditions

2), except

were

that

initially

were

identical

U50,488 trained

for

used

was

a second

were

group

designated

(N monkeys

of monkeys

drug.

to discriminate

trials

until the percentage a mean of 85% over

as the training

to criterion

whereas

injection-inappro-

emitted,

as incorrect. These conditions remained in effect of correct trials during a session was at or above 20 consecutive sessions.

0.75

Both

mg/kg

=

of U50,488

the monkeys (7-14) subsequently lost the discrimination. As a result, the training dose ofU5O,488 for this monkey was raised to 1.7 mg/kg, and the monkey was retrained to criterion. Thus, for the remainder of the experiment, one monkey (7-9) discnimfrom

water.

However,

mated

0.75

(7-14)

discriminated

one

mg/kg

of

of U50,488 1.7

was designated

as the

should

that

be noted

to discriminate monkeys failed

from

mg/kg

water,

of U50,488

U50,488-appropniate attempts

U50,488

from

to

criterion

reach

were

made

water

using despite

whereas

the

second

from

water.

The

lever

for both

to train

three

monkey left

lever

monkeys.

other

It

monkeys

these procedures, training for more

but these than 100

sessions.

Substitution tenon

was

and antagonism

met,

substitution

tests.

and

Once the discrimination

antagonism

tests

were

cni-

initiated.

Test

differed

from training sessions in three respects. First, during completion of an FR-i response on either lever terminated the trial. Second, the escape component during a test session extended for a maximum of five shocks (rather than for a maximum of is shocks). Third, test sessions automatically terminated if a monkey failed to complete two (rather than three) consecutive trials. The second and third changes were implemented to protect monkeys from excessive exposure to shock during administration of sedative doses of the test drugs. Except for these differences, conditions during testing were sessions

a test session,

identical

time-out.

During the timeout, the house light and shock were turned off, but the stimulus lights remained on. At the end of the 30-sec time-out, a new trial was initiated with illumination ofthe house light and the beginning of a new 5-sec avoidance component. This sequence of discrete trials followed by 30-sec time-out periods continued until a maximum of 20 trials was completed. During initial shaping of the lever press response, only one stimulus light was illuminated, and completion of a FR-i response on the lever beneath that stimulus light during either the avoidance or escape component terminated the trial and initiated the 30-sec time-out period.

The

the

to those

of testing, whereas

and

described

test

during

sessions

training

were

sessions

training

sessions.

conducted

were

on

continued

During

Tuesdays

on

all and

Mondays,

phases Fridays,

Wednesdays

Thursdays. During

for

substitution

tests,

mu agonists kappa agonists

three

three antagonist

dose-effect

(fentanyl,

(U50,488,

(naloxone)

and

relationships

buprenorphine

and

bremazocine

a barbiturate

were and

determined

(-)-metazocine),

tifluadom),

(pentobarbital)

an opioid

in both

groups

of monkeys. A test drug was said to substitute for the training stimulus if some dose of the test drug produced at least 85% drug-appropriate responding. The dose-effect curves for the training drugs were determined end

twice, of the

During ing

dose

once

antagonism

of

fentanyl

beginning

tests

was

tifluadom,

bremazocine,

fentanyl

at the

of the

experiment

and

again

at the

experiment.

dose-effect

in

the fentanyl-trained

combined naloxone

curve

was

with or

monkeys,

selected

pentobarbital.

redetermined

in the

doses

the trainof

U50,488,

In addition, presence

the

of a high

dose of U50,488 (0.56 mg/kg), bremazocine (0.Oi or 0.03 mg/kg) or tifluadom (0.1 mg/kg). In the U50,488-trained monkeys, the training dose of U50,488 was combined with selected doses of fentanyl, buprenorphine, (-)-metazocine, naloxone or pentobarbital. The U50,488 doseeffect curve was also redetermined in the presence of a high dose of fentanyl

(0.017

mg/kg),

(3.0 or 5.6 mg/kg).

buprenorphine

(0.03

mg/kg)

or (-)-metazocine

Downloaded from jpet.aspetjournals.org at ASPET Journals on August 30, 2016

(1977), stimulus

and

Five

individually

treatment and that

151

Agonists

was not given for more than two consecutive number of water and fentanyl injections was approximately equal. When water was administered, completion of an FR-i response on one lever (water-appropriate lever) terminated the trial, whereas when fentanyl was administered, completion of an FR-i response on the other lever (fentanyl-appropniate lever) terminated the for two

adult male squirrel monkeys (Saimiri sciureus) were in a colony maintained on a 12-hr light-dark cycle and maintained at free-feeding weights. Four of the monkeys were experimentally naive at the start of the experiment, and one monkey (5-45) had had previous exposure to opioid agonists and antagonists. All monkeys had free access to water in the home cage and received 8 to 14 Purina Monkey Chows daily. Their diet was supplemented with fresh fruit. All housing facilities were accredited by the American Association for the Accreditation of Laboratory Animal Care. Apparatus. Each monkey was held at the waist in the seated position in a primate chair, while its tail was held motionless by a small stock. Electric current was delivered via hinged brass electrodes that rested lightly on a shaved portion of the tail. Electrode paste was applied to the tail to ensure low resistance electrical contact. The electric shock was 120 V a.c., 60 Hz, delivered through an 18 k dropping resister. The shock intensity was adjusted to a final current of 3.0 mA by gating the current through a potentiometer. Two response levers were mounted side by side on the front wall facing the monkey. Each lever was located approximately 3.5 cm from the adjacent side wall. When either lever was pressed with a minimum force of 30 g, a response was recorded and an audible click produced. A Plexiglas barrier approximately 26 cm tall and 0.5 cm wide protruded 7 cm into the chamber between the two levers. The barrier was installed to discourage monkeys from pressing both levers simultaneously. A single red stimulus light was located 6 cm above each lever. The entire chair was enclosed in a ventilated, sound-attenuating chamber provided with continuous white masking noise and a house light. Programming and recording equipment were located in an adjacent room. Behavioral procedure. A discrete-trial, shock-avoidance drug discnimination procedure, similar to that described by Schaefer and Holtz-

man

same

sessions

trial.

Methods housed

the

Mu and Kappa

between

152

et al.

Negus

Dose-effect

curves

Vol. 256

for

all

drugs

in

both

groups

of

monkeys

were

probed up to doses that produced agonist effects (e.g., substituted for the training drug), antagonist effects (e.g., attenuated the discriminative stimulus effects of the training drug) or overt physiologic effects. All drug doses were administered i.m. 15 mm before the start of the session

in a volume

of0.15

to 0.7

ml.

When

two

drugs

were

administered

in combination, the test drug was administered immediately training drug. All doses were administered in an irregular varied across monkeys. Data analysis. The percent DAR was calculated as: no. drug-appropriate

trials

before

TABLE 1 of drug-appropriate responding (%DAR) and average response latency (ARL; in seconds) on drug and water trainIng days In Individual monkeys trained to discrIminate fentanyl (0.017 mg/kg) or U50,488 (0.75 mg/kg in monkey 7-9 or 1.7 mg/kg In monkey 7-14) from water Percentage

DrugTrng

the

order

that

x 100

DAR

then constructed by determining of drug dose. Data were used only were completed. The dose of a test

curves

percentage from sessions

were

as a function

of in

between

the

response

during

beginning

of

that

Control

trial.

each

trial

and

the

latencies

emission

after

7-13 7-12

99.8

±

6.7 ± 0.6

1.02 ± 0.02

99.7

± 0.2

1 .02 ± 0.02

0.9

± 0.3

1 .19 ± 0.02

5-45

99.8 ± 0.1

1 .53 ± 0.06

4.4 ± 0.7

1 .05 ± 0.02

98.6 ± 0.1 87.7 ± 1 .4

0.9 ± 0.03 1 .82

3.2 ± 0.5 1 .2 ± 0.1

1.16 ± 0.03 1 .1 5 ± 0.03

monkeys 7-9 7-1 4

water

was

dissolved

and pentobarbital propylene glycol expressed

in ethanol

and

(Sigma Chemical and distilled water

in terms

Control

of the

propylene

Co.) in

forms

performance. 0.017 and

cniminate testing

duration

glycol

was

a 1:2:7

the

of

All three

experiment.

in

Doses

for

ethanol, all

on drug

and

water U50,488

training

for

testing

and

discriminate criterion

the

throughout

duration

U50,488-appropniate

and

water

Substitution trained

the

of

Fentanyl kg)

manner

in

dose-effect in

2 shows in the

agonists

(-)-metazocine for

are

mu

Figure

mu

mg/kg),

also

agonists

the

to dis-

percentage

of

shown

in table

in

buprenorphine

(0.1-10.0

mg/kg)

of fentanyl Redetermination of the study

the

individual

of

discrimination

The percentage of for these monkeys

the

1.

0.1

substituted

mg/

to

fentanyl

0.0

from

water

(bottom

panel).

Abscissa:

test

drug

dose

in milli-

grams per kilogram, log scale. Ordinate: percentage of fentanyl-appropilate responding (top panel) or percentage of U50,488-appropnate responding (bottom panel). All points in the top panel represent the mean a single determination in each of three monkeys except for points marked by which represent the mean of a single determination in two monkeys. All points in the bottom panel represent the mean of a single determination in each of two monkeys. For both the fentanyl and U50,488-trained monkeys, the training drug dose-effect curve no. 1 was determined at the beginning of the study, and the training drug doseeffect curve no. 2 was determined at the end of the study, approximately 1 year later. of

during for

the

course

of the

each

>

of

of the

study.

agonists

in

mu the

three

mu

stimulus

equipotent

and

Table

the

monkeys. in producing

were

fentanyl at least

2 shows

individual

agonists

effects

Thus,

(-)-metazocine.

roughly

and

values relative

fentanyl-like

fentanyl

32 times

ED The

buprenorphine

buprenorphine more

were

potent

(-)-

than

metazocine.

Fentanyl

com-

in a dose-dependent of the fentanyl revealed little or no

.0

(mg/kg)

determinations for mu opioid agonists in squirrel trained to discriminate fentanyl from water (top panel) or for oploid agonists in squirrel monkeys trained to discriminate

discriminative

stimulus monkeys.

(0.001-1.0

monkeys

001

2. Dose-effect

potencies

fentanyl-

the discriminative fentanyl-trained

the training dose all three monkeys. curves at the end sensitivity

trained

reached criterion throughout the

their

experiment. and ARLs

days

with

(0.001-0.03

and

pletely

change

training

tests

monkeys.

effects

maintained

of the responding

000’

monkeys

and ARLs for these monkeys days. Two monkeys trained to or 1.7 mg/kg) from water reached

(0.75

a,

Fig.

drugs

I

I

I00-

kappa U50,488

monkeys

1 shows

0-

Dose

above.

from water discrimination

Table

responding

C

in a 1:4 ratio,

dissolved

ratio.

described

mg/kg of fentanyl maintained their

fentanyl-appropniate

on drug

± 0.03

a

Results

for

± 0.02

1.15

were

England)

are

0.2

IIoo

of the

administration

determined to be slightly more than 1.0 sec for all monkeys (see below) and, as the study progressed, it became apparent that increases in average response latency to values greater than 2.0 sec correlated with the emergence of overt physiologic effects such as sedation, tremors, rigidity (mu agonists) and/or salivation (kappa agonists). Thus, an increase in ARL to values greater than 2.0 sec was used as a criterion to identify the upper range of drug doses that could be probed safely. Drugs. U50,488 methanesulfonate hydrate, (-)-metazocine fumarate, buprenorphine hydrochloride (all supplied by the National Institute on Drug Abuse), bremazocine methanesulfonate (Sandoz LT., Basel, Switzerland), fentanyl citrate (Janssen Pharmaceuticals, Beerse, Belgium) and naloxone hydrochloride (Sigma Chemical Co., St. Louis, MO) were all dissolved in distilled water. dl-Tifluadom hydrochloride (Dr. M. Rance, Imperial Chemicallndustnies, Inc., Wilmslow, Cheshire, of

ARL

creases of

0.03

three

pleting

and in

mg/kg monkeys,

the

(-)-metazocine

ARL

all three

in of

fentanyl and

session.

produced monkeys increased

prevented

(-)-Metazocine

one

dose-dependent

(data

not

ARL

above

monkey

increased

in-

shown). 2.0

(7-13)

ARL

A dose sec from

above

in all com-

2.0

Downloaded from jpet.aspetjournals.org at ASPET Journals on August 30, 2016

first

%DAR

U50,488-trained

which all 20 trials drug required to increase DAR to 50% (EDo) was determined where possible as follows. The linear portion of the dose-effect curve was defined as the line connecting the data points for doses producing an effect immediately above and immediately below 50% DAR. From these lines, the ED was determined by log-linear interpolation. In addition, ARL was calculated as the average latency during a session

WaterTraftg Days

ARL

Fentanyl-trained monkeys

20 Dose-effect

Days

%DAR

TABLE 2

Mu and Kappa

between

Interactions

1991

monkeys

to discrIminate

trained

fentanyl

Monkey

Tifluodom

I00

4Vo

r.TestDrAlone1 0.017

\/

)

olestDrug+

water.

from

_______

________ Bremozocine

U50, 488

ED values In milligrams per kIlogram for fentanyl alone (FENT), buprenorphine (BUP), (-)-metazoclne (MTZ), fentanyl + 0.56 mg/kg U50,488 (FENT+U50), fentanyl + 0.01 or 0.03 mg/kg bremazocine (FENT+BREM), or fentanyl + .01 mg/kg tlfluadom (FENT+TIFL) In

153

Agonlsts

FenJ

50

No.

Treatment 7-13

7-12

545

FENT

No. 1 FENT No. 2

0.006 0.012

0.006 0.005

BUP MTZ FENT+U50 FENT + BREM FENT + TIFL

0.015 0.47

0.017 0.56

0.005 0.004 0.005 0.16

0.012

0.005

0.004

0.072

a,

I

I

1

100

0 0. U)

a,

-‘

0.023

-

/IrJ///J

C

.

ED, could not be determined.

a

0

C

.a

0

50

TABLE

3

+

per kilogram for U50,488 alone (U50), (BREM), tifluadom (TIFL), U50,488 + 0.03 mg/kg of (U50 + BUP), U50,488 + 3.0 or 5.6 mg/kg of (-)(U50 + MTZ) or U50,488 + 0.017 mg/kg fentanyl (U50 In monkeys trained to discriminate U50,488 from water

FENT)

In milligrams

0

I

I

100

1

1

1

1

F

I

1

0.1

1.0

o-o--o

Monkey No. Treatment

5-45 7.9

7-14

U50 No. 1 U50 No. 2 BREM

0.39 0.22

0.42 0.41

0.005

0.005

TIFL U50+FENT U50 + BUP

0.033 0.19 2.26

0.055 0.56 2.44

0.87

1.00

U50

MTZ

+

50

_

0

sec

in

one

two

monkeys,

little

effect

monkeys

but

ARL,

on

mg/kg

but

2.0 sec

above

monkeys.

stimulus

effects

the

of

monkeys.

two

in one

kappa

to increase

in the

U50,488-

mg/kg),

the the

in

discriminative

bremazocine

mg/kg) substituted in a dose-dependent

Redetermination

the

of

U50,488 little or to U50,488

course

study.

ED

of the

kappa

des

of

the

and

U50,488, was

U50,488,

increased

0.3

mg/kg

bremazocine

the

training

above

at

44 times and

ARL

in were

was

at least

Substitution and in the fentanyl-trained

criminative

effects

in

the

The

bremazocine

more

six

2.0

of bremazocine

sec

by and

>

times potent

tifluadom all both monkeys

in

doses

in contrast,

in the

uated

each

of

poten-

more than

potent

3.0

mg/kg

3 shows

the

to

administered

stimulus effects of the kappa agonists U50,488, and tifluadom either alone or in combination with dose in the fentanyl-trained monkeys. U50,488

agonists effects

U50,488-trained sec

in

(7-12,

5-45)

above

2.0 sec

being

more

to

1.7

in monkey

plateaued

at 45 Ti-

in

monkey

7-12,

but

stimulus

effects

agonists

not

potent

shown),

of

monkeys

at

ranging

mg/kg

(7-13).

each

latencythan

ARL from

Bremazocine (5-45)

produced

with

in producing

monkeys

mg/kg

dose

Tifluadom

5-45.

increased

of 0.01

atten-

monkey

U50,488

at doses

and

in

kappa

(data

fentanyl-trained doses

in the

monkey.

all three ARL

in

in the

fentanyl

in this

monkeys.

individual

that

of

mg/kg)

training

for fentanyl

effects

discriminative

alone,

increases

kappa

increasing

dis-

the

of fentanyl

7-13,

monkeys.

responding

antagonized

effects

of the

all three

completely

for

dose tifluadom,

(0.001-0.056 in monkey

agonist

substitute

dose

antagonist

effects

in

partial

not

training

the

degrees

fentanyl-appropniate did

and

antago-

training and

Bremazocine

substituted

dose-dependent of

agonist

stimulus

produced

nor

of the

Bremazocine

for fentanyl

various

mg/kg)

and

When of

both

fentanyl

effects

monkeys.

discriminative

(0.01-0.3 50%

the

of

completely the

fentanyl

the

1.0 mg/kg of tifluadom. kappa agonists

antagonism tests with monkeys. Figure

any

monkeys.

completely

U50,488.

0.1 0.0’ (mg/kg)

for

stimulus

produced

fluadom

produced dose-de(data not shown). of

of

to

tifluadom

0.OOP 0.01 Dose Test Drug

substituted

neither

fentanyl-trained

7-13,

U50,488-like

producing

least

for

relative

in

substituted

change during

/T1

3.0

discriminative

fentanyl

for in

dose-effect no

values

monkeys.

agonists

bremazocine increases

ARL

kappa

Bremazocine

tifluadom

pendent

3 shows

individual

stimulus

U50,488.

than

in

three

discriminative

>

Table

agonists

mgI

completely manner

end of the study revealed of individual monkeys

mg/kg)

the

nized

(0.001-0.3

.b

0.3

Fig. 3. Dose-effect determination for U50,488, bremazocine and tifiuadom either alone or in combination with the training dose of fentanyl in individual squirrel monkeys trained to discriminate fentanyl from water. Abscissa: test drug dose in milligrams per kilogram, log scale. Ordinate: percentage of fentanyl-.appropriate responding. All points represent the effects of a single determination in each monkey. (0.1-1.7

U50,488-trained

curves at the the sensitivity the

(5-45),

failed

monkeys.

agonists

(0.01-1.0 of U50,488

both at a dose

monkey

0.i

other had

prevented

mg/kg

kappa agonists 2 also shows

(0.1-3.0

and tifluadom training dose

mg/kg

sec

to 1.0

other

with

to

In the 10.0 mg/kg

Buprenorphine

to 2.3

Figure

U50,488

both

in the

tests

of 17.0

up

mg/kg.

up

session.

ARL at doses

trained

kg) the

the

3.0

of doses

a dose

increased

Substitution

monkeys.

at

completing

buprenorphine

ARL

a dose

at

(-)-metazocine

from

0.1

of

(5-45)

monkey

in the

above 0.56

increased and

0.56

2.0

mg/kg

mg/kg

ARL (7-

Downloaded from jpet.aspetjournals.org at ASPET Journals on August 30, 2016

EDea values brmazoclne buprenorphine metazocine

154

Negus

12,

7-13).

dose-effect

each

of the these

kappa

each

0.56

mg/kg

and mg/kg

the

fentanyl

of

ED50

for

the

U50,488 any

dose

did of

the

not

range

curves.

mg/kg

the with values

(0.03

mg/kg

increased

bremazocine

In

two

produced

monkeys,

in monkey

7-13;

0.01

fentanyl-appropriate

of fentanyl,

decreased

by higher dose-effect

doses curve

monkeys.

mg/kg

responding

but

In monkey

consistent with

in monkey produced

fentanyl-appropriate of fentanyl. was shifted 7-12,

the

brema5-

by low respond-

with

0.03

mg/

stimulus

and

the

Thus, the top half of slightly to the right

pretreatment

inative

Bremozocine

Tifluadom p

training

.

0-

dose

in

did but of the

also failed producing in

1

1

1

one

attenuated monkey

11

for

A

for

dose

antagdose

and

Buprenorphine U50,488

in

(0.003-0.3

either

and effects

of the

(-)-

effects

of

the

complete

of the

training

(1.0-10.0

training

two

antagdose mg/kg)

U50,488 in either monkey and a complete antagonism

effects

Fentonyl

with Fentanyl

antagonist

(-)-Metazocine

(7-9). A dose the discriminative 7-14, reducing DAR 75%.

buprenor-

Buprenorphine

stimulus

monkeys.

dose

while of the

of U50,488

of 5.6 mg/kg of (-)-metazocine stimulus effects of U50,488 induced by the training dose

monkey

to

agonists in the discrim-

monkeys.

a dose-dependent

to substitute a dose-dependent

U50,488

I00

curve

fentanyl,

primarily

monkeys.

stimulus

0.1 mg/

or in combination

monkeys.

discriminative

discriminative

of fentanyl. with

dose-effect

agonists alone

0.1

on fentanyl-

doses

fentanyl

produced

substitute

in both

no effect

higher

substituted for U50,488 nor stimulus effects of the training

of the

produced

across

responding

U50,488-trained

contrast,

not

of U50,488

ri

the

had

of

10.0

mg/kg

the

with

pretreatment

mu

either

in

effects

tests with mu Figure 5 shows

the

of

U50,488-trained

monkeys,

j

effects

in either

the

hand,

antagonism monkeys.

of U50,488

onism

50-

other

mg/kg) neither discriminative

mg/kg)

I

by

(0.003-0.03 onized the

in

S

and

(-)-metazocine

metazocine,

_________ U 50,488

and

of

to

in

pretreatment

fentanyl-appropriate

shifted the entire 4-fold to the right.

Substitution U50,488-trained

phine

profile

5-45),

curve

increase

of

Buprenorphine

in of

(-)-metazocine

(-)

Metozocine

50-

:: I

S

0-

I00-

. I

d

00-

55 I

1

1

1

50-

S S

I

0

I

003

01

1

003

I

0 003

0 01

Dose Fentonyl

-1_I

003

0

I

0000301

0 to

I

I

I

o--o

0

Test Drug Alone Test Drug+l.7U50

I

003

(mg/kg)

4. Redeterminations of the fentanyl dose-effect curve in the presence of a high dose of U50,488 (0.56 mg/kg), bremazocine (0.01 mg/kg in monkey 5-45; 0.03 mg/kg in monkeys 7-13 and 7-12) or tifluadom (0.1 mg/kg) in individual monkeys trained to discriminate fentanyl from water. Abscissa: fentanyl dose in milligrams per kilogram, log scale. Ordinate: percentage of fentanyl-appropriate responding. The shaded regions in each graph show the range of values for two determinations of the fentanyl dose-effect curve, one obtained at the beginning of the study and one obtained at the end of the study. All points represent the effects of a single determination in each monkey. Fig.

0.003

0.01 0.03 0.003

0.01

Dose

Test

0.03

0.1

Drug

(mg/kg)

0.3

0.3

.0

3.0

0.0

Fig. 5. Dose-effect determination for fentanyl, buprenorphine and (-)metazocine either alone or in combination with the training dose of U50,488 in individual squirrel monkeys trained to discriminate U50,488 from water. Abscissa: test drug dose in milligrams per kilogram, log scale. Ordinate: percentage of U50,488-appropriate responding. All points represent the effects of a single determination in each monkey.

Downloaded from jpet.aspetjournals.org at ASPET Journals on August 30, 2016

produced fentanyl

a less

pretreatment

dose-effect 10-fold

mixed

produced

on the

kg of tifluadom approximately

a

of fentanyl

responding 7-12,

fentanyl than

(7-13,

increased

by low doses

In monkey

entire

a more

produced monkeys

two

of tifluadom

produced

the

produced also

In

appropriate

monkeys.

ED50

shifted

and ED50.

Tifluadom monkeys.

affect

three

of the

of

kg bremazocine the right fentanyl

values

ED

in combination

the

of fen-

a high

dose-effect

fentanyl

within

at doses

individual

2 shows

in

was

with

of effects.

both

the

sec

alone.

Pretreatment

zocine

2.0

with

table

relationship

of U50,488

fentanyl

profile

in

0.56

monkey,

above

pretreatment of

with

For

ing

after

agonists,

dose-effect

doses

ARL

and 1.0 mg/kg (7-12). effects of redetermining

redeterminations

fentanyl

the

7-13) the curves

Pretreatment

45)

increased

(5-45, 4 shows

tanyl

for

Vol. 256

Tifluadom

0.3 mg/kg Figure

for

et al.

Interactions

1991 appeared

to

stimulus

the

produce

effects

reduction

but

the

in

the

monkey

discriminative

did

not

complete

session. Fentanyl

and

creases

(-)-metazocine

at doses

in ARL

ARL

the

in

fentanyl,

lowest

7-9;

in

from

mg/kg

dose

one

monkeys

(7-9)

monkey

of buprenorphine

2.0 sec

in either

Figure

6

U50,488 these

shows

effects

produced effect

slightly

and No

ARL

above

either

left

ED50

dose-effect the

curves.

Pre-

only

U50,488

in monkey

for

7-9,

minor

than

2-fold

to

pentobarbital drug

Neither

alone

of

pen-

stimulus

had either

no effect

fentanyl

a dose-dependent Naloxone was of fentanyl

nor

training

pentobarbital

produced U50,488.

in comU50,488-

mg/kg)

for the effects

as an antagonist

or and

(0.01-1.0

stimulus

and stimulus

fentanyl-

substituted In addition,

but naloxone fentanyl and

naloxone

either the

in

naloxone

mg/kg)

with discriminative

or

antagonism 10- to 30-fold

than

as an antagonist

U50,488.

bital or

and

monkeys.

potent

more

tests the

training

discriminative

The

dose

values

produced

with

buprenorphine

rightward

10-fold

in both

mg/kg

0.03

rightward

monkeys,

or

shifts

with

Pretreatment

(3.0

U50,488

the

a high

of the

U50,488, of both more

the

(1.0-5.6

the

on

of

individual with

of fentanyl

to the

with

a 5- to

metazocine

tobarbital in any

curve

dose-effect

curves

in combination fentanyl

were

2.0 sec in each doses

probed

for pentobarbital

with

probed monkey

in the

the up

to

(data

dose

that shown).

and

pentobar-

of either

increased The range

doses

not

present

alone

training

experiment

had

U50,488 ARL above of naloxone

no effect

on ARL.

dose-effect and

slightly

to

Discussion

7-14.

produced

curves

monkeys.

session.

redetermining 3 shows

U50,488,

to

in monkey

curves.

the

of

Pretreatment

effect

the

pretreatment

Table

mg/kg

sensitivity

contrast,

trained

monkeys,

increased

of naloxone

(0.03 of

dose-effect

monkeys.

and antagonism Figure 7 shows

With monkeys

U50,488

Substitution pentobarbital. with

a dose

completing

the in both

bination

sec

the

in both

mg/kg of

after

agonists.

0.017

shifting

right

2.0

shifted right

155

Agonists

mg/kg shift

in monkey

U50,488

7-9;

agonists,

dose-

combination

with

5.6 mg/kg

(-)-

in monkey

7-

(-) Metozocine ____________

Buprenorphine _____________

was

covered period

like

be

were

drug

in

between either and, insofar of

agonists naloxone tested

squirrel

the selective mu agonist U50,488 from water.

than

more

Thus,

time.

1987; trained

training

either agonist

a period

monkeys, stra,

the

accurate

of

a series of mu opioid antagonist

pentobarbital,

with

discrimination

water

100

study, as the

barbiturate

to discriminate selective kappa the

Fentonyl

present well

as

nonopioid

U50,488

pretreatment

the

dose-

of buprenorphine

in the

whereas

In

(-)-metazocine,

the

in

other

this

as

alone

(Colpaert,

1978;

kappa the

and

in

trained

fentanyl

Once

or

the

established, U50,488 and experiment

1 year, maintained study demonstrates

species

and

monkeys

fentanyl or the present

Picker and Dykstra, 1989; Picker to discriminate either fentanyl

and

over a long that squirrel Picker

and

Dyk-

et al., 1990), or U50,488

can from

mu agonists substituted

com-

vehicle. In the fentanyl-trained tanyl, buprenorphine

and

pletely

stimulus

three

for the drugs

training

acted

as full

monkeys, only (-)-metazocine

mu

the

in all three agonists

monkeys.

the

in

fen-

Thus,

present

study.

all The

S

I

l00

E1 :..

/

1

TIT

i

0 0.1

,

l

.0

I

0 0.1

Dose U5Q488

I

1.0

order

priate

responding

zocine.

This

mu

was potency

agonists

in

fentanyl order

producing

T

I

10.0

I

0 0.1

.0

agrees

with

the

>

potency

(-)-meta-

order

of

Pentoborbitol

0,100C V en,ayI-Trxined

0

0

1

t t

Fig. 6. Redeterminations of the U50,488 dose-effect curve in the presence of a high dose of fentanyl (0.01 7 mg/kg), buprenorphine (0.03 mg/ kg) or (-)-metazocine (3.0 mg/kg in monkey 7-9; 5.6 mg/kg in monkey 7-14) in individual monkeys trained to discriminate U50,488 from water. Abscissa: U50,488 dose in milligrams per kilogram, log scale. Ordinate: percentage of U50,488-appropnate responding. The shaded regions in each graph show the range of values for two determinations of the U50,488 dose-effect curve, one obtained at the beginning of the study

the effects

Test

Drug

+ Fenlonyl

U50.488-Trotned Monkeys #{163} Test Drug Alone A Test DrUQ + U50.488

0)

3.0

Mon

. TestDruqAlone 0

(mg/kg)

and one obtained at the end of the study. All points represent of a single determination in each monkey.

fentanyl-appro-

buprenorphine

Noloxone

I ,

of the

potency

oJ

-.

#{149};:::-i.---0.003

001

003

01

03

Dose

Test

0

Drug

______ 0

30

56

(mg/kgl

Fig. 7. Dose-effect determination for naloxone and pentobarbital either alone or in combination with the training dose of the training drug in squirrel monkeys trained to discriminate either fentanyl or U50,488 from water. Abscissa: test drug dose in milligrams per kilogram, log scale. Ordinate: percentage of drug-appropriate responding. Points marked by * show data for only one monkey. All other points for the fentanyl-trained monkeys represent the mean of a single determination in each of three monkeys, whereas all other points for the U50,488-trained monkeys represent the mean of a single determination in each of two monkeys.

Downloaded from jpet.aspetjournals.org at ASPET Journals on August 30, 2016

curve

in

the

mu

with in

shown).

prevented

2.0 sec

1.0

not above

14) the

effects

increasing

(-)-metazocine,

from to

curves

redeterminations

changes

also

in-

monkey.

the

of

treatment

the

up

dose-effect

each

(data

With above

to those

ARL

in 7-14)

session. ARL

dose-dependent

equivalent

to increase

mg/kg the

increased

prevented

roughly

doses

0.56

completing

10.0

produced

fentanyl-trained

the

mg/kg

of

a further

U50,488,

of

Mu and Kappa

between

156

Negus

these

et al.

compounds

et at.,

other

assays

and

et al.,

1984;

Slifer

in

1981;

Dykstra,

Vol. 256

Young

In addition,

the

and

other

full mu

demonstrating

agonists in drug agonist as the training 1989a).

tazocine

drug

other

produce

assays

if any but

in monkeys, ent

on

i1.,

1977;

as

et

at mu ligands

effects

as

of

relative

and

in the

in the

dosages

inasmuch

increased that

produced

suggest interact

by mu

does

that

effects

mediated

with

the

both

produced trained

kappa

agonist

monkeys.

of

both

mu

strated

or

similar

and

1987;

both

considerably

between monkey

(5-45) and an this differential

1984;

Dykstra,

within acted

the

in

it acted similar

most

pronounced

being

most

a

(7-13),

Ureta

each as

an

partial

monkey: agonist

monkey

in

suggesting

at mu

receptors.

antagonist

as

those

in

had no antagonist tifluadom lacked

as an

antagonist. Bremazocine produced results, with bremazocine’s agonist effects in monkey 7-13, and the antagonist

pronounced

in

monkey

7-12.

The

demonstration

which

have

low

et at.,

of

To

our for

previous

kappa receptors studies have

act

a kappa

to

as

antagonist

this

between

the

in the

receptors. and

antagonist at

the

present

studies does

(Magnan demonstrated both

an

al., that

in vitro

such

antagonist (Richards and Dykstra, 1988;

with bind et

in the demon-

receptors

kappa

results as

(-)-me-

effects been

has

efficacy

present U50,488-

the effects with the

by kappa

as a kappa 1987; Negus

binding metazocine

that

In the

fentanyl

agree

antagonist

knowledge, the relative binding mu and kappa opioid receptors

that

et

in the masking

and

buprenorphine

buprenorphine

however,

concluded

have

and

(Negus that,

of morphine. by

Buprenorphine

intrinsic

1989b),

the

rat

interaction

primarily

monkeys.

with

perceptually

mediated

agonists

it functions exclusively Sadee, 1985; Leander,

explored;

of

mu

effects

attenuate

in squirrel monkeys, do not interact

receptors

produced

characterization

ity

effect

effects

selective

doses mon-

mediated by mu and kappa example of perceptual masking in in that U50,488 did not attenuate

that,

opioid

to

of U50,488,

effects

of an

to

contrast

in the

of

monreflect

not

et al. concluded

capable

agonist

stimulus results

a biologic

suggests

U50,488-trained

Negus

Dykstra,

probed up U50,488-trained

U50,488

effects

this

mu

(-)-metazocine

qualibeing effects

be

effects

lack

both

receptors.

effects, agonist

to

stimulus

less

to

with kappa

and neither

morphine

Negus

stimulus

by

strated

monkey

study,

of

reciprocated

the

These

effects

reflects

monkeys

that and

ago-

(7-12). However, of tifluadom was monkeys

experiment,

was

in the

and

stimulus

discriminative

varied

in a second

monkey effects

discriminative

full

a

Picker

discriminative

fentanyl

appear

not

sec

clear

Interestingly,

was

tazocine

and

high-efficacy

produced

fentanyl

2.0

stimulus

the

In the

effects

acted

both

presumably

kappa on the

it has

in

all is

characterized

the U50,488-trained probably does

of

monkeys.

mu agonists discriminative

The

et at.,

studies

as

fentanyl

because

above

In that

press).

rat

that

by

stimulus

the

Sheldon

1987;

of

mediated

Negus

have

et al., 1987;

either

produced

discriminative

trained

the 1985;

and tifluadom experiment. This

that

fentanyl

of effect

that

receptors.

with

(Leander,

1988;

tifluadom

in

fentanyl-trained

in

bremazocine

agrees

discrimination

Hayes

agonist

ARL

the

for

and

for

agonists

kappa

assays

Massie,

agonists

completely

order

in other

drug

kappa

was

potency

procedures,

mu

discriminative

demonagonist

other

dosages

ability

al., rat, the

the of the

bremazocine in the present

effects lack

and

only substituted

and

1985;

increased

masking

drugs

has been weak mu

et aL,

agonist

in

it which

by

mediated

Tifluadom

in the third to the

sensitivity

tifluadom

tatively

do

that

nonselective

1989),

monkeys.

antagonist

consistent

effects

and

fentanylagonist

be explained

can

Tifluadom antagonist and

mu

and

were

This

the

bremazocine

in the neither

keys.

the

brethat drug

et al., in press).

antagonist

keys,

that

U50,488, agonists

other

selective

nor

in

mediated

it is unlikely

results

Sewell,

Picker

effects produced

of these

receptors.

and

and

Negus

inadequate

dem-

receptors

effects

tifluadom

low to intermediate intrinsic efficacy present study, its profile of agonist and

whereas

opioid

stimulus

bremazocine

affinities

produce

in one

the

bre-

receptor.

mu

contention

order

drugs

bremazocine

1989;

the

Dykstra

both

(Leander,

that

in the

with

the discriminative et a!., in press),

by kappa

monkeys,

these

kappa

(Jackson

et at.,

in these

Rather,

the to

effects

that

effects

agree

modify (Negus

antagonist U50,488

Because

receptors.

basis

not in rats

agonists

and

with

The

monkeys

stimulus results

discriminative

nor antagonist effects effects of tifluadom opioid

doses

1987;

using

U50,488,

receptors.

less selective

et at.,

studies

for

mouse by the

at mu opioid receptors assays such as the

responding

This

ofthese

press). In addition, acted as full kappa

of fentanyl

to

potency

U50,488.

potencies

consistent

agonist

fentanyl-trained

discriminative These

up

The

>

ability

stimulus.

tifluadom

U50,488-appropriate

Hayes

support efficacy sensitive

and

tifluadom

of the

the that

at the

effects

monkeys,

bremazocine

relative

in

reversed

procedure.

producing

between uganda

conacts

suggesting

agonist

U50,488-trained

in

substituted

probed

in the

U50,488 of morphine

opioid

The

was

sec

monkeys.

that effects

stimulus

2.0 clear

U50,488-trained

onstration

U50,488

above

detected

discrimination

>

monkeys. This lack of agonist or antagwas probably not a result of inadequate

as

ARL

liminal only in

effects

to the

effects

further

have

an intrin-

the

neither

stimulus

results may

agonists

U50,488

some

training

to produce full-agonist that the squirrel monkey sensitive

present

effects

be partially

f3-funaltrexamine,

produce

the

a discussion

Furthermore,

is highly

procedure

fentanyl-trained effects by U50,488

onist

for

efficacies).

effects of mu receptor ligands. The selective kappa agonist nor antagonized the discriminative

have

et

analgesic could

test

study

bremazocine

(Corbett and Kosterlitz, Hayes and Birch (1988)

However,

antagonist

may

U50,488,

Cowan

1989).

present

that

receptors

bremazocine’s

mu

In the

depend-

is intermediate and high efficacy

1987,

to

at mu

aL,

in the

indicating

constriction

mazoeme can be

example,

1970;

et

abdominal

The

reported

assay-dependent

(-)-metazocine study suggests

present

discrimination

Villarreal,

naloxone

Kenakin,

partial

bremazocine

studies

antagonist

that

mazocine

(-)-me-

in monkeys

that

Craft

administration

(-)-metazocine

receptors

such

been

chronic

These and

(see

of buprenorphine

1969;

1981).

opioid

fentanyl

determination

after

et a!.,

aL,

the

For

have

1986;

selective

and

activity.

as an

other

with at

has

this kappa

affinity of not been

racemic metazocine with moderate affin1982). In (-)-metazocine (Berzetei-Gurski

addition, can and

Downloaded from jpet.aspetjournals.org at ASPET Journals on August 30, 2016

efficacy

such

agonist

purely

mu

a

Negus

by

effects

with

reported

1989; with

agonist

trasts

agree with act as full using

contrast

withdrawal

buprenorphine

sic efficacy low

mu

dependence

(Ager

Dum that

suggest

fist

mu

and

bupren-

Dykstra,

(-)-metazocine

to precipitate

morphine

fentanyl,

of buprenorphine

of

and

little

of

and

results

effects

buprenorphine

not

(Young Negus

procedures

(Picker

these

antagonist

in

both

effects

discrimination

However,

and

agonist

they

1986;

in the present study that these compounds

mu

et at.,

agonist

(-)-metazocine

studies

and

species

et al.,

1988).

orphine

drug

in other

Interactions

1991 Loew,

1990)

results

concur

and

a low-efficacy the

indicating

tanyl

and

more,

naloxone

U50,488

were

of

for et al.,

mu 1982)

training

in

results

monkeys. antagonism

both stimulus more

potent

receptors

of

selectivity

(Wood et al., the contention

supports

effects

effects 1981;

that

of fentanyl

are mediated

by

of U50,488

are

by

mediated

even sec,

produced

group

of

(Barry, data

fects

et al.,

indicating

do

by either

The in both 2-fold

of the

U50,488-trained

difference

in

monkey

7-9

no.

kappa

and

agonists

trained with with previous

increases,

training

no. potent

et aL,

1990).

phine,

(-)-metazocine

potent

in

of with the

lower

training

dose

in

in monkey

7-14.

This

U50,488 phine

than

was

7-9

fects

of

the

1.7

than

mg/kg

of

rightward

dose-effect

buprenorphine

shifts

in both

In conclusion,

this

characterized produce

as interacting

ination procedure. on drug-dependent observed selectivity highly

each

biologic

only for

resulted

in

potency doses of monkeys buprenor-

of

the

U50,488

in

stimulus

7-14,

ef-

redetermination

pretreatment

either effects

presents mu

equivalent

However,

between

or

squirrel

these

mechanisms

agonists

evidence

agonists

in the

(see

la)

involving and

stimulus

the

fig.

receptors.

The U50,488 effects

discriminative

that

kappa monkey

interactions

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