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Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with with permission permission of the of copyright the copyright owner. owner.Further reproduction Further reproduction prohibited without prohibited permission. without permission. AN ASSESSMENT OF NALORPHINE’S RELATIVE OPIOID EFFICACY WITHIN
A CHOLECYSTOKININ DRUG DISCRIMINATION PROCEDURE
by
Sheri D. Grabus
submitted to the
Faculty of the College of Arts and Sciences
of American University
in Partial Fulfillment of
the Requirements for the Degree of
Master of Arts
in
Psychology
Chair: Anthony L J i j i
John R. Glowa
Dean of the College ft f a k /tftf
1998
American University
Washington, D.C. 20016
THE AMERICAN UNIVERSITY LIBRARY
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Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. AN ASSESSMENT OF NALORPHINE’S RELATIVE OPIOID EFFICACY WITHIN
A CHOLECYSTOKININ DRUG DISCRIMINATION PROCEDURE
BY
Sheri D. Grabus
ABSTRACT
The partial agonist nalorphine appears to lie between naloxone (with little
intrinsic activity) and morphine (with full intrinsic activity) on a continuum of
relative efficacy (Smurthwaite & Riley, 1995). However, it is unclear whether
nalorphine is more like naloxone or morphine. Using a drug discrimination
procedure (Melton & Riley, 1993) that differentiated opioid antagonists and
agonists on the basis of their ability to potentiate or block, respectively, CCK
stimulus control, the present experiment attempted to assess nalorphine's
relative efficacy. Nalorphine acted as an antagonist (i.e., potentiated CCK's
stimulus properties) for some animals and as an agonist (i.e., blocked CCK
stimulus control) for others, indicating that nalorphine may lie near the
endogenous opiates on the continuum of relative efficacy. That is, in some
animals nalorphine has less efficacy (i.e., acts as an opioid antagonist) and in
others equal or greater efficacy than the endogenous opiates (i.e., acts as an
opioid agonist).
ii
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS
All my gratitude to Tony Riley for his persistence, wisdom and support
during this long process. In addition, thanks to the remainder of my committee
members, Scott Parker and John Glowa, for their input and advise.
iii
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS
ABSTRACT...... ii
ACKNOWLEDGEMENTS...... iii
LIST OF ILLUSTRATIONS...... v
Chapter
I. INTRODUCTION...... 1
II. M ETHO D...... 5
Subjects ...... 5
Apparatus...... 5
Drugs...... 6
Procedure ...... 6
Data Analysis...... 9
III. RESULTS...... 11
Acquisition ...... 11
Generalization ...... 11
CCK/Nalorphine Interactions ...... 15
IV. DISCUSSION...... 21
BIBLIOGRAPHY...... 32
iv
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF ILLUSTRATIONS
1. Amount of saccharin consumed for individual subjects in Group L and for five subjects in Group W following various doses of CCK during generalization testing ...... 12
2. Amount of saccharin consumed for individual subjects in Group L and for five subjects in Group W following various doses of nalorphine during generalization testing ...... 14
3. Amount of saccharin consumed for individual subjects in Group L following various doses of nalorphine in combination with a dose of CCK that produced intermediate levels of saccharin consumption when administered alone ...... 16
4. Amount of saccharin consumed for individual animals in Group L at their training dose of CCK and at an ineffective dose of nalorphine combined with the training dose of CCK ...... 18
5. Amount of saccharin consumed for a single subject in Group L in which various doses of nalorphine were given in combination with the training dose of CCK ...... 20
v
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER I
INTRODUCTION
Partial opioid agonists are compounds that possess opioid activity, yet are
not as efficacious as full agonists in their behavioral and physiological effects
(Martin, 1967; Colpaert, 1986). As such, these compounds produce weak
agonist effects when administered alone but decrease the effects of full agonists
when given in combination (by preventing full agonists from binding to the
receptor) (Holtzman, 1985). One such partial agonist is nalorphine. For
example, nalorphine produces analgesia and respiratory depression (i.e., has
opioid agonist activity), but when given in combination with morphine it blocks
morphine's analgesic and respiratory depressive effects (i.e., demonstrates
opioid antagonist activity) (Martin, 1967). In addition to demonstrations within
these preparations, researchers have also examined nalorphine's partial agonist
activity within drug discrimination learning, a design in which drugs serve as
discriminative stimuli to control behavior (for reviews, see Overton, 1971;
Colpaert, Niemegeers & Janssen, 1975; Schuster & Balster, 1977; Jarbe &
Swedberg, 1982; Holtzman, 1985; Overton, Leonard & Merkle, 1986; Jarbe,
1987; Preston & Bigelow, 1991; Goudie & Leathley, 1993; Stolerman, 1993; fora
bibliography on drug discrimination learning, see Stolerman, Samele, Kamien,
Mariathasan & Hague, 1995). In this preparation, once an animal acquires the
1
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discrimination (e.g., pressing one lever for reinforcement in the presence of the
drug stimulus and another lever for reinforcement in the absence of the training
drug), other drugs may be administered alone or concurrently with the training
drug to determine whether these compounds share, potentiate or block the
stimulus properties of the training drug (Overton, 1971; Colpaert et al., 1975;
Schuster & Balster, 1977; Holtzman, 1985; Overton etal., 1986; Jarbe, 1987;
Goudie & Leathley, 1993; Stolerman, 1993). This procedure, therefore, is useful
in classifying compounds that are agonists or antagonists of the specific training
drug utilized. Using a drug discrimination procedure, Holtzman (1985)
demonstrated that in rats trained to discriminate 3 mg/kg morphine from saline in
a two-choice discrete-trial avoidance procedure, nalorphine partially substituted
for the training stimulus, i.e., nalorphine engendered 50% morphine-appropriate
responding. In these same subjects, when various doses of nalorphine were
given in combination with morphine (0.03-3 mg/kg), nalorphine blocked
morphine's subjective effects, i.e., the generalization curve obtained converged
upon the original partial generalization curve for nalorphine determined in the
absence of morphine (Holtzman, 1985). Nalorphine, thus, appears to have
efficacy at the mu receptor between that of a pure antagonist (like naloxone) and
that of a full agonist (like morphine) (Picker, Smith & Morgan, 1994; Smurthwaite
& Riley, 1995).
The specific question addressed in the present experiment is where along
this continuum of relative efficacy nalorphine lies, i.e., is it more like naloxone or
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3
morphine. The procedure used in this assessment was recently described by
Melton and Riley (1993; see also Melton & Riley, 1994 ; Riley & Melton, 1997) in
their analysis of the effects of opioid agonists and antagonists on the stimulus
properties of the gut peptide, cholecystokinin (CCK). Melton and Riley utilized
the conditioned taste aversion baseline of drug discrimination learning (see
Mastropaolo, Moskowitz, Dacanay & Riley, 1989; Riley eta l., 1991; Stevenson,
Pournaghash & Riley, 1992; Sobel, Wetherington & Riley, 1995; Riley, 1995;
Riley, 1997 for reviews of the aversion baseline) to train subjects to discriminate
CCK from its vehicle. Specifically, animals were injected with CCK prior to a
saccharin-LiCI pairing and with just the CCK vehicle prior to saccharin alone.
Under these conditions, subjects learned to avoid the saccharin solution when it
was preceded by CCK and consume the same solution when preceded by the
drug's vehicle. When naloxone was administered in combination with CCK, it
potentiated CCK's stimulus properties. That is, animals avoided the saccharin
solution when it was preceded by naloxone plus an ineffective dose of CCK (i.e.,
one that had no effect on consumption). In contrast, when morphine was
administered in combination with CCK, it blocked CCK's stimulus properties.
That is, animals consumed the saccharin solution when it was preceded by
morphine plus the training dose of CCK. These differential effects of opioid
antagonists and agonists on CCK's stimulus effects are consistent with reports of
the interaction of the opioids and CCK within other preparations (see Itoh &
Katsuura, 1981; Fan's, Komisaruk, Watkins & Mayer, 1983; Wilson, Denson,
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4
Bedford & Hunsinger, 1983; Fan's, 1985; Dourish, Coughlan, Hawley, Clark &
Iverson, 1988; Barbaz, Hall & Liebman, 1989; Kapas, Benedeck & Penke, 1989;
Li & Han, 1989; Dourish etal., 1990; Hoffmann & Wiesenfeld-Hallin, 1994) and
suggest that the CCK drug discrimination baseline is useful in classifying the
opioids in terms of their antagonist and agonist properties.
Given the differential effects of opioid agonists and antagonists in CCK-
trained animals, it is possible that nalorphine's relative efficacy may be revealed
within this preparation. That is, if nalorphine is more like an opioid antagonist
(i.e., like naloxone) it would be expected to potentiate CCK’s stimulus properties.
In contrast, if nalorphine is more like an opioid agonist (i.e., like morphine) it
would be expected to block CCK’s stimulus effects. To determine nalorphine's
effects on CCK's discriminative control, in the present experiment animals were
trained to discriminate CCK from its vehicle within the conditioned taste aversion
baseline of drug discrimination learning. Once subjects acquired the
discrimination, they were given nalorphine (alone and in combination with CCK)
to assess its ability to potentiate (like an opiate antagonist) or block (like an
opiate agonist) CCK's stimulus effects.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER II
METHOD
Subjects
Subjects were ten experimentally naive, female rats of Long-
Evans descent, approximately 210-290 g at the start of the experiment. They
were housed in individual wire-mesh cages and maintained on a 12-h L:12-h D
cycle and at an ambient temperature of 23°C for the duration of the experiment
Rat chow (Prolab Rat, Mouse, Hamster 3000) was available ad libitum.
Apparatus
For Subjects 1 and 3-8, experimental sessions were conducted in one of six
identical 25 x 30 x 18-cm Plexiglas operant chambers; experimental sessions for
Subjects 2 and 9-10 were conducted in their home cages. The floor of each
operant chamber consisted of 13 stainless-steel rods (19 x 0.5 cm) spaced 2 cm
center to center. The front wall of the chamber contained three horizontal holes,
the center of which allowed access to a stainless-steel drinking tube (a blunted
23-gauge needle). Responses (tube licks) were registered by a Lafayette
drinkometer (Model 58008) whenever a circuit was completed between the
chamber floor and the drinking tube. A white light was placed 1 cm below the
drinking tube, and a white houselight was centered 9 cm above this opening. A
5
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solenoid valve (General Valve Corp., Model 3) attached via Tygon tubing (14-
169-la) to a fluid reservoir (60-cc syringe) controlled the delivery of a water
reinforcer to the drinking tube. Experimental sessions were programmed on an
Apple IIGS computer, which also recorded all responses made during the
experimental sessions. The computer was interfaced to ail six operant chambers
through a Med Associates interface (Model 1080-01).
Drugs
The sulfated form of cholecystokinin octapeptide (generously supplied by
the Squibb Institute) and nalorphine hydrochloride (generously supplied by the
National Institute on Drug Abuse) were dissolved in distilled water and injected
intraperitoneally (ip) in a volume of 0.18 -1 ml/kg and 1 ml/kg of body weight,
respectively.
Procedure
Phase I: Acquisition
At the outset of training, subjects were given restricted access to water for
23 consecutive days in their home cages. During this period, the duration of
water access was decreased from 20 min (Days 1-8) to 10 min (Days 9-16) to
the final value of 5 min (Days 17-23). On Day 24, Subjects 1 and 3-8 were
placed in operant chambers; Subjects 2, 9 and 10 remained in their home cages.
Within the chambers, water access was again decreased from 20 min (Days 24-
25) to 10 min (Day 26) to the final value of 5 min (Days 27-36); Subjects 2, 9 and
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7
10 continued to receive 5-min water access in their home cages during this
period. On Days 37-39, a novel saccharin solution (0.1% w/v saccharin sodium
salt, Sigma Chemical Co., St. Louis, MO) replaced water during the 5-min
access period (saccharin habituation) and was preceded on the last day of
saccharin habituation by an ip injection of distilled water (0.56 ml/kg).
On Day 40, all subjects were given an ip injection of 5.6 uglkg CCK 5 min
prior to 5-min saccharin access, immediately following saccharin access,
subjects were ranked according to saccharin consumption (i.e., from lowest
consumption to highest) and assigned to one of two groups (Groups L and W, n
= 5 per group). Subjects in Group L were given an ip injection of 1.8 mEq/0.15 M
LiCI (76.8 mg/kg), while subjects in Group W were given an equivolume injection
of the distilled water vehicle. On the following three days, all subjects were
injected with distilled water (0.56 ml/kg) 5 min prior to saccharin access. No
injections were given following saccharin access on these recovery days. This
alternating procedure of one conditioning session (CCK-saccharin-LiCI or CCK-
saccharin-distilled water) followed by three recovery sessions (distilled water-
saccharin) was repeated until discriminative control had been established for all
experimental subjects (i.e., each subject in Group L had consumed at least 50%
less than the mean of Group W on two consecutive conditioning trials). One
subject (Subject 4) did not acquire the CCK vs. vehicle discrimination, so the
training dose for this subject (and for one subject in Group W) was increased to
7.5 i/g/kg.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8
Phase II: Generalization
The procedure followed in this phase was identical to that of Phase I with
one exception. On the second day following conditioning (the second recovery
day within Phase I, but a probe day in this phase), subjects were administered
one of a range of doses of CCK (0.0-10 ug/kg) or nalorphine (0.56-18 mg/kg) 5
or 10 min prior to saccharin access, respectively. A subject in Group L was
tested only if its consumption was 50% or less than the mean of control subjects
for the two preceding conditioning trials. Individual subjects in Group L were
tested up to the dose that decreased consumption to drug-appropriate levels for
that particular subject (maximum doses of CCK and nalorphine were 10 ug/kg .
and 18 mg/kg, respectively); the dose tested was decreased by 1/4 or 1/8 log
doses to one that produced vehicle-appropriate responding. Individual subjects,
therefore, differed in the doses of each drug that were tested. Subjects in Group
W received all doses administered to any subject in Group L. No injections
followed these probe sessions.
Phase III: CCK/Nalorphine Interactions
The procedure during this phase was identical to that of Phase II except
that on the second day following conditioning (i.e., the probe day) one of a range
of doses of nalorphine was administered 5 min prior to an intermediate dose of
CCK (one that produced neither vehicle- nor drug-appropriate levels of
consumption for the subject under examination), which in turn was administered
5 min prior to saccharin access. This portion of Phase III examined whether
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9
nalorphine potentiated CCK’s stimulus properties for subjects in Group L. That
is, since the intermediate dose of CCK alone produced levels of consumption for
individual subjects in Group L that were approximately 50% of the mean amount
consumed by controls, it would be hard to interpret increases in consumption for
Group L following the nalorphine/CCK combination (i.e., blocking). In the second
portion of this phase, an ineffective dose of nalorphine (one that produced
vehicle-appropriate responding) was administered 5 min prior to the training
dose of CCK. This portion of Phase III examined whether nalorphine blocked
CCK's stimulus properties for subjects in Group L. Potentiation was not
determined, since it would be difficult to define potentiation at the training dose of
CCK (i.e., consumption levels were already reduced to levels approaching 0 ml).
Dose combinations differed for individual subjects in Group L, since the doses of
CCK and nalorphine chosen were based upon results from Phase II (see above).
Subjects in Group W received all dose combinations administered to any
subject in Group L. No injections followed these probe sessions.
Data Analysis
Discriminative control by CCK was demonstrated on conditioning days
when consumption for a subject in Group L following CCK administration was
50% or less than the mean amount consumed by Group W following CCK. For
individual subjects in Group L, various doses of nalorphine were considered to
substitute for the training dose of CCK within the generalization phase when
consumption following nalorphine was 50% or less than the mean of control
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 10
subjects following this dose of nalorphine. Finally, for Phase III (CCK/Nalorphine
interactions), nalorphine was considered to have potentiated the stimulus effects
of an intermediate dose of CCK when nalorphine in combination with CCK
produced levels of consumption for individual subjects in Group L that were 50%
or less than the mean amount consumed by Group W following the same drug
combination. Nalorphine was considered to have blocked the stimulus effects of
the training dose of CCK when nalorphine in combination with CCK produced
levels of consumption for individual subjects in Group L that were greater than
50% of the mean amount consumed by Group W following the same drug
combination. Consumption by subjects in Group W under conditions similar to
those of Group L was also examined to evaluate the unconditioned effects of
nalorphine and CCK, both alone and in combination.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER III
RESULTS
Phase I: Acquisition
Experimental subjects acquired the CCK discrimination (i.e., drinking less
than 50% of the mean of control subjects for at least two consecutive
conditioning trials) within 20 trials. Mean consumption (+/- SEM) on conditioning
days was determined for individual subjects within Group L and for the compiled
subjects in Group W by averaging the amount consumed on the two conditioning
trials prior to each probe and ranged from 0.1 to 1.3 ml for subjects in Group L
and from 4.8 to 7.1 ml for subjects in Group W. Mean consumption (+/- SEM) on
recovery days was determined for individual subjects within Group L and for the
compiled subjects in Group W by averaging the amount consumed on the
recovery days prior to each probe and ranged from 6.1 to 9.1 mi for subjects in
Group L and 4.8 to 9 ml for subjects in Group W.
Phase II: Generalization
Figure 1 represents the amount (or mean amount, +/> SEM, if a particular
probe was repeated) of saccharin consumed for individual subjects in Group L
and the mean (+/- SEM) amount of saccharin consumed by subjects in Group W
following various doses of CCK. As indicated, all subjects in Group L decreased
11
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 12
V-Recovery D-Conditioning GROUP L GROUP W
RA£ #2 RAT # 3 lo RAT #1 g m s' T\ 7- 6- -Q -. - o S --E 5- \ *□ 4- 3-
2 - 1 - Cl T— ¥ —------l 1--- 1— W~ n ------1------1- 1------1— T ¥ ---- 1 1----1----1--- V D 0.0 1.8 3.2 5.6 V D 1.8 3.2 5.6 V D 3.24.2 5.6 7.5 10 io- RAT # 4 RAT #5 9- 3 T C/5 8- Z a o 7- X'-. u 6- o i S - a . . 5- ■ **. '□ 4- 3- 2- 1 ■ 0- 1 1 1 1 1 1 1- 1— ¥ — i— i— i—¥ “ V D 0.0 3.25.67.5 10 V D 0.0 1.8 3.2 5.6
CCK DOSE (u g /kg )
FIG. 1. Amount o f saccharin consumed for individual subjects in Group L (filled squares; + /- SEM if a probe was repeated) and for 5 subjects in Group W (open squares; + / - SEM) following various doses o f CCK during generalization testing (Phase II). V and D points at the left o f each graph indicate the mean amount of saccharin consumed ( + /- SEM) for individual subjects in Group L and for 5 subjects in Group W on recovery and conditioning days, respectively (Phase I). All subjects in Group W were probed at all doses at which any subject in Group L was tested, although each graph shows only those probes completed for an individual subject in Group L (compared to the same doses probed for 5 subjects in Group W).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 13
saccharin consumption as the dose of CCK increased. Control subjects
displayed a slight decrease in saccharin consumption over increasing doses of
CCK, but this decrease was not as dramatic as that seen in Group L. At lower
CCK doses (0.0 -1.8 ug/kg), consumption by subjects in Group L did not differ
from that of Group W (i.e., consumption for individual subjects in Group L did not
decrease to 50% less than the mean amount consumed by Group W ). However,
at higher doses (3.2 - 10 ug/kg) differences in consumption began to appear.
That is, at these doses subjects in Group L consumed at least 50% less than
subjects in Group W. The dose at which this 50% difference became apparent
differed for individual subjects.
Figure 2 presents the amount of saccharin consumed by individual subjects
in Group L and the mean (+ /- SEM) amount of saccharin consumed by subjects
in Group W following various doses of nalorphine. As shown, individual subjects
in Group L differed as to whether or not nalorphine substituted for CCK stimulus
control (i.e., as to whether consumption for individual subjects in Group L
following nalorphine was 50% or less than the mean amount consumed by
Group W). Specifically, Subjects 1, 2 and 4 generalized CCK stimulus control to
nalorphine, decreasing consumption as the dose of nalorphine increased (i.e.,
like CCK). In contrast, CCK control did not generalize to nalorphine for Subjects
3 and 5. In these subjects, as well as in controls, increasing doses of nalorphine
only slightly decreased saccharin consumption.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 14
* GROUP L
— □ — ' GROUP W
10' RAT #1 RAT # 2 RAT # 3 9 8 7 6 5- 9 - 5 H X 4-
w£ 2- 3 ' O T "i— i— i— i— i— r- “i------r E ° ‘ z .56 1.0 1.8 3.2 5.6 10 1.8 10 18 1.8 3.2 5.6 10 18 3 in RAT # 4 RAT #5 uo 10n 9-
8 - 7 -
6 - 5 - 4 - 3 -
2 - 1 - 0J“ i ------1 1------1------r~ - i 1------1------1------1------r ~ 3.2 5.6 7.5 10 18 1.0 1.8 3.2 5.6 10 18 NALORPHINE DOSE (MG/KG)
FIG. 2. Amount of saccharin consumed for individual subjects in Group L (filled squares; + /- SEM if a probe was repeated) and for 5 subjects in Group W (open squares; + /- SEM) following various doses of nalorphine during generalization testing (Phase II). All subjects in Group W were probed at all doses at which any subject in Group L was tested, although each graph shows only those probes completed for an individual subject in Group L (compared to the same doses probed for 5 subjects in Group W).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 15
Phase III: CCK/Nalorohine Interactions
Figure 3 illustrates the amount of saccharin consumed for individual
subjects in Group L and the mean (+/> SEM) amount consumed by subjects in
Group W when various doses of nalorphine were combined with CCK. As
illustrated, for three subjects (i.e., Subjects 1, 2 and 3) nalorphine potentiated the
stimulus properties of a dose of CCK that had intermediate effects when
administered alone (i.e., doses of CCK that produced levels of consumption that
were intermediate between levels consumed on training and recovery days
based on Phase II). For these subjects, consumption following the
nalorphine/CCK combination was 50% or less than the mean amount consumed
by Group W following the same combination. The amount consumed at the
intermediate CCK doses are depicted at the 0 mg/kg dose of nalorphine (i.e., the
nalorphine vehicle). The lowest dose at which nalorphine potentiated CCK’s
stimulus properties differed among subjects and ranged from 1.0 to 5.6 mg/kg.
In one subject (Subject 4), nalorphine generally had no effect on CCK’s stimulus
properties. For this subject, consumption following the combination was the
same as that following CCK alone. There may have been potentiation at the
highest dose of nalorphine for Subject 4 (i.e., 18 mg/kg; data not shown);
however, at this dose of nalorphine alone (see Figure 2), consumption was
already reduced. Therefore, any further reductions may be difficult to attribute to
a potentiation of CCK’s stimulus properties. Subject 5 died before this portion of
the experiment could be completed, so data for this subject are not shown.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. without prohibited reproduction Further owner. copyright the of permission with Reproduced
CONSUMPTION (ML) All subjects in Group W were probed at all dose combinations at which any subject in subject any which at combinations dose all at probed were GroupinW subjects All subjects in GroupinW). subjects an for completed probes those only shows graph each although tested, was L Group 18 - (0.0 nalorphine of doses various following squares) (filled GroupL in subjects SEM) of saccharin consumed for subjects in Group W is represented by open squares. open by /- represented is W (+ Group in amount mean subjects The for saccharin consumed of SEM) alone. administered when consumption saccharin of levels individual subject in Group L (compared to the same dose combinations probed for 5 for probed combinations dose same the to (compared L Group in subject individual gk) ncmiainwt ads C (oe i isr) htpoue intermediate produced that insert) in CCK (noted f o dose a with incombination individual for mg/kg) repeated) was probe a SEM, if /- (+ Saccharinconsumption FIG3. o- io - 4 2 6 - 7 8 - 5 - 9 - - - T 4.2 ug/kgCCK 4.2 3.2 ug/kgCCK 3.2 0.0 RAT #1 RAT RAT #3 RAT 1.0 AOPIEDS ( KG) G /K G (M DOSE NALORPHINE 3.2 - . 18 . 56 0 18 10 5.6 3.2 1.8 0.0 0.0 3.2 ug/kg CCK ug/kg 3.2 3.2 ug/kg CCK ug/kg 3.2 r ~ T ~ 3.2 — — A 4 # RAT A 2 # RAT -' T 5.6 GROUP W GROUP GROUP L GROUP 7.5 —r~ 10
16
17
However, the results collected from this subject were similar to those of Subject
4, in that consumption following the combination was the same as that following
CCK alone. Specifically, nalorphine (3.2 mg/kg), when combined with this
subject’s intermediate dose o f CCK (i.e., 1.8 ug/kg), failed to affect CCK stimulus
control. Overall, controls showed modest decreases in saccharin consumption
following the nalorphine/CCK combination, although these decreases were not
consistent or as dramatic as those seen in Group L.
Figure 4 illustrates the amount of saccharin consumed for individual
subjects in Group L following an ineffective dose of nalorphine (i.e., one at which
subjects consumed levels that were +/- 2 ml from vehicle levels) combined with
the training dose of CCK. Subject 1 died before this portion of the phase could
be completed, so data for this animal are not shown. For two subjects (Subjects
4 and 5), nalorphine blocked CCK stimulus control. Specifically, following the
nalorphine/CCK combination, these subjects consumed amounts that were
greater than 50% of the mean amount consumed by Group W following the
same drug combination. Interestingly, in the previous manipulation (see Figure
3) nalorphine failed to potentiate CCK’s stimulus properties for Subject 4. For
one subject (Subject 2), nalorphine also may have blocked CCK stimulus control
(i.e., this subject consumed levels that were greater than 50% of the mean
amount consumed by Group W ). However, following the drug combination, this
subject drank an amount only slightly above the 50% criteria (i.e., Subject 2
consumed 3 ml while controls drank a mean of 5.5 ml). In contrast, for one
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 18
□ CCK ALONE (GROUP L) S I NALORPHINE + CCK (GROUP L) □ NALORPHINE + CCK (GROUP W) RAT # 2 RAT #3 8 -
7 - 5.6 mg/kg Nalorphine +• 10 mg/kg Nalorphine + 5.6 ug/kg CCK 5.6 ug/kg CCK 6
5 -
4 -
3 - > ■%.%*v■ s ■ s "S■
2 - ■AMMMM yI• s»%■fW s«s■ r tw \* y %« ■ % ■ s • % ■ s ■ % ■ 1 - 1 ■s• % /?/■«s■%«s■% /> ^ • J* .
Z o RAT # 4 RAT #5 3 8 “I 5.6 mg/kg Nalorphine + 3.2 mg/kg Nalorphine + (/5 7.5 ug/kg CCK 5.6 ug/kg CCK O 7“ u 6 -
5 - W M 'P iV ■S»%■ % ■ V ■ ■ s ■ % ■ > ■ S ■ %■ % ■ %1 4 -
•S • S ■%<%■V ■ V ■ 3 - 'MVW l'lV ,%" S "V■ % • S \% ■ %1 '■ .'•.'•.'W lV y y y M fW ' MAMMla•S"V"%*%»V*S 2 - V"% 1 - jpP P P P l tv>vv>%>%>v 0- a-.vagtt-.y.vi
FIG 4. Amount of saccharin consumed (+ /- SEM) for individual animals in Group L at their training doses o f CCK (left column) and at an ineffective dose of nalorphine combined with the training dose of CCK (middle column; + /- SEM if probe was repeated). Mean amount of saccharin consumed (+ /- SEM) for Group W following the nalorphine/CCK drug combination is indicated in the right-most column. All subjects in Group W were probed at all dose combinations at which any subject in Group L was tested, although each graph shows only the probe completed for an individual subject in Group L (compared to the same drug combination for 5 subjects in Group W). Doses o f each drug are in inserts.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 19
subject (Subject 3), nalorphine did not block CCK control. Specifically, this
subject consumed levels that were less than 50% of the mean amount
consumed by Group W. In the previous manipulation (see Figure 3), nalorphine
potentiated CCK’s stimulus properties in both Subjects 2 and 3. In the current
manipulation, it would be unlikely that potentiation would be observed, since
reductions in consumption below those observed at the training dose would be
difficult to produce. Given the earlier results for these subjects it would not be
expected that nalorphine would block CCK stimulus control in the current
manipulation. In controls, these combinations had no effect upon CCK (i.e.,
consumption following the combination were the same as that following CCK
alone; data not shown).
Figure 5 illustrates a single subject (i.e., Subject 5) for which various doses
of nalorphine were given in combination with the training dose of CCK. As
shown, all doses of nalorphine (i.e., 1.0 - 5.6 mg/kg) blocked the training dose of
CCK (5.6 ug/kg). For this animal, consumption following nalorphine in
combination with the training dose of CCK converged upon consumption by
Group W following this combination.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 20
' RAT # 5
— □ — GROUP W
RAT #5 10-1
9 - 5.6 ug/kg CCK
8 - 7 -
6 - z o fc 3z 4 - to z <_}o
2 -
0.0 1.0 1.8 3.2 5.6
NALORPHINE DOSE (MG/KG)
FIG 5. Amount of saccharin consumed for a single subject in Group L (filled squares) in which various doses of nalorphine were given in combination with the training dose of CCK (noted in insert). The mean amount ( + /- SEM) of saccharin consumed by 5 subjects in Group W is represented by open squares.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CHAPTER IV
DISCUSSION
Although nalorphine has greater intrinsic activity than that of an antagonist
but less than that of a full agonist, it is not clear where along the continuum of
relative opioid efficacy nalorphine lies, i.e., whether nalorphine is more like a
pure antagonist (a compound with zero efficacy) or a full agonist. Using a drug
discrimination procedure (Melton & Riley, 1993; see also Riley & Melton, 1997)
that differentiated opioid antagonists and agonists on the basis of their ability to
potentiate or block, respectively, CCK stimulus control, the present experiment
attempted to assess nalorphine’s relative efficacy. Specifically, it was suggested
that if nalorphine was more like an antagonist (i.e., like naloxone), it would
potentiate CCK’s stimulus effects. Conversely, if nalorphine was more like an
agonist (i.e., like morphine), it would block CCK’s stimulus effects. As described,
in the present experiment nalorphine potentiated CCK’s stimulus properties (like
naloxone) in some animals while it blocked CCK control (like morphine) in
others. Thus, in this experiment, nalorphine appeared to act as an opioid
antagonist for three subjects, while for two subjects it acted as an opioid agonist.
One explanation for these results may be that nalorphine’s efficacy lies near
a point on the continuum of efficacy at which endogenous opiates lie.
Compounds that possess less intrinsic efficacy than the endogenous opiates
21
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. /
22
would block endogenous “tone” (i.e., the effects produced by constant, low-level
release of endogenous opiates) to produce a distinct behavioral state. That the
blocking of endogenous tone produces a distinct behavioral state is supported by
the fact that the opioid antagonist naloxone can serve as a discriminative cue in
opioid-naive subjects (Kautz et al., 1989; Smurthwaite, Kautz, Geter & Riley,
1991). In contrast, compounds that lie at or above the endogenous opiates on
the continuum would act as opioid agonists (e.g., morphine). As such, these
compounds should produce behavioral effects similar to those of morphine, with
the strength of the agonist effect dependent upon the amount of distance the
compound lies above the endogenous opiates (i.e., the greater its intrinsic
efficacy, the more it is like morphine). That nalorphine acts as an antagonist or
agonist in different subjects suggests that nalorphine possesses efficacy similar
to that of the endogenous opiates, with its ability to act as either an agonist or
antagonist dependent upon whether its efficacy is less than or greater than that
of the endogenous opiates for the specific animal under observation.
If nalorphine lies near the endogenous opiates on the continuum such that
nalorphine's efficacy for individual animals falls either slightly below, at or above
these compounds, it might be expected that individual differences within drug
discrimination learning would be greater for nalorphine (and possibly other partial
agonists) than for full antagonists or agonists, neither of which possesses
efficacy similar to that of the endogenous opiates. That is, slight deviations in
individuals relative to the endogenous opiates could cause nalorphine to be
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 23
perceived as either an antagonist or agonist, depending upon whether
nalorphine has lesser or equal/greater efficacy than the endogenous opiates for
the particular subject. In contrast, slight differences in efficacy for individual
animals for full antagonists and agonists would not alter their perceived
antagonist or agonist effects, respectively, since these two compounds lie at
extremes on the continuum. Because of their positions on the continuum, a pure
antagonist would consistently act as an antagonist and a full agonist would
always act as an agonist, regardless of whether individual differences in efficacy
exist for these compounds. Consistent with this, it has been demonstrated that
individual differences are greater for partial than for full agonists in drug
discrimination learning (Picker et al., 1993; Morgan & Picker, 1996). For
example, in rats trained to discriminate 3.0 mg/kg morphine from saline there
were minimal differences among individuals in the lowest doses of morphine and
fentanyl that served as discriminative cues (see Morgan & Picker, 1996).
Specifically, subjects showed a three-fold (i.e., from 1.0 to 3.0 mg/kg) and a ten
fold (i.e., from 0.01 to 0.1 mg/kg) difference in the lowest dose of morphine and
fentanyl that substituted for the morphine training stimulus, respectively. In
contrast, there were large individual differences in the relative potencies for the
partial agonists nalbuphine and levallorphan (for a description of the partial
agonist effects of these compounds, see Holtzman, 1985). Specifically, there
was a 1,000-fold (i.e., from 0.1 to 100 mg/kg) and a 30-fold (i.e., from 0.3 to 10
mg/kg) difference in the lowest dose of nalbuphine and levallorphan that
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 24
substituted for the morphine training stimulus, respectively (although two animals
failed to show complete substitution even at the highest dose of levallorphan
tested). Further, large interanimal differences in antinociception were
demonstrated for the partial agonists (i.e., butorphanol, nalbuphine and
levallorphan) but not for the full agonists (i.e., morphine and fentanyl) (Morgan &
Picker, 1996).
Similarly, individual differences have been shown when subjects were
trained to discriminate either fentanyl (Colpaert & Janssen, 1984; Picker &
Dykstra, 1989; Picker e ta l., 1993) or morphine (Herling, Coale, Valentino, Hein
& Woods, 1980; Holtzman, 1985; Riley & Smurthwaite, 1995) from saline.
Specifically, subjects differed as to whether nalorphine substituted for or
antagonized these compounds. That is, in some studies subjects showed
complete substitution for the full agonist, whereas in others only partial and/or
non-substitution plus antagonism was seen. Although these different
substitution patterns may reflect different parameters used in each study (i.e.,
training dose utilized, whether rats or pigeons were used as subjects),
interestingly, other studies assessing partial agonist efficacy have demonstrated
clear individual differences within the same preparation. Specifically, within the
same study individual animals differed as to whether partial agonists substituted
for a full agonist training compound (Colpaert, 1988; Picker et al., 1993; Morgan
& Picker 1996), although other full agonists consistently substituted for this
training compound for all subjects (Picker etal., 1993). For example, in pigeons
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 25
trained to discriminate 0.18 mg/kg fentanyl from saline, subjects differed as to
whether the partial mu agonists profadol and meperidine (for a description of the
partial agonist effects of these compounds, see Holtzman, 1985 and Paronis &
Holtzman, 1991, respectively) substituted for or antagonized fentanyl’s stimulus
properties. In one group of pigeons, profadol and meperidine (n = 4 and 3
respectively) substituted for but did not antagonize fentanyl (i.e., these
compounds were like fentanyl); in a second subgroup profadol and meperidine
(n = 1 for both compounds) failed to substitute for but did antagonize fentanyl
(i.e., these compounds were like naloxone); and in a third subgroup profadol and
meperidine (n = 3 and 4, respectively) failed to substitute for or antagonize
fentanyl’s stimulus control (i.e., the lack of substitution may have been due to the
rate-decreasing effects of the partial agonists and the failure to antagonize
fentanyl was an indication of these compound’s fentanyl-like properties). In
contrast, the full opioid agonists fentanyl and morphine completely substituted for
fentanyl in all subjects (Pickeretal., 1993).
Not only do subjects differ as to whether partial agonists substitute for a full
agonist training compound, but individual animals also differ as to whether partial
agonists substitute for a full antagonist training compound. For these same
animals, however, other full antagonists substituted for the training compound for
all subjects. For example, in animals trained to discriminate naloxone from
saline within the conditioned taste aversion baseline of drug discrimination
learning, five of twelve subjects completely generalized naloxone control to
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 26
nalorphine, whereas for the remaining seven subjects nalorphine failed to
substitute for naloxone at any dose tested. In contrast, the pure antagonist
naltrexone substituted for naloxone in all subjects tested (Smurthwaite et al.,
1991). Similar to the present experiment, these differences are consistent with
the position that some partial agonists are more like an antagonist for some
animals and more like an agonist for others (i.e., some partial agonists, including
nalorphine, may possess efficacy similar to that of the endogenous opiates).
Although classification of a partial agonist as an antagonist or agonist
differs according to the specific subject examined (see also Picker et al., 1993),
in animals in which a partial agonist initially acted as an antagonist (i.e., by failing
to substitute for a full agonist within drug discrimination learning), it generally
continued to act as an antagonist within the same design (i.e., by antagonizing
the discriminative stimulus effects of the full agonist). The same held true for
animals in which the partial agonist initially acted as a full agonist (i.e., it later
failed to antagonize the discriminative stimulus effects of the full agonist) (Picker,
Smith & Morgan, 1994). Within the present experiment, although individual
animals differed as to whether nalorphine acted as an antagonist or agonist (see
above), for each animal nalorphine consistently acted as either an antagonist or
agonist. That is, in those animals in which nalorphine initially acted as an
antagonist (i.e., when an intermediate dose of CCK was combined with a range
of doses of nalorphine), nalorphine subsequently continued to act as an
antagonist (i.e., when an ineffective dose of nalorphine was combined with the
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 27
training dose of CCK) (although see Subject 2). The same was true for animals
in which nalorphine initially acted as an agonist (i.e., it continued to act as an
agonist). Thus, although nalorphine’s position on the continuum may differ for
individual subjects, it would be fixed for any specific animal. That is, nalorphine
would consistently act as an antagonist in those animals in which nalorphine fell
below the endogenous opiates and as an agonist in subjects in which nalorphine
fell at or above the endogenous opiates on the continuum.
The basis for the specific results in the present experiment has assumed
that nalorphine’s position on the continuum of relative efficacy for opioid activity
varies for individual subjects with nalorphine lying below the point of endogenous
opioid activity for some subjects and above this point for others. This, however,
is not the only possible account of the variability reported here. For example, it is
also possible that nalorphine’s position on the continuum of relative efficacy is
the same for individual subjects. Instead, what may vary is the point at which the
endogenous opiates lie. This view can also account for the fact that for some
subjects nalorphine appeared to block CCK’s stimulus effects while for others
these effects were potentiated. Specifically, although nalorphine may fall at the
same point on the continuum for all subjects, for those subjects for which the
endogenous opiates lie to the right of nalorphine’s efficacy, nalorphine would
block the endogenous opioid tone (i.e., act as an antagonist and potentiate
CCK’s stimulus effects). Conversely, for subjects for which the endogenous
opiates lie to the left of nalorphine’s efficacy, nalorphine would mimic the opioid
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 28
effect (i.e., act as an agonist and block CCK’s stimulus control). O f course,
some combination of the two views noted above is also possible with the
positions of both nalorphine and the endogenous opiates concurrently varying for
individual subjects. The present experiment did not directly test any of these
three hypotheses. As such, the specific basis for the effects in the present
experiment remains unknown.
In the present study, nalorphine’s opioid activity was revealed through
examining its interactions with CCK, not by determining whether nalorphine
substituted for (or failed to substitute for) CCK’s stimulus properties. That is,
nalorphine’s ability to potentiate (like naloxone) or block (like morphine) CCK’s
stimulus properties for an individual animal was only somewhat consistent with
whether CCK control generalized to nalorphine for the particular subject
examined. Specifically, for Subjects 1 and 2 nalorphine substituted for and
potentiated CCK control, whereas for Subject 5 nalorphine failed to substitute for
and blocked CCK’s stimulus properties (i.e., whether nalorphine substituted for
CCK was consistent with whether it potentiated or blocked its stimulus properties
for these three subjects). In contrast, for Subject 3 nalorphine substituted for
CCK control but blocked/had no effect on its stimulus properties. Similarly, for
Subject 4 nalorphine failed to substitute for CCK but potentiated CCK’s stimulus
properties (i.e., whether nalorphine substituted for CCK was not consistent with
whether it potentiated or blocked its stimulus properties for these two subjects).
These findings are consistent with those of Melton and Riley (1993) who
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demonstrated that neither naloxone nor morphine substituted for CCK, although
naloxone consistently potentiated and morphine consistently blocked CCK’s
stimulus properties. It, therefore, appears that classification of opioids as
antagonists or agonists within this preparation relies solely upon their interactions
with CCK, and not upon whether these compounds share stimulus properties
with CCK.
In an attempt to determine the receptor at which opioids and CCK interact
within the conditioned taste aversion baseline of drug discrimination learning,
Melton and Riley (1997) found that naloxone potentiated, while naltrindole (a
delta agonist) had no effect upon CCK’s stimulus properties, suggesting that
opioids and CCK interact at the mu receptor within the present design. However,
within other designs CCK has been shown to interact with delta (Hong &
Takemori, 1989; Ossipov, Kovelowski, Vanderah & Porreca, 1994; Vanderah,
Lai, Yamamura & Porreca, 1994; although see Wang & Han, 1990; Wang, Wang
& Han, 1990) and kappa (Wang & Han, 1990; Wang, Wang & Han, 1990) opioid
agonists, indicating that the opioids and CCK may interact at receptors other
than mu. Nalorphine shows greatest affinity for the mu receptor, but it also binds
to delta and kappa receptors (Magnan, Paterson, Tavani & Kosterlitz, 1982;
Wood, 1982). Thus, although the present design focused on the relative efficacy
of nalorphine at the mu receptor subtype, it is possible that nalorphine’s relative
efficacy at other receptor subtypes may also be assessed within this preparation.
Overall, it appears that the conditioned taste aversion baseline of drug
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discrimination learning may be useful in assessing the relative efficacy of partial
mu opioid agonists. Specifically, compounds that potentiate CCK’s stimulus
control (like naloxone) act as antagonists, while those that block CCK’s stimulus
control (like morphine) act as agonists. Because nalorphine appeared to act as
an antagonist for some animals but as an agonist for others in the present
experiment, it may be that nalorphine lies near the endogenous opiates on the
continuum of relative opioid efficacy. Compounds that lie below these
endogenous opiates would block endogenous tone (e.g., naloxone) while those
that lie near them would mimic the endogenous opiates (e.g., morphine). If
nalorphine does possess efficacy similar to the endogenous opiates, individual
differences in relative efficacy among subjects may cause nalorphine to lie
slightly below the endogenous opiates (i.e., act as an antagonist) in some
animals while causing nalorphine to lie at or slightly above the endogenous
opiates (i.e., act as an agonist) in others. It, therefore, appears that the present
design may not only be able to assess the efficacy of partial opioid agonists
relative to naloxone and morphine, but it may be useful in assessing these
compounds in relation to the endogenous opiates. That is, some partial agonist
compounds may be near enough to either naloxone or morphine on the
continuum that individual differences among subjects may not be apparent (i.e.,
the compound would consistently act as either an antagonist or agonist for all
subjects). This procedure, therefore, appears to provide a very sensitive
measure of relative efficacy (i.e., more sensitive than differentiating compounds
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 31
solely upon whether they are more naloxone- or morphine-like).
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