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Vol. 290, Issue 3, 1157-1164, September 1999
-Opioid
Agonist SNC80 in Rhesus Monkeys1
Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, Belmont, Massachusetts (M.R.B., S.S.N., N.K.M.); and Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (M.S.F., X.Z., K.C.R.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Five rhesus monkeys were trained to discriminate the nonpeptidic,
-opioid agonist SNC80 (0.32 mg/kg i.m.) from saline by using a
food-reinforced drug-discrimination procedure. Cumulative doses of
SNC80 produced a dose-dependent increase in SNC80-appropriate responding and a dose-dependent decrease in response rate. In time-course studies, peak effects of the training dose of SNC80 were
observed after 15 min, and these effects diminished over 240 min. In
substitution studies, other piperazinyl benzamide agonists (SNC86,
SNC162, and SNC243A) substituted for SNC80 with relative potencies
similar those of SNC80. However, SNC67, the (
)-enantiomer of SNC80,
did not occasion SNC80-appropriate responding up to a dose (32.0 mg/kg)
that produced convulsions in one monkey. The µ agonists morphine and
fentanyl and the 
agonists U-50,488 and enadoline failed to
substitute for SNC80 up to doses that eliminated responding. Two
nonopioids (the N-methyl-D-aspartate antagonist ketamine and the monoamine reuptake inhibitor cocaine) also
produced primarily saline-appropriate responding. Both the discriminative stimulus and rate-decreasing effects of SNC80 were antagonized by the -selective antagonist naltrindole (0.01-1.0 mg/kg) but not by doses of the opioid antagonist quadazocine (0.1-1.0 mg/kg) that block the effects of µ and agonists. These data suggest that the discriminative stimulus effects of SNC80 are mediated
by -opioid receptors and that the discriminative stimulus effects
of opioids in primates can be differentiated from the effects of
other opioid and nonopioid compounds.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Opioids
act at three main types of opioid receptors, the µ, , and receptors (Martin et al., 1976
; Lord et al., 1977; Wood et al., 1981).
Drug-discrimination procedures have been used extensively to
characterize the stimulus properties of compounds that interact with
these types of opioid receptors (Schaefer and Holtzman, 1977; Herling
and Woods, 1981a; France and Woods, 1989; Negus et al., 1994). Often in
drug discrimination studies, drugs that share pharmacologic mechanisms
of action with the training drug substitute for the training drug
(i.e., produce training drug-associated responding), whereas drugs that
do not share pharmacologic effects with the training drug do not
substitute (i.e., produce vehicle-associated responding). For example,
in monkeys trained to discriminate the µ agonist etorphine from
saline, other µ agonists produced etorphine-associated responding,
whereas agonists did not (Herling and Woods, 1981b). Conversely, in
monkeys trained to discriminate the agonist ethylketocyclazocine (EKC) from saline, other agonists substituted for EKC, whereas µ agonists did not (Hein et al., 1981). The discriminative stimulus effects of µ and opioids have been well characterized, in part because of the availability of selective agonists and antagonists that
readily cross the blood-brain barrier after systemic administration.
In contrast, the discriminative stimulus effects of opioids have
not been fully characterized. Until recently, the only agonists
available have been peptidic compounds such as
[D-Pen2-D-Pen5]enkephalin
(DPDPE). However, DPDPE and other peptides do not readily cross the
blood-brain barrier and must be administered i.c.v. This poses some
methodological problems for training and maintaining discrimination
performance. However, one study did train pigeons to discriminate
between i.c.v. injections of DPDPE and saline (Jewett et al., 1996). In
substitution studies, other peptidic agonists substituted for
DPDPE, whereas the agonist U-50,488 and the µ agonists DAMGO and
morphine did not (Jewett et al., 1996). This study demonstrated a
clear, -selective discrimination with DPDPE. Recently, (±)-BW373U86
was described as the first nonpeptidic, systemically active -opioid
agonist (Chang et al., 1993). In pigeons, the discriminative stimulus
effects of (±)-BW373U86 (0.56 mg/kg) were antagonized by the
-selective antagonist naltrindole (Comer et al., 1993b;
Picker and Cook, 1998). These antagonism studies suggested that the
discriminative stimulus effects of (±)-BW373U86 were mediated by receptors. However, in substitution studies, µ agonists (e.g.,
morphine) substituted for the (±)-BW373U86 discriminative stimulus in
more than half of the pigeons studied (Comer et al., 1993b;
Picker and Cook, 1998). Moreover, in pigeons trained to discriminate µ agonists (e.g., fentanyl), (±)-BW373U86 produced high levels of
substitution in the majority of pigeons (Negus et al., 1996; Picker,
1997). These findings suggest that the discriminative stimulus effects
of (±)-BW373U86 are not selective for agonists in pigeons.
Although (±)-BW373U86 appears to share discriminative stimulus effects
with µ agonists in pigeons, it may produce more selective agonist
effects in primates. For example, (±)-BW373U86 did not produce µ- or
-like discriminative stimulus effects in rhesus monkeys trained to
discriminate the µ agonist alfentanil or the agonist EKC from
saline (Negus et al., 1994). In addition, piperazinyl benzamide
derivatives of (±)-BW373U86 recently have been developed that are far
more selective for receptors than the parent compound. For example,
SNC80 is the methyl ether derivative of (+)-BW373U86, and SNC80 was
reported to have more than 800-fold selectivity for versus µ receptors, whereas (±)-BW373U86 was between 7- and 50-fold selective
for receptors (Chang et al., 1993; Calderon et al., 1994, 1997;
Knapp et al., 1996). Moreover, we reported recently that SNC80
functions as a systemically active and highly selective agonist in
rhesus monkeys (Negus et al., 1998). Taken together, these findings
suggest that a drug discrimination based on SNC80 in rhesus monkeys
could provide a sensitive and selective assay for the evaluation of opioids.
Accordingly, the purpose of the present study was to determine whether
SNC80 would serve as a selective opioid discriminative stimulus in
monkeys. After adequate stimulus control was established, the potency
and time course of SNC80 were determined. In substitution studies, the
other piperazinyl benzamide agonists SNC86 [the (+)-enantiomer of
(±)-BW373U86], SNC162, and SNC243A were evaluated to determine
whether these compounds shared discriminative stimulus effects with
SNC80. The stereoselectivity of the discriminative stimulus effects of
SNC80 also was assessed by using SNC67, which is the ()-enantiomer of
SNC80. Substitution studies with compounds selective for µ (i.e.,
fentanyl and morphine) and (i.e., enadoline and U-50,488) opioid
receptors, as well as nonopioid receptors (i.e., the
N-methyl-D-aspartate receptor antagonist
ketamine and the monoamine reuptake blocker cocaine), were conducted to
determine the selectivity of the SNC80 discriminative stimulus. In
antagonism studies, the -selective antagonist naltrindole and µ-
and -selective doses of the opioid antagonist quadazocine were
administered as pretreatments to SNC80 to assess the role of , µ,
and receptors in mediating the discriminative stimulus effects of SNC80.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Subjects. Two male and three female rhesus monkeys (Macaca mulatta) were studied. All monkeys had previous exposure to cocaine self-administration procedures; however, none of the monkeys had previous drug-discrimination experience. Monkeys had free access to water and were maintained on a diet of multiple vitamins, fresh fruit, and five to eight Lab Diet Jumbo Monkey biscuits (PMI Feeds, Inc., St. Louis, MO). In addition, monkeys could earn up to 70 1-g food pellets (Precision Primate Pellets Formula L/I Banana Flavor; P.J. Noyes Co., Lancaster, NH) during daily operant sessions (see below). A 12-h light/dark cycle was in effect (lights on from 7:00 AM to 7:00 PM).
Animal maintenance and research were conducted in accordance with the guidelines provided by the National Institutes of Health Committee on Laboratory Animal Resources. The laboratory facility was licensed by the United States Department of Agriculture, and research protocols were approved by the McLean Hospital Institutional Animal Care and Use Committee. Consulting veterinarians periodically monitored the health of the monkeys. Monkeys had visual, auditory, and olfactory contact with other monkeys throughout the study. Operant procedures for food-maintained responding provided an opportunity for environmental enrichment (Line et al., 1989).
Apparatus. Monkeys were housed individually in stainless steel chambers (56 × 71 × 69 cm). An operant panel (28 × 28 cm) was mounted on the front of each home cage. Each panel contained a horizontal row of three response keys (6.4 × 6.4 cm) that were arranged 2.5 cm apart and 3.2 cm from the top of the operant panel. Keys could be transilluminated with red or green stimulus lights (Superbrights LEDs; Newark Electronics, Woburn, MA). An externally mounted pellet dispenser (model G5210; Gerbrands) delivered 1-g banana-flavored pellets to a food receptacle mounted on the cage beneath the operant panel. Control of experiments and data recording were accomplished with a microprocessor, interface, and software (MED Associates Inc., Georgia, VT) located in a separate room.
Discrimination Training. Monkeys were trained under a single-cycle procedure during experimental sessions conducted 5 days each week. Each training cycle consisted of a 15-min pretreatment period followed by a 10-min response period. During the pretreatment period, stimulus lights were not illuminated, and responding had no scheduled consequences. During the response period, stimulus lights were illuminated, and monkeys could earn a maximum of 20 food pellets under a fixed ratio 20 schedule of reinforcement. For three of the monkeys, the right key was illuminated red and the left key was illuminated green. The colors of the response keys were reversed for the other two monkeys. The center key was inactive, and responding on this key had no programmed consequences. If 20 food pellets were delivered before the end of the 10-min response period, the stimulus lights were extinguished, and further responses had no scheduled consequence for the remainder of the response period.
An injection of either saline or 0.32 mg/kg SNC80 was administered i.m. during the first minute of the pretreatment period. After the administration of saline, only responses on the green key (i.e., saline-appropriate key) produced food, and after the administration of the training dose of SNC80, only responses on the red key (i.e., drug-appropriate key) produced food. Responding on the injection-inappropriate key reset the fixed ratio requirements on the injection-appropriate key. Three dependent variables were determined during the response period of each cycle: 1) the number of responses on each key before the first food reinforcer; 2) the percent responses on the injection-appropriate key for the entire cycle [(injection-appropriate responses
total responses) × 100]; and 3) response rate for the cycle
(total responses emitted total time stimulus lights were illuminated).
Monkeys were considered to have acquired the discrimination when the
following three criteria were met for seven of eight training sessions:
1) fewer than 20 responses on the injection-inappropriate key before
the first reinforcer, 2) at least 90% responding on the
injection-appropriate key over the entire session, and 3) response
rates of at least 0.5 responses/s after the administration of either
saline or the training dose of SNC80.
Initially, training consisted of a double-alternation schedule of drug
or saline administration on consecutive days (i.e., sal-sal-drug-drug).
Analysis of performance during early training indicated that the
criteria for adequate stimulus control more often were obtained on the
first drug presentation than on the second drug presentation in the
schedule. Because studies in our laboratory suggest that tolerance may
develop to some of the behavioral effects of agonists (unpublished
observations), training was modified so that drug was never
administered on consecutive days (e.g., either a saline session or no
session occurred between drug-training days).
Discrimination Testing. Once monkeys met the criteria for accurate discrimination, testing began using a multiple-cycle procedure. Each cycle during a test session was identical with training cycles except: 1) the 15-min pretreatment period was followed by a 5-min response period (i.e., 20-min cycles), 2) responding on either key produced food, and 3) a maximum of 10 food pellets was available during each cycle. Test sessions consisted of up to seven consecutive test cycles and were conducted only if the criteria for adequate stimulus control were met during the two training days immediately preceding the test day. If responding did not meet criterion levels, training was continued until criterion levels of performance were obtained for at least two consecutive sessions (one drug and one saline training session). A saline training day always preceded test days, and a minimum of 5 days separated tests with piperazinyl benzamides.
Three series of experiments were conducted to examine the discriminative stimulus effects of SNC80. In experiment 1, the potency and time course of the discriminative stimulus and rate-decreasing effects of SNC80 were examined. The potency of SNC80 was assessed by using a cumulative dosing procedure. Under this procedure, saline was administered at the beginning of the first cycle, and cumulative doses of SNC80 were administered i.m. during the first minute of each subsequent cycle. Doses increased cumulatively in 0.25 or 0.5 log unit increments. SNC80 dose-effect curves were determined at the start and at the conclusion of these studies. In addition, a separate test session consisted of seven cycles during which saline was administered during the first minute of each cycle. To examine the time course of the training dose of SNC80, a single dose of 0.32 mg/kg SNC80 was administered, and 5-min response periods were scheduled to begin after 4, 15, 60, and 240 min. In experiment 2, the ability of opioid and nonopioid drugs to substitute for the SNC80 discriminative stimulus was examined. During these studies, saline was administered during the first cycle, and cumulative doses of the test drug were administered i.m. during the first minute of subsequent cycles. The four classes of drugs studied were as follows: 1) piperazinyl benzamides structurally related to SNC80 (SNC67, SNC86, SNC162, and SNC243A), 2) µ agonists (morphine and fentanyl), 3) agonists (U-50,488 and enadoline), and 4)
nonopioids (the N-methyl-D-aspartate receptor
antagonist ketamine and the monoamine reuptake blocker cocaine). All
test compounds were evaluated at least once in each of four monkeys. During the evaluation of the U50,488 dose-effect curve, which used
1/2 log unit increments between doses, U50,488 substituted for
SNC80 in one of four monkeys. To assess the replicability of this
finding, the U50,488 dose-effect curve was redetermined in these
monkeys by using 1/4 log unit increments between doses. Experimental sessions were terminated when: 1) at least 90% of the
responses occurred on the drug-appropriate key, 2) rates of responding
decreased to less than 10% of the average rate of the five previous
saline training sessions, or 3) signs of overt toxicity were observed.
In experiment 3, the -opioid selectivity of the behavioral effects
of SNC80 was evaluated by pretreating monkeys with the opioid
antagonists naltrindole or quadazocine. During antagonism studies, a
single dose of naltrindole (0.01, 0.1, or 1.0 mg/kg) or quadazocine
(0.1 or 1.0 mg/kg) was administered at the beginning of the first
cycle, and cumulative doses of SNC80 were administered during the first
minute of each subsequent cycle (i.e., 20-min antagonist pretreatment).
We have reported previously that naltrindole, at doses of up to 1.0 mg/kg, acts as a selective antagonist in rhesus monkeys (Negus et
al., 1998). Quadazocine selectively antagonizes µ agonists at a dose
of 0.1 mg/kg and blocks both µ and agonists at a dose of 1.0 mg/kg in rhesus monkeys (Bertalmio and Woods, 1987; Negus et al.,
1993).
Data Analyses. Results of drug-discrimination studies are presented as the average percentage of drug-appropriate responses (i.e., % DR) on the SNC80-appropriate key ± 1 S.E.M. and are plotted as a function of either dose or time. A drug was considered to substitute for SNC80 when at least 90% of the responses were on the drug-appropriate key. Rates of responding are presented as a percentage of the control response rate ± 1 S.E.M. The control response rate was defined as the average response rate of the five saline training sessions immediately preceding the test. The % DR was not calculated for a monkey for a given cycle if response rates were less than 10% of the control rate. In addition, a mean % DR was calculated and plotted in group graphs only if at least two monkeys contributed to the data point.
ED50 values were defined as the dose of a drug that produced either 50% SNC80-appropriate responding or 50% decrease in control response rates. Individual ED50 values were calculated by linear regression when at least three data points were available on the linear portion of the dose-effect curve or by interpolation when two data points (one above and one below 50%) were available. Individual ED50 values were converted to their log values for calculation of means and 95% CL and then converted back to linear values for presentation. One monkey was removed midway through these studies because of health problems that were unrelated to the current experiment. The number of monkeys in each testing condition is indicated in the figure legends.Drugs.
SNC67, SNC80, SNC162, and SNC243A were synthesized as
free bases by K.C.R. and colleagues (National Institutes of Health, Bethesda, MD). SNC86 HCl and naltrindole HCl also were synthesized by
K.C.R. and colleagues. ()-Cocaine HCl, fentanyl HCl, and morphine sulfate were supplied by the National Institute on Drug Abuse (Bethesda, MD). Quadazocine methanesulfonate was generously supplied by
Sanofi Pharmaceuticals (Malvern, PA), and enadoline HCl was generously
supplied by Warner-Lambert (Parke-Davis Research Division, Ann Arbor,
MI). (±)-trans-U50,488 methanesulfonate was purchased from
Research Biochemicals International (Natick, MA), and ketamine-HCl was
purchased from Fort Dodge Laboratories (Fort Dodge, IA). SNC67, SNC80,
SNC162, and SNC243A were dissolved in 3% lactic acid and water. The
commercially available Ketaset solution was used for ketamine. All
other compounds were dissolved in sterile water. Drugs were
administered i.m., and the sites of injection were rotated so that the
same site was never used on 2 consecutive days. Signs of tissue damage
were not observed after injections with any of the test compounds.
Doses were based on the free base or salt forms described above.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Control Performance and Effects of SNC80.
Monkeys satisfied
the criteria for adequate stimulus control after an average of 80 training sessions (range, 59-119). The mean control rate of responding
(determined from saline training sessions preceding test sessions
throughout the study) was 1.53 ± 0.20 responses per second.
Figure 1 shows the potency and time course of SNC80. Cumulative administration of SNC80 produced a dose-dependent increase in SNC80-appropriate responding and a dose-dependent decrease in response rates (Fig. 1, left). Complete substitution was observed at doses of SNC80 higher than 0.32 mg/kg, and
a dose of 3.2 mg/kg eliminated responding. The potency of SNC80 was
determined by using cumulative dosing procedures at the beginning and
again at the end of these studies. Mean ED50 values (±95% CL) for the discriminative stimulus effects of SNC80 were similar for the first [0.13 (0.06-0.18)] and second [0.13 (0.09-0.17)] determination. Mean ED50 values
(±95% CL) for the rate-decreasing effects of SNC80 were also similar
for the first [0.69 (0.12-1.50)] and the second [1.36
(0.47-2.03)] determination. Because there was substantial overlap in
95% CL between the first and second determination, the two dose-effect
curves were combined in all Figs. 1-4, and ED50
values were combined in Tables 1 and 2. In contrast to the effects of
cumulative SNC80 administration, injections of saline during seven
cycles produced primarily saline-appropriate responding (i.e., less
than 17% SNC80-appropriate responding) and response rates between 83 and 106% of control throughout the test (data not shown).
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Effects of Other Piperazinyl Benzamide Agonists.
SNC86,
SNC162, and SNC243A dose-dependently substituted for the SNC80
discriminative stimulus in nearly all monkeys and decreased rates of
responding (Fig. 2). SNC86 substituted in
three monkeys at a dose of 0.32 mg/kg and in the fourth monkey at a
dose of 1.0 mg/kg. However, average drug-appropriate responding did not exceed 88%, because in two monkeys, a dose of 1.0 mg/kg SNC86 produced
80 and 74% drug-appropriate responding. SNC243A substituted in three
of the four monkeys; in the fourth monkey, a dose of 0.32 mg/kg SNC243A
produced 88% SNC80-appropriate responding and a higher dose of 1.0 mg/kg SNC243A eliminated responding. The potencies of SNC86, SNC162,
and SNC243A in substituting for SNC80 and decreasing response rates
were similar as indicated by overlapping 95% confidence limits (Table
1). SNC67, which is the ()-isomer of
SNC80, substituted for SNC80 in only one monkey at a cumulative dose of
3.2 mg/kg and produced primarily saline-appropriate responding in the
other three monkeys. SNC67 had minimal effects on response rates up to
10.0 mg/kg. One monkey received a cumulative dose of 32.0 mg/kg SNC67,
and this high dose produced tonic-clonic convulsions approximately 3 min after administration. Consequently, SNC67 was tested only up to
10.0 mg/kg in the other three monkeys.
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Effects of µ Agonists, Agonists, and Nonopioids.
The µ agonists fentanyl and morphine and the agonists
enadoline and U50,488 failed to substitute for the SNC80 discriminative stimulus when administered in 1/2 log unit increments up to
doses that eliminated responding (Fig. 3,
left and center; Table 1). In two cases, mean group data for
SNC80-appropriate responding were not shown in Fig. 3, because only one
of four monkeys responded. First, a high dose of 0.001 mg/kg enadoline
eliminated responding in three monkeys, and in the fourth monkey, this
dose of enadoline produced 0% SNC80-appropriate responding and
decreased response rates to 62% of control. Second, a high dose of
0.32 mg/kg U50,488 eliminated responding in three of four monkeys, and
in the fourth monkey, this dose of U50,488 produced 100%
SNC80-appropriate responding and decreased response rates to 23% of
control. To evaluate further the effects of U50,488, the U50,488
dose-effect curve was redetermined by using 1/4 log unit
increments. Under these conditions, U50,488 produced primarily
saline-appropriate responding in all four monkeys, including the monkey
in which U50,488 substituted during the first test, and a dose of 0.32 mg/kg U-50,488 eliminated responding in all four monkeys.
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Effects of the Opioid Antagonists Naltrindole and Quadazocine.
Naltrindole dose-dependently antagonized the discriminative stimulus
and rate-decreasing effects of SNC80 (Fig.
4, left). A dose of 0.01 mg/kg
naltrindole did not modify the dose-effect curve for either the
discriminative stimulus or the rate-decreasing effects of SNC80. A
larger dose of 0.1 mg/kg naltrindole produced a 4-fold increase in the
ED50 values for both the discriminative stimulus
effects and rate-decreasing effects of SNC80 (Table
2). After pretreatment with 1.0 mg/kg
naltrindole, SNC80 substituted completely in two monkeys and produced a
maximum of 60% drug-appropriate responding in the other monkey. This
dose of naltrindole produced a 27-fold increase in the
ED50 values for the discriminative stimulus effects of SNC80 but only a 9-fold increase in the
ED50 values for the rate-decreasing effects of
SNC80.
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agonists
but not agonists, also failed to alter significantly either the
discriminative stimulus or rate effects of SNC80.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The present study is the first demonstration that rhesus monkeys
can be trained to discriminate between SNC80 and saline. Two lines of
evidence suggest that the discriminative stimulus effects of SNC80 were
mediated by -opioid receptors and not by µ- or -opioid
receptors. First, the -selective agonists SNC86, SNC162, and SNC243A
each substituted for SNC80, whereas µ-opioid agonists, -opioid
agonists, and nonopioids produced primarily vehicle-appropriate
responding. Second, the -selective antagonist naltrindole
dose-dependently shifted the dose-effect curves for the discriminative
stimulus and rate-decreasing effects of SNC80 to the right. In
contrast, the opioid antagonist quadazocine, up to doses that
antagonize the effects of µ and agonists, did not modify the
discriminative stimulus or rate-decreasing effects of SNC80. Taken
together, these results provide the first evidence that -opioid
agonists serve as selective, discriminative stimuli in primates.
Potency and Time Course of SNC80.
SNC80 produced
dose-dependent increases in drug-appropriate responding and decreases
in response rates. The potency of SNC80 for decreasing response rates
in the present study was similar to results obtained from a previous
study of schedule-controlled behavior in monkeys treated intermittently
with -opioid agonists (Negus et al., 1998). Moreover,
redeterminations of the potency of SNC80 at the beginning and at the
end of the study were similar. These findings suggest that tolerance
did not develop to the discriminative stimulus or rate-decreasing
effects of SNC80 under the current dosing conditions.
).
Effects of Other Piperazinyl Benzamides.
The greatest degree
of substitution for SNC80 was obtained with the piperazinyl benzamides
SNC86 [the (+)-enantiomer of (±)-BW373U86], SNC162, and SNC243A.
These piperazinyl benzamides produced high levels (at least 88%) of
SNC80-appropriate responding in all monkeys, and we have shown
previously that these compounds produced other receptor-mediated
effects in monkeys (Negus et al., 1998). These results also agree with
the finding that (±)-BW373U86 and SNC80 shared discriminative stimulus
effects in pigeons (Picker and Cook, 1998). The potencies of SNC80,
SNC86, SNC162, and SNC243A for producing drug-appropriate responding
and decreasing rates of responding were similar. These results were
consistent with their potencies for decreasing rates of
scheduled-controlled responding in other rhesus monkeys (Negus et al.,
1998) and with their relative affinities at cloned human receptors
but not cloned human µ receptors (Knapp et al., 1996).
)-enantiomer of SNC80, did not substitute for the SNC80
discriminative stimulus up to a dose of 10.0 mg/kg. These results
provide evidence that the discriminative stimulus effects of SNC80 are
stereoselective. A higher dose of 32.0 mg/kg SNC67 produced convulsions
in one monkey and, therefore, was not tested in the other monkeys. In a
previous study, a cumulative dose of 32.0 mg/kg SNC67 decreased rates
of responding to less than 25% of control rates, and a larger dose of
56.0 mg/kg produced convulsions in one monkey (Negus et al., 1998). The
mechanisms underlying the convulsant effects of SNC67 are not known.
Both (±)-BW373U86 and SNC80 produce naltrindole-reversible convulsant
effects in mice (Comer et al., 1993a; Bilsky et al., 1995),
suggesting that the convulsant effects of these compounds are mediated
by opioid receptors. However, SNC80 at doses of up to 56.0 mg/kg
does not produce convulsions in rhesus monkeys (Negus et al., 1998;
M.R.B., unpublished observations). To the extent that convulsions were obtained only with the ()-enantiomer of SNC80, these results suggest
that the convulsant effects of these compounds also may be
stereoselective in primates.
Effects of µ- and -Opioid Agonists and Nonopioids.
In
rhesus monkeys, µ- and -opioid agonists failed to
substitute for SNC80. Similarly, in pigeons, µ- and -opioid
agonists did not substitute for DPDPE, and agonists did not
substitute for (±)-BW373U86 (Comer et al., 1993b; Jewett et
al., 1996). However, in contrast to the results of the present study,
µ-opioid agonists produced high levels of substitution in pigeons
trained to discriminate (±)-BW373U86 (Comer et al., 1993b;
Picker and Cook, 1998). Moreover, (±)-BW373U86 and SNC80 substituted
in the majority of pigeons trained to discriminate µ agonists (Negus
et al., 1996; Picker, 1997; Morgan and Picker, 1998). In contrast,
(±)-BW373U86 did not substitute for the discriminative stimulus
effects of the µ agonist alfentanil in monkeys (Negus et al., 1994),
and µ agonists did not substitute for SNC80 in the present study.
Together, these results suggest that the discriminative stimuli
associated with nonpeptidic -opioid agonists may be more selective
in primates than in pigeons.
; Picker and Cook,
1998). However, both peptidic and nonpeptidic -opioid agonists
produced high levels of cocaine-appropriate responding in monkeys and
rats trained to discriminate cocaine (Ukai et al., 1993; Suzuki et al.,
1997; Negus et al., 1998). The reasons for this asymmetrical
cross-substitution are not clear. The discriminative stimulus effects
of cocaine are thought to be mediated primarily by its effects on
dopaminergic systems (Kleven et al., 1990; Spealman et al., 1991), and
dopamine also has been implicated in some of the behavioral effects of
agonists (Longoni et al., 1991; Spina et al., 1998). In monkeys,
however, the cocaine-like discriminative stimulus effects of SNC80 were
not antagonized by the dopamine antagonist flupenthixol, which suggests
that the cocaine-like effects of SNC80 were not mediated by its actions on dopaminergic systems (Negus et al., 1998). Moreover, it is important
to note that asymmetric cross-generalization also has been observed
between cocaine and other drug classes (Spealman et al., 1991;
Rosenzweig-Lipson and Bergman, 1993). Thus, asymmetric cross-generalizations with cocaine may reflect the ability of cocaine
to produce a relatively nonselective discriminative stimulus. Overall, µ agonists, agonists, cocaine, and the
N-methyl-D-aspartate antagonist ketamine
produced primarily saline-appropriate responding in SNC80 trained
monkeys. These findings suggest that the discriminative stimulus
effects of SNC80 in rhesus monkeys are highly selective and are shared
only by other drugs that act as -opioid agonists.
Antagonist Effects of Naltrindole and Quadazocine.
The
antagonism of the SNC80 discriminative stimulus by naltrindole in the
present study confirms and extends previous studies in which
naltrindole selectively antagonized the discriminative stimulus effects
of (±)-BW373U86 and DPDPE in pigeons (Comer et al., 1993; Jewett et
al., 1996). Moreover, the magnitude of shifts in the SNC80 dose-effect
curves produced by 1.0 mg/kg naltrindole was similar to the magnitude
of shifts observed for the rate-decreasing and antinociceptive effects
of (±)-BW373U86 and SNC80 in other monkeys (Negus et al., 1994, 1998;
Butelman et al., 1995). Finally, we have shown previously that
naltrindole at doses up to 1.0 mg/kg does not antagonize the effects of µ or agonists in monkeys (Negus et al., 1994, 1998). These
findings provide further evidence that the discriminative stimulus
effects of SNC80 are mediated by -opioid receptors.
). In the current study, an increase from 0.1 to 1.0 mg/kg
naltrindole produced only a 7-fold and a 2-fold increase in the
ED50 values for the discriminative stimulus and rate-decreasing effects of SNC80, respectively. The reasons for this
deviation are not clear. One possibility is that the rate-decreasing effects of naltrindole might limit shifts in the agonist dose-effect curve. Alternatively, these results raise the possibility that interactions between naltrindole and SNC80 might not consist of a
simple competitive interaction for a homogenous population of receptors.
The opioid antagonist quadazocine at doses of up to 1.0 mg/kg failed to
antagonize the discriminative stimulus and rate-decreasing effects of
SNC80. These data are concordant with previous studies in rhesus
monkeys that demonstrated that 1.0 mg/kg quadazocine antagonized the
behavioral effects of µ and agonists but not agonists
(Bertalmio and Woods, 1987; Negus et al., 1993). Consequently, the
inability of quadazocine to antagonize the discriminative stimulus or
rate-decreasing effects of SNC80 suggests that these effects were not
mediated by µ-or -opioid receptors.
Implications.
As the current study demonstrates,
discriminations based on -opioid agonists in rhesus monkeys can
provide an effective approach to the rapid identification and
evaluation of novel -opioid ligands. These findings also may have
implications for the development of agonists as analgesics. Under
some conditions, agonists produce antinociceptive effects (Negus et
al., 1998), and, therefore, they are being evaluated as possible
alternatives to µ agonist analgesics such as morphine and mixed
µ/ analgesics such as butorphanol. The use of both µ and agonists for the treatment of pain is limited by their subjective
effects in humans. For example, µ agonists produce effects that have
been described as "euphoric" in humans (Kumor et al., 1986; Kreek,
1992), and these subjective effects contribute to a high abuse
potential. In contrast, agonists produce effects that have been
described as "dysphoric" or "psychotomimetic" (Kumor et al.,
1986; Pfeiffer et al., 1986; Rimoy et al., 1991; Reece et al.,
1994), and these subjective effects might reduce patient acceptance.
Although the clinical implications of agonist-induced, subjective
effects remain to be determined, the discriminative stimulus effects of
agonists in the present study suggest that agonists such as
SNC80 might produce different subjective effects than either µ or agonists in humans.
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Acknowledgments |
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We thank Elizabeth Hall, D.V.M., and Beth Moseley, D.V.M., for veterinary assistance.
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Footnotes |
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Accepted for publication May 7, 1999.
Received for publication March 11, 1999.
1 These studies were supported in part by Grants RO1-DA02519, P50-DA04059, T32-DA0752, and KO5-DA00101 from the National Institute on Drug Abuse, National Institutes of Health. We also thank the National Institute on Drug Abuse for partial support for the Laboratory of Medicinal Chemistry, National Institute of Diabetics, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Send reprint requests to: Michael R. Brandt, Ph.D. Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, 115 Mill St., Belmont, MA. E-mail: mbrandt{at}hms.harvard.edu
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Abbreviations |
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EKC, ethylketocyclazocine; % DR, percent drug responding; DPDPE, [D-Pen2-D-Pen5]enkephalin.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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