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Vol. 296, Issue 3, 939-946, March 2001
-Opioid Agonists in Rhesus Monkeys:
Effects on Chemically Induced Thermal Hypersensitivity
Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, Belmont, Massachusetts (M.R.B., N.K.M., S.S.N.); and the Laboratory of Medicinal Chemistry, National Institute of Diabetics, Digestive and Kidney Diseases and National Institute of Health, Bethesda, Maryland (M.S.F., 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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The effects of SNC80 and other structurally related 
-opioid receptor
agonists were assessed under conditions of chemically induced
hypersensitivity to thermal stimuli in four rhesus monkeys. The shaved
tail of each monkey was exposed to warm water (38, 42, 46, and 50°C),
and the tail-withdrawal latency from each temperature was recorded. The
effects of drugs on the temperature that produced a 10-s
tail-withdrawal latency (the T10 value) were
examined. Capsaicin (0.01-0.32 mg) injected into the tail of monkeys
dose dependently decreased the T10,
indicating that capsaicin increased sensitivity to thermal stimuli. A
dose of 0.1 mg of capsaicin decreased the
T10 from 48.0 to 42.1°C (a 
5.9°C
change) 15 min after injection. SNC80 (1.0-10.0 mg/kg s.c.) dose
dependently blocked the capsaicin-induced decrease in the
T10, and 10.0 mg/kg SNC80 fully blocked the
effects of capsaicin. The -selective antagonist naltrindole
(0.1-1.0 mg/kg) dose dependently antagonized the effects of SNC80,
whereas a µ-selective dose of the opioid antagonist quadazocine (0.1 mg/kg) did not. Two other -selective agonists, SNC162 (1.0-10.0
mg/kg) and SNC243A (1.0-10.0 mg/kg), also dose dependently blocked
capsaicin-induced thermal hypersensitivity. In contrast, neither SNC67
(10.0 mg/kg), which is the ()-enantiomer of SNC80, nor the
nonsteroidal anti-inflammatory drug (NSAID) ketorolac (1.0-10.0 mg/kg)
modified the effects of capsaicin. SNC80 was also effective in
reversing thermal hypersensitivity induced by prostaglandin
E2 (0.0158 mg) and Freund's complete adjuvant (10%
concentration). These findings suggest that -agonists have
antinociceptive effects in primates under conditions of chemically induced thermal hypersensitivity and might be effective under a broader
range of conditions than clinically available NSAIDs.
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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 receptors, the µ-, 
-, and -opioid
receptors (Kieffer, 1995
). Although the analgesic activity of µ- and
-opioid agonists is well established, the potential utility of
-agonists as analgesics has been examined less extensively, in part
because the only selective -agonists available for study until
recently were peptidic compounds with poor bioavailability. However,
both spinal and supraspinal administration of peptidic -agonists
produce thermal antinociception in mice and rats (e.g., Heyman et al.,
1987; Stewart and Hammond, 1993). Moreover, the simultaneous
administration of -agonists into both spinal and supraspinal sites
produces synergistic effects under some conditions (Hurley et al.,
1999; Kovelowski et al., 1999). These findings parallel the synergistic
antinociceptive effects of spinal and supraspinal administration of
µ-agonists and suggest that -agonists may be reasonable candidates
for further evaluation as potential analgesics.
(±)-BW373U86 was developed as the first selective and nonpeptidic
-opioid agonist (Chang et al., 1993). As one consequence of its
enhanced bioavailability relative to the peptidic agonists, the effects
of (±)-BW373U86 could be readily examined in nonhuman primates
as well as in rodents. However, (±)-BW373U86 was relatively ineffective in standard assays of antinociception in mice, squirrel monkeys, and rhesus monkeys (Dykstra et al., 1993; Negus et al., 1993b;
Wild et al., 1993; see for review, Negus and Picker, 1996). The isomers
of (±)-BW373U86 were subsequently resolved (Calderon et al., 1994,
1997), and some derivatives of (+)-BW373U86 displayed improved
pharmacologic profiles relative to the parent compound. SNC80, the
O-methyl derivative of (+)-BW373U86, was reported to be more
than 800-fold selective for - versus µ-receptors, whereas (±)-BW373U86 was only between 7- and 50-fold selective for
-receptors (Calderon et al., 1994, 1997). In addition, SNC80
produced more robust antinociceptive effects than (±)-BW373U86 in both
mice and rhesus monkeys (Bilsky et al., 1995; Negus et al., 1998). For
example, in rhesus monkeys, SNC80 produced dose-dependent antinociception against low intensity thermal stimuli, whereas (±)-BW373U86 was ineffective (Negus et al., 1998). SNC80-induced antinociception was surmountably antagonized by the -selective antagonist naltrindole, indicating that these effects were -receptor mediated. In addition, the effects of SNC80 were also blocked by
pretreatment with (±)-BW373U86, suggesting that SNC80 and
(±)-BW373U86 acted at the same receptor type in monkeys, and that
SNC80 had higher efficacy at these receptors. Taken together, these
findings suggest that SNC80 may have greater potential than the parent compound as an analgesic agent.
The studies cited above assessed the effects of peptidic and
nonpeptidic -agonists in assays that used noxious thermal or electrical stimuli. However, assays that model the clinical conditions of allodynia and hyperalgesia may provide a greater degree of sensitivity to the potential analgesic effects of drugs. Allodynia is
defined as a pain-like response to a normally innocuous stimulus, and
hyperalgesia is defined as an exaggerated response to a normally noxious stimulus (Willis, 1992). Allodynia and hyperalgesia associated with inflammation are components of many pain states encountered clinically, such as postoperative pain and arthritis, and models of
allodynia and hyperalgesia may be useful for identifying potential therapeutic compounds (Negus et al., 1993b, 1995a). In some models of
inflammatory allodynia and hyperalgesia, chemical agents are used to
produce hypersensitivity to thermal or mechanical stimuli, and drug
effects on chemically induced thermal or mechanical hypersensitivity can then be evaluated. Both peptidic and nonpeptidic -agonists are
effective in at least some of these models (Stein et al., 1989; Stewart
and Hammond, 1994; Butelman et al., 1995; Fraser et al., 2000). For
example, peptidic -agonists blocked mechanical hypersensitivity
produced by intraplantar administration of Freund's complete adjuvant
(FCA) in mice (Stein et al., 1989). More recently, we compared the
antinociceptive effects of (±)-BW373U86, morphine, and the
nonsteroidal anti-inflammatory drug ketorolac in rhesus monkeys
(Butelman et al., 1995). All three drugs blocked thermal hypersensitivity produced by the inflammatory mediator bradykinin. However, only morphine blocked thermal hypersensitivity by another inflammatory mediator, prostaglandin E2
(PGE2). Thus, even in models of allodynia and
hyperalgesia, (±)-BW373U86 may produce antinociceptive effects under
only a limited range of conditions.
Because SNC80 has greater selectivity and may have greater efficacy
than the parent compound (±)-BW373U86 at -opioid receptors, the
purpose of the present study was to further evaluate the potential analgesic effects of SNC80 and related piperazinyl benzamides in a
model of thermal allodynia and hyperalgesia in rhesus monkeys. Initial
studies assessed the ability of these -agonists to block thermal
hypersensitivity produced by capsaicin. Capsaicin binds to vanilloid
receptors located on primary afferent nociceptors (Szallasi and
Blumberg, 1999), and previous studies demonstrated that
capsaicin-induced thermal hypersensitivity in rhesus monkeys was
blocked by both µ- and -opioid agonists (Ko et al., 1998, 1999).
The stereoselectivity of the antinociceptive effects of SNC80 was
assessed using SNC67, the ()-enantiomer of SNC80. In addition, the
role of -opioid receptors in mediating the effects of SNC80 was
examined in antagonism studies using the -selective antagonist
naltrindole and the µ-selective antagonist quadazocine. Finally, the
generality of the effects of SNC80 against other chemical irritants was
examined using PGE2 and FCA.
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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. Four male rhesus monkeys (Macaca mulatta) had free access to water and were maintained on a daily diet of fresh fruit and vegetables, multiple vitamins, and 10 to 15 Lab Diet Jumbo Monkey biscuits (PMI Feeds, Inc., St. Louis, MO). A 12-h light/12-h 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. A consulting veterinarian periodically monitored the health of the monkeys. Monkeys had visual, auditory, and olfactory contact with other monkeys throughout the study. Daily access to rubber toys and puzzle feeders provided additional environmental enrichment.Procedure. Monkeys were seated in primate chairs, and the lower 10 cm of the shaved tail of each monkey was exposed to warm water (38, 42, 46, and 50°C). The latency (seconds) for monkeys to remove their tails from warm water was used as a measure of nociception. If monkeys failed to remove their tails within 20 s, the experimenter removed the tail and assigned a latency of 20 s to that measurement. Each experimental session began by determining baseline tail-withdrawal latencies at each temperature. Temperature presentations were separated by approximately 1 min.
Chemically Induced Thermal Hypersensitivity.
Thermal
hypersensitivity was produced by the subcutaneous administration of
capsaicin (0.01-0.1 mg), PGE2 (0.0158 mg), or FCA (1-10% concentration) into the terminal 1 to 3 cm of the tail. All chemical irritants were injected in a volume of 0.1 ml. To determine the effects of capsaicin, tail-withdrawal latencies were
assessed at 15, 30, 45, and 60 min after an injection of capsaicin
(0.01-0.1 mg). We have previously reported that a dose of 0.0158 mg of
PGE2 injected into the tail produces thermal
hypersensitivity (Negus et al., 1995a). To determine the effects of
PGE2 in the current experiment, a dose of 0.0158 mg was injected and tail-withdrawal latencies were determined 15, 30, 45, 60, 90, and 120 min later. To determine the effects of FCA (1-10%
concentration), tail-withdrawal latencies were assessed 0.25, 0.5, 1, 2, 4, 24, and 48 h after an injection of FCA. Vehicle controls for
each chemical irritant were also assessed. A minimum of 1 week
separated tests with capsaicin and PGE2, and a
minimum of 2 weeks separated tests with FCA.
Effects of -Opioid Agonists under Conditions of Thermal
Hypersensitivity Produced by Capsaicin.
Initial studies examined
the antinociceptive effects of -agonists and other drugs under
conditions of capsaicin-induced thermal hypersensitivity. Based on
observations of the potency and duration of capsaicin (see
Results), the antinociceptive effect of a single dose of
drug was assessed 15 min after administration of 0.1 mg of capsaicin.
Three series of experiments were conducted.
)], and ketorolac was administered 60 min before
capsaicin [the time of its peak effect (Negus et al., 1995a)].
In experiment 3, the -opioid selectivity of the
antinociceptive 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 mg/kg) was administered 30 min before the SNC80. SNC80 was administered 15 min before capsaicin. For comparison, a dose of 1.0 mg/kg naltrindole or 0.1 mg/kg quadazocine was
administered 30 min before a dose of 0.32 mg/kg morphine. Morphine was
administered 30 min before capsaicin. We have reported previously that
naltrindole at doses of up to 1.0 mg/kg acts as a selective
-antagonist in monkeys, whereas a dose of 0.1 mg/kg quadazocine
selectively antagonizes the behavioral effects of µ-agonists and not
-agonists in monkeys (Negus et al., 1993a, 1998; Brandt
et al., 1999).
Effects of SNC80 under Conditions of Thermal Hypersensitivity
Produced by PGE2 or FCA.
Capsaicin has a short
duration of action that necessitated the administration of drugs before
the induction of thermal hypersensitivity. As a result, these
experiments evaluated the ability of SNC80 to prevent the effects of
capsaicin. However, analgesic drugs used clinically are often
administered after an allodynic state has been established.
Accordingly, two additional series of experiments were conducted to
examine the ability of SNC80 to reverse thermal hypersensitivity when
SCN80 was administered after treatment with longer-acting chemical
irritants. The first study evaluated the ability of SNC80 to reverse
PGE2-induced thermal hypersensitivity. Tail-withdrawal latencies were assessed 15, 30, 45, 60, 90, and 120 min
after an injection of 0.0158 mg of PGE2 in the
tail. Based on results from a previous study (Negus et al., 1995a) and
observations of the duration of PGE2-induced
thermal hypersensitivity in the current study (see Results),
the ability of SNC80 to reverse the effects of
PGE2 was assessed using a cumulative dosing
procedure. Three sequential doses of SNC80 were administered in a
single session, and each dose increased the total cumulative dose by 0.5 log units. Two overlapping SNC80 dose-effect curves (0.1-1.0 and
0.32-3.2 mg/kg) were determined. Cumulative doses of SNC80 were
administered at 15, 30, and 45 min after PGE2,
and tail-withdrawal latencies were determined 10 to 15 min after each injection.
Data Analyses.
Temperature-effect curves were generated for
each experimental condition for individual monkeys. A
T10 value was determined from each
temperature-effect curve, and the T10
value was defined as the temperature that produced a tail-withdrawal
latency of 10 s, which is one-half the maximal tail-withdrawal
latency of 20 s (see Negus et al., 1993b). The
T10 was determined by interpolation from a line drawn between the point above and the point below 10 s
on the temperature-effect curve. Individual
T10 values were averaged to provide a
mean (±1 S.E.M.). For the purposes of the present study, thermal
hypersensitivity was operationally defined as a leftward shift in the
temperature-effect curve and a decrease in the
T10 value. Antinociception was defined
as a blockade or reversal of chemically induced thermal
hypersensitivity. Antinociception was quantified as the percentage
maximum possible effect (% MPE) according to the following equation:
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is the
T10 after the agonist in combination
with the chemical irritant (capsaicin, PGE2, or
FCA), T
is the
T10 after the chemical irritant alone
(capsaicin, PGE2, or FCA), and
T
is the
T10 under control conditions. The
number of monkeys in each testing condition was three except where
noted in text and in the figure legends.
Statistical analysis of pretreatment tests was done using one-way ANOVA
for repeated measures. Significant main effects were analyzed further
by subsequent paired comparisons using the Student-Newman-Keuls method.
The criterion for significance was p < 0.05.
Drugs. Naltrindole HCl, SNC67, SNC80, SNC86, SNC162, and SNC243A were synthesized by K. C. Rice and colleagues (National Institutes of Health, Bethesda, MD). Quadazocine methanesulfonate was generously supplied by Sanofi Pharmaceuticals (Malvern, PA). Morphine sulfate was supplied by the National Institute on Drug Abuse (NIDA, Bethesda, MD). Prostaglandin E2 and Freund's complete adjuvant were purchased from Sigma Chemical Co. (St. Louis, MO). Capsaicin was purchased from Research Biochemicals International (Natick, MA), and ketorolac tromethamine was purchased as an injectable solution from Abbott Laboratories (North Chicago, IL). The free-base forms of SNC67, SNC80, SNC162, and SNC243A were dissolved in 3% lactic acid and sterile water to a final concentration of 50 mg/ml, and dilutions were made with sterile water. The HCl salt form of SNC86 was dissolved in sterile water. Capsaicin was dissolved in 10% EtOH, 10% Emulphor, and 80% sterile water. FCA was diluted in sesame oil (Sigma Chemical Co.). All other compounds were dissolved or diluted in sterile water. All drugs were administered subcutaneously. Signs of tissue damage were not observed after injections with any of the test compounds. Doses were based on 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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Baseline Thermal Nociception and Capsaicin-Induced Thermal Hypersensitivity. Under baseline conditions, maximal tail-withdrawal latencies (i.e., 20 s) were typically obtained with temperatures of 38, 42, and 46°C. When the water temperature was increased to 50°C, tail-withdrawal latencies for individual monkeys were between 0.75 and 3 s. The baseline T10 value was 48.2 ± 0.04°C.
Capsaicin produced a dose- and time-dependent thermal hypersensitivity manifested as a leftward shift in the temperature-effect curve and a decrease in the T10 value. Maximal decreases in tail-withdrawal latencies for all doses of capsaicin occurred 15 min after administration, and latencies returned to baseline by 60 min after injection (data not shown). Figure 1 shows the T10 value 15 min after administration of vehicle or doses of capsaicin. The T10 (±1 S.E.M.) under capsaicin vehicle conditions was 48.0 ± 0.3°C (point above "V"). Doses of 0.01 and 0.032 mg of capsaicin only slightly decreased the T10. A larger dose of 0.1 mg of capsaicin decreased the T10 to 42.9 ± 1.0°C (a5.1°C change from vehicle control). A
redetermination of the thermal hypersensitivity produced by 0.1 mg of
capsaicin midway through these studies in each monkey was similar to
the first determination (T10 = 41.3 ± 0.8°C). Therefore, the first and second determination
were combined (T10 = 42.1 ± 0.7°C) in Fig. 1 and used for analysis of % MPE in other figures. A
larger dose of 0.32 mg of capsaicin did not further decrease the
T10. Based on these results, the
antinociceptive effects of drugs were studied 15 min after a dose of
0.1 mg of capsaicin.
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Effects of Piperazinyl Benzamide -Agonists under Conditions of
Capsaicin-Induced Thermal Hypersensitivity.
Figure
2 shows that SNC80 produced a
dose-dependent (left panel) and time-dependent (right panel) blockade
of capsaicin-induced thermal hypersensitivity. Doses of 1.0 and 3.2 mg/kg SNC80 partially blocked the effects of capsaicin. A higher dose
of 10.0 mg/kg SNC80 fully blocked the effects of capsaicin, and the
ED50 value for SNC80 is shown in Table
1. Importantly, although SNC80 increased tail-withdrawal latencies at the intermediate temperature of 46°C, higher temperatures of water (e.g., 50°C) elicited tail-withdrawal latencies near control values demonstrating that monkeys could make the
tail-withdrawal response. The antinociceptive effects of SNC80 had a
rapid onset and a short duration of action. The effects of SNC80 were
near maximal after 4 min, peaked at 15 min, and had nearly dissipated
after 60 min.
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|
)-enantiomer of SNC80, did not
produce antinociception at a dose of 10.0 mg/kg. Larger doses of SNC67
have been reported to produce convulsions in rhesus monkeys (Brandt et
al., 1999) and were not tested.
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-agonists, the effects of the
µ-agonist morphine and the NSAID ketorolac were also examined (Fig.
3, right panel). Morphine dose dependently and completely blocked
thermal hypersensitivity produced by capsaicin. A dose of 0.32 mg/kg
morphine fully blocked the effects of capsaicin. Morphine was 32-fold
more potent than SNC80 (Table 1). In contrast, ketorolac at doses up to
10.0 mg/kg did not block thermal hypersensitivity produced by capsaicin.
Figure 4 shows the effects of 10 mg/kg
SNC80 (left panel) or 0.32 mg/kg morphine (right panel) alone and in
combination with the -selective antagonist naltrindole or the
µ-selective opioid antagonist quadazocine. Naltrindole (0.01-1.0
mg/kg) dose dependently antagonized the antinociceptive effects of
SNC80 (left panel), and a dose of 1.0 mg/kg naltrindole significantly
antagonized the effects of 10.0 mg/kg SNC80. In contrast, 1.0 mg/kg
naltrindole did not antagonize the antinociceptive effects of morphine.
A µ-selective dose of quadazocine (0.1 mg/kg) antagonized the
antinociceptive effects of morphine but not of SNC80.
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Effects of SNC80 under Conditions of PGE2- and
FCA-Induced Thermal Hypersensitivity.
Figure
5 compares the effects of
PGE2 and FCA. PGE2 produced
a time-dependent thermal hypersensitivity with a longer duration of
action than capsaicin. Under baseline conditions, the
T10 was 48.2 ± 0.02°C. Maximal
thermal hypersensitivity of 0.0158 mg of PGE2
occurred 0.5, 0.75, and 1 h after injection, and
T10 values (±S.E.M.) at these times
were 44.3 (±0.06), 44.3 (±0.02), and 44.2 (±0.02)°C, respectively
(approximately a 4°C change from baseline; Fig. 5, left panel). The
effects of PGE2 began to dissipate at 1.5 h
and were similar to control values at 2 h. FCA also produced a
time-dependent thermal hypersensitivity with a long duration of action.
However, unlike capsaicin and PGE2, which
produced thermal hypersensitivity in all monkeys, concentrations of FCA up to 10% produced thermal hypersensitivity in only two of the three
monkeys. Therefore, the third monkey unresponsive to FCA was excluded
from the final study. Figure 5 (right panel) shows the magnitude and
duration of the effects of FCA. A concentration of 1% FCA had peak
effects between 0.5 and 2 h. T10
values at these times where between 44.2 and 44.6°C (approximately a
4°C change from baseline). A higher concentration of 10% FCA
decreased the T10 to values similar to
the lower FCA concentration; however, the duration of effect was
substantially longer with 10% FCA and lasted for more than 24 h.
Subsequent redetermination of tail-withdrawal latencies
(T10 = 48.1 ± 0.03°C) were
similar to original determinations.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The present series of studies was conducted to assess the effects
of SNC80 and other related -agonists under conditions of thermal
hypersensitivity in rhesus monkeys. -Agonists produced dose-dependent, stereoselective, and naltrindole-reversible
antinociception against three different chemical irritants. Moreover,
SNC80 was able both to prevent thermal hypersensitivity when it was
administered before the chemical irritant (capsaicin) and to reverse
thermal hypersensitivity when it was administered after the chemical
irritant (PGE2 and FCA). Finally, -agonists
produced antinociception as effectively as morphine and more
effectively than the clinically available NSAID ketorolac. These
findings suggest that -agonists may be useful clinically for the
management of some types of inflammatory pain, such as postoperative
pain or arthritis.
Thermal Hypersensitivity Produced by Chemical Irritants.
The
thermal hypersensitivity produced by capsaicin and
PGE2 observed in the present study replicates and
confirms earlier findings in rhesus monkeys (Negus et al., 1993b,
1995a; Ko et al., 1998, 1999). Capsaicin is a plant-derived compound
that acts as an agonist at vanilloid receptors located on primary
afferent nociceptors (Szallasi and Blumberg, 1999). In contrast,
PGE2 is a metabolite of the arachidonic
acid cascade that is produced endogenously under conditions of
inflammation or tissue damage, and it is thought to produce thermal
hypersensitivity by binding to endoperoxide receptors that are also
located on primary afferent nociceptors (Halushka et al., 1989; Taiwo
et al., 1989). Like capsaicin and PGE2, FCA also
produced thermal hypersensitivity in monkeys. FCA is a heat-killed
macrobacteria that produces thermal hypersensitivity by provoking an
inflammatory response at the site of injection. Taken together, these
findings indicate that thermal hypersensitivity can be produced in
monkeys by chemical irritants with differing mechanisms of action.
Moreover, thermal hypersensitivity induced by these irritants provides
a model for the assessment of drugs that may be useful for the
treatment of inflammatory pain.
Effects of -Agonists on Capsaicin-Induced Thermal
Hypersensitivity.
SNC80, SNC162, and SNC243A dose dependently
blocked the effects of capsaicin. The antinociceptive effects of SNC80
were stereoselective, because SNC67, the ()-enantiomer of SNC80, did
not block thermal hypersensitivity produced by capsaicin. In addition,
the antinociceptive effects of SNC80 were dose dependently antagonized
by -selective doses of naltrindole and not by a µ-selective dose
of quadazocine. These findings suggest that the antinociceptive effects
of SNC80 were mediated by -opioid receptors and extend our previous
studies on the -mediated behavioral effects of SNC80 in rhesus
monkeys (Negus et al., 1998; Brandt et al., 1999). These results also agree with the finding that peptidic -agonists attenuate chemically induced thermal hypersensitivity in rodents (e.g., Stein et al., 1989;
Stewart and Hammond, 1994; Zhou et al., 1998; Fraser et al., 2000).
; Brandt
et al., 1999). In agreement with the present findings, SNC80 also
produced discriminative stimulus effects and decreases in rates of
schedule-controlled behavior with a rapid onset of action. However,
these behavioral effects of SNC80 were still present after 1 h and
took several hours to dissipate completely. Moreover, these other
behavioral effects were produced by lower doses of SNC80. The reason
for this difference in the potency and time course of SNC80 in
producing different behavioral effects is not known. One possibility is
that blockade of capsaicin-induced thermal hypersensitivity requires
higher levels of -receptor stimulation than the other behavioral
measures, and as a result, antinociception can be achieved only with
high doses of high efficacy -agonists.
The findings with SNC86 in the present study are consistent with this
hypothesis. SNC86 is the active (+)-enantiomer of (±)-BW373U86, and
like SNC80, SNC86 and (±)-BW373U86 decrease rates of
schedule-controlled behavior and substitute for cocaine in monkeys
trained to discriminate cocaine from saline (Negus et al., 1993a, 1998;
Brandt et al., 1999). However, SNC86 and (±)-BW373U86 were less
effective than SNC80 in producing several other behavioral effects in
rhesus monkeys. For example, SNC86 and (±)-BW373U86 were less
effective than SNC80 in producing thermal antinociception (Negus et
al., 1998), antinociception against PGE2 or
capsaicin [cf. Butelman et al. (1995) and present study], and
cocaine-like discriminative stimulus effects in monkeys trained to
discriminate cocaine from saline (Negus et al., 1995b, 1998).
Similarly, (±)-BW373U86 was less effective than SNC80 in producing
antinociception in mice (cf. Wild et al., 1993; Bilsky et al., 1995)
and in enhancing the discriminative stimulus effects of cocaine in
squirrel monkeys (cf. Spealman and Bergman, 1994; Rowlett and Spealman,
1998). Finally, pretreatment with (±)-BW373U86 attenuated the
antinociceptive effects of SNC80 (Negus et al., 1998), and in the
present study, pretreatment with SNC86 attenuated the antinociceptive
effects of SNC80 against capsaicin-induced thermal hypersensitivity.
Taken together, these results are consistent with the view that SNC80 may have higher efficacy than SNC86 or (±)-BW373U86 at -opioid receptors. These findings also suggest that SNC86 has sufficient efficacy to produce some SNC80-like effects, such as suppression of
operant response rates and SNC80-like discriminative stimulus effects
(Brandt et al., 1999), but that it does not have sufficient efficacy to
block capsaicin-induced thermal hypersensitivity.
Previous studies found that µ-, -, and -agonists can reverse
chemically induced hypersensitivity in rats (Levine and Taiwo, 1989;
Stein et al., 1989; Zhou et al., 1998; Fraser et al., 2000) and µ-
and -agonists can reverse chemically induced thermal
hypersensitivity in monkeys (Ko et al., 1998, 1999) by acting at
peripheral opioid receptors. The present study did not determine
whether SNC80 and related -agonists produced antinociception by
acting at central or peripheral -receptors. However, as noted above,
the potency of SNC80 for producing antinociception in the present study
was similar to or lower than its potency for producing other behavioral effects that are presumably mediated by central -opioid receptors (e.g., rate suppression, discriminative stimulus effects, and antinociceptive effects against noxious thermal stimuli). Although these findings do not exclude a role for peripheral receptors in
mediating -agonist-induced antinociception, they do suggest that
central receptors are activated by antinociceptive doses of SNC80, and
these central receptors may contribute to the antinociceptive effects
of -agonists. In support of this conclusion, intracerebroventricular administration of SNC80 reverses thermal hypersensitivity associated with the administration of FCA into the plantar surface of the hindpaw
in rats (Fraser et al., 2000).
Effects of SNC80 on PGE2- and FCA-Induced Thermal
Hypersensitivity.
Capsaicin had a short duration of action that
necessitated the administration of drugs before the induction of
thermal hypersensitivity. However, analgesic agents used clinically are
typically administered after a state of inflammatory pain has been
established. Accordingly, we also conducted studies with longer-acting
chemical irritants to determine the degree to which SNC80 could reverse
chemically induced thermal hypersensitivity. SNC80 produced a
dose-dependent and complete reversal of the effects of both
PGE2 and FCA. Moreover, SNC80 was more potent in
reversing the effects of PGE2 and FCA than it was
in blocking the effects of capsaicin. Taken together, these findings
indicate that -agonists produce antinociceptive effects under a wide
range of conditions in rhesus monkeys.
-receptor activation. Finally,
recent anatomical evidence suggests that -receptors are
predominately localized intracellularly on the membranes of large
dense-core vesicles in the terminals of small dorsal root ganglia
neurons. These receptors may be externalized onto the plasmalemma under
conditions of chemical stimulation or inflammatory pain that would be
expected to stimulate these neurons (Zhang et al., 1998). These
findings raise the possibility that prolonged thermal hypersensitivity,
in contrast to the short thermal hypersensitivity induced by capsaicin,
may increase the density of active -opioid receptors and the potency
of -opioid agonists. Consistent with this last view, we and others
have demonstrated that -agonists produce antinociceptive effects
under conditions of chemically induced thermal hypersensitivity
(Butelman et al., 1995; current study) but only weak antinociceptive
effects in the absence of inflammation or chemical stimulation (Dykstra
et al., 1993; Negus et al., 1998; M. R. Brandt, unpublished
observation). Moreover, a recent study has demonstrated that the
potency of the -agonist
[D-Ala2,Glu4]deltorphin
is progressively enhanced 4 h, 4 days, and 2 weeks after the
intraplantar administration of FCA into the hindpaw of rats (Hurley and
Hammond, 2000). Together, these findings suggest that the therapeutic
potential of -agonists may be most evident under conditions of
allodynia and hyperalgesia.
Antinociceptive Effects of Morphine and Ketorolac under Conditions
of Capsaicin-Induced Thermal Hypersensitivity.
Results from the
current study confirm and extend previous studies indicating that
morphine potently prevents thermal hypersensitivity produced by
capsaicin and PGE2 in monkeys (Negus et al.,
1993b, 1995a). In contrast, the NSAID ketorolac did not prevent thermal hypersensitivity produced by capsaicin, and previous studies found that
ketorolac did not reverse thermal hypersensitivity produced by
PGE2 (Negus et al., 1995a). The failure of
ketorolac to produce antinociceptive effects under these conditions of
chemically induced thermal hypersensitivity was probably not a result
of inadequate dosing. In the present study, ketorolac was tested up to
a dose of 10.0 mg/kg, which is approximately 10 times the recommended analgesic dose for humans (i.e., 60 mg/70 kg). In addition, a dose of
1.0 mg/kg ketorolac effectively blocked thermal hypersensitivity induced by bradykinin in rhesus monkeys (Negus et al., 1995a). Thus, in
contrast to -agonists, NSAIDS are relatively ineffective in
attenuating thermal hypersensitivity induced by agents that act
directly on primary nociceptors.
Potential Adverse Effects.
Numerous adverse effects are
associated with nonopioid and opioid analgesics. For example, NSAIDs
may produce gastric irritation, µ-opioid agonists produce respiratory
depression and have abuse potential in humans, and -opioid agonists
have been shown to produce subjective effects in humans that have been
described as "dysphoric" or "psychotomimetic". In the present
study, doses of -agonists that produced antinociception under
conditions of chemically induced thermal hypersensitivity did not
produce signs of overt behavioral toxicity. In particular, although
SNC80 may produce convulsions in some strains of mice (e.g., Bilsky et
al., 1995), antinociceptive doses of SNC80 did not produce convulsions in the present study, and in previous studies, doses of SNC80 up to 56 mg/kg did not produce convulsions or other signs of severe toxicity in
rhesus monkeys (Negus et al., 1998; Negus, 1999). However, in agreement
with previous findings, antinociceptive doses of -agonists did
produce mild sedation, and similar doses of SNC80 and other
-agonists have been shown to decrease rates of schedule-controlled
responding and to produce discriminative stimulus effects (Negus et
al., 1998; Brandt et al., 1999). The potential impact of these effects
on the clinical utility of SNC80 and related -agonists remains to be determined.
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Acknowledgment |
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We thank Beth Moseley, D.V.M. for veterinary assistance.
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Footnotes |
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Accepted for publication November 20, 2000.
Received for publication September 5, 2000.
1 Current address: Wyeth-Ayerst Research, Wyeth Neuroscience, CN-8000, Princeton, NJ 08543-8000. E-mail: brandtm{at}war.wyeth.com
These studies were supported in part by Grants RO1-DA11460, P50-DA04059, T32-DA0752, and KO5-DA00101 from the National Institute on Drug Abuse (NIDA), National Institutes of Health. We also thank the NIDA for partial support for the Laboratory of Medicinal Chemistry, National Institute of Diabetics, Digestive and Kidney Diseases and National Institute of Health, Bethesda, MD.
Send reprint requests to: S. Stevens Negus, Ph.D., Harvard Medical School-McLean Hospital, Alcohol and Drug Abuse Research Center, 115 Mill St., Belmont, MA 02178-9106. E-mail: negus{at}mclean.org
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Abbreviations |
|---|
(±)-BW373U86, (±)-4-[(
R*)--[2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide;
SNC80, (+)-4-[(R)--[2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-methoxybenzyl]-N,N-diethylbenzamide;
SNC67, ()-4-[(S)--[2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-methoxybenzyl]-N,N-diethylbenzamide;
SNC86, (+)-4-[(S)--[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide;
SNC162, (+)-4-[(R)--[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-benzyl]-N,N-diethylbenzamide;
SNC243A, (+)-4-[(R)--[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-fluorobenzyl]-N,N-diethylbenzamide;
FCA, Freund's complete adjuvant;
% MPE, percentage maximum possible
effect;
NSAID, nonsteroidal anti-inflammatory drug;
PGE2, prostaglandin E2;
T10, temperature producing a 10-s tail-withdrawal latency.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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opioid agonist SNC80 in rhesus monkeys.
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, SNC243A; 
, SNC162; 
, SNC86; 
, SNC67; 
, morphine;
, ketorolac.
