Introduction

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Cocaine abuse continues to be a significant public health problem, and no consistently effective pharmacotherapy has been identified (Mendelson and Mello, 1996). One approach to the evaluation of candidate medications for cocaine abuse has been to examine medication effects on cocaine-maintained responding in drug self-administration procedures. We have proposed that a promising medication might be one that produced dose-dependent and sustained decreases in cocaine self-administration across a broad range of cocaine doses while producing minimal evidence of toxicity (Mello and Negus, 1996). The mixed action opioid buprenorphine appears to approach these criteria. In rhesus monkeys (Macaca mulatta), for example, chronic treatment with buprenorphine decreased cocaine self-administration for up to 120 days while producing smaller changes in responding maintained by food presentation and little other evidence of toxicity in the same monkeys (Mello et al., 1989; for review, see Mello and Mendelson, 1995). The ability of buprenorphine to decrease cocaine self-administration without major toxicity has been confirmed and extended in studies with rodents (Carroll and Lac, 1992), nonhuman primates (Carroll et al., 1992; Winger et al., 1992), and humans (Foltin and Fischman, 1994).

The basis for buprenorphine's effects on cocaine self-administration is not well understood. Buprenorphine is a mixed action opioid that binds with high affinity to the three major types of opioid receptors, the µ-, -, and -receptors (Rothman et al., 1995). Buprenorphine has intermediate efficacy at µ-receptors and acts as a partial µ-agonist, and it has very low efficacy at - and -receptors and acts primarily as a - and -antagonist (Cowan, 1995; Dykstra and Negus, 1995; S. S. Negus, unpublished observations). Current evidence suggests that the µ-agonist effects of buprenorphine are most important for its effects on cocaine self-administration. Buprenorphine-induced decreases in cocaine self-administration were blocked by the µ-selective antagonist naltrexone (Mello et al., 1993b), and cocaine self-administration was decreased by acute administration of other µ-agonists (Winger et al., 1992). It is also interesting to note that maintenance on both buprenorphine and the more selective µ-agonist methadone has often been reported to decrease cocaine use by polydrug abusers (Kosten et al., 1989; Gastfriend et al., 1993; Strain et al., 1994; Schottenfeld et al., 1997; Borg et al., 1999). In contrast, the - and -receptor-mediated effects of buprenorphine appear to be less important, because neither - nor -selective antagonists produced consistent decreases in cocaine self-administration in rhesus monkeys (Negus et al., 1995; Mello and Negus, 2000).

The intermediate efficacy of buprenorphine at µ-receptors may contribute to its ability to decrease cocaine self-administration without producing other severe adverse effects. Efficacy can be defined as the ability of a drug to activate transduction mechanisms associated with its receptor (Kenakin, 1993), and the influence of efficacy on µ-receptor-mediated behavioral and physiological effects has been extensively studied (Picker and Dykstra, 1989; Gerak et al., 1994; Butelman et al., 1995; Gatch et al., 1995; Negus and Mello, 1999; Cook et al., 2000). It is now well established that high-efficacy µ-agonists produce a broad range of effects (including antinociception, respiratory depression, discriminative stimulus effects, and changes in schedule-controlled responding) within a relatively narrow dose range. Lower efficacy agonists, in contrast, produce some agonist effects but not others, and there can be substantial differences in either the potency or the maximal effects of a lower efficacy agonist across different experimental endpoints.

Accordingly, the present study examined the hypothesis that relative efficacy at the µ-receptor might be an important determinant of the magnitude and selectivity of µ-opioid agonist effects on cocaine self-administration. Specifically, we postulated that opioids with low-to-intermediate efficacy at µ-receptors would decrease cocaine self-administration more selectively than high-efficacy µ-agonists. To test this hypothesis, we selected four opioid agonist analgesics that differ in relative efficacy at the µ-receptor, and that produce behavioral effects mediated primarily by µ-opioid receptors in rhesus monkeys (Gerak et al., 1994; Butelman et al., 1995; Gatch et al., 1995; Emmerson et al., 1996). Specifically, fentanyl has relatively high efficacy, morphine has intermediate efficacy, and butorphanol and nalbuphine have low efficacy at µ-opioid receptors. It should be noted, however, that these drugs also differ in their relative selectivity for µ-receptors, and nalbuphine and butorphanol in particular bind with relatively low selectivity to both µ- and -opioid receptors and may produce some effects in monkeys that are mediated by -opioid receptors (Vivian et al., 1999). The effects of continuous treatment for 7 consecutive days with all four opioids were examined on behavior maintained under identical second order schedules by 1-g food pellets and by a range of cocaine doses. Parallel studies examined the effects nalbuphine and butorphanol on the discriminative stimulus effects of cocaine in rhesus monkeys. These studies were conducted to assess the degree to which selective decreases in cocaine self-administration produced by nalbuphine and butorphanol could be attributed to a selective blockade of the abuse-related effects of cocaine. For comparison, we have shown previously that fentanyl and morphine produced cocaine-like discriminative stimulus effects in some monkeys, and these high-efficacy µ-agonists also produced additive effects with cocaine when they were administered in combination with cocaine (Negus et al., 1998).

	Materials and Methods

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Subjects

A total of nine male and three female rhesus monkeys were subjects in drug self-administration studies, and seven male monkeys were subjects in drug discrimination studies. All monkeys had an experimental history involving the evaluation of dopaminergic and/or opioid compounds in assays of drug self-administration or drug discrimination. Monkeys weighed 5 to 12 kg and were maintained on a diet of multiple vitamins, fresh fruit, and Lab Diet Jumbo Monkey biscuits (PMI Feeds, Inc., St. Louis, MO). In addition, monkeys could receive 1-g banana flavored pellets (Precision Primate Pellets Formula L/I Banana Flavor; P.J. Noyes Company, Inc., Lancaster, NH) during daily operant sessions (see below). Water was continuously available. 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 facility was licensed by the United States Department of Agriculture, and protocols were approved by the Institutional Animal Care and Use Committee. The health of the monkeys was periodically monitored by consulting veterinarians. Monkeys had visual, auditory, and olfactory contact with other monkeys throughout the study. Operant procedures and foraging toys provided opportunities for environmental manipulation and enrichment. Music or nature video tapes were also played daily in animal housing rooms to provide additional environmental enrichment.

Cocaine Self-Administration Procedures

Apparatus. Each monkey was housed individually in a well ventilated stainless steel chamber (64 × 64 × 79 cm) equipped with a custom-designed operant panel (28 × 28 cm) mounted on the front wall. Three square translucent response keys (6.4 × 6.4 cm) were arranged 2.54 cm apart in a horizontal row 3.2 cm from the top of the operant panel. Each key could be transilluminated by red or green stimulus lights (Superbright LEDs; Fairchild Semiconductor, San Jose, CA). In addition, three circular translucent panels (1.9 cm in diameter) were located in a vertical column below the center response key and could be transilluminated by red or green stimulus lights. Each housing chamber was also equipped with a pellet dispenser (model G5210; Gerbrands, Arlington, MA) and two syringe pumps (model B5P-lE; Braintree Scientific, Braintree, MA; or model 980210; Harvard Apparatus, South Natick, MA), one for each lumen of the double-lumen catheter. Operation of the operant panels and data collection were accomplished with microprocessors and software purchased from MED Associates (Georgia, VT).

Surgical Procedures. Double-lumen silicone rubber catheters (inside diameter 0.028 in.; outside diameter 0.088 in.; Saint Gobain Performance Plastics, Beaverton, MI) were implanted in the internal jugular or femoral vein and exited in the midscapular region. All surgical procedures were performed under aseptic conditions. Monkeys were initially sedated with ketamine (5-10 mg/kg), and anesthesia was induced with sodium thiopental (10 mg/kg i.v.). Atropine (0.05 mg/kg) was administered i.m. or s.c. to reduce salivation. After insertion of an endotracheal tube, anesthesia was maintained with isoflurane (1-2% in oxygen). After surgery, monkeys were given the antibiotic procaine penicillin G (300,000 units/kg/day i.m.) for 5 days. An analgesic dose of buprenorphine (0.032 mg/kg i.m.) was administered twice daily for 3 days.

Behavioral Procedures. Procedures for the evaluation of cocaine- and food-maintained responding were identical to those used in our previous studies of the effects of -opioids on cocaine self-administration (Mello and Negus, 2000). The conditions of food and cocaine availability were associated with different colored stimulus lights projected on the center response key of the operant response panel. The two side keys were not transilluminated during the food and drug self-administration studies, and responding on these keys had no scheduled consequences. During sessions of food availability, the center key was transilluminated with a red stimulus light, whereas during sessions of cocaine availability, the center key was transilluminated with a green stimulus light. Four food sessions and four drug sessions were conducted during each experimental day. Food sessions began at 6:00 AM, 11:00 AM, 3:00 PM, and 7:00 PM, and drug sessions began at 7:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM. At all other times, responding had no scheduled consequences. The experimental room was dark during all food and drug sessions. Each food and drug session lasted 1 h or until 25 food pellets or 20 injections had been delivered, whichever occurred first. Monkeys could earn a maximum of 100 food pellets per day and 80 injections per day.

Training Procedures. After initial shaping of key pressing by using food reinforcement, responding was maintained on a variable ratio (VR) schedule that was gradually increased from a VR1 to a VR16. Under this schedule, the response requirement for individual ratios varied randomly across a range of ±25%, and under the terminal VR16 schedule, the response requirement for individual ratios varied from 12 to 20. Completion of the VR response requirement resulted in the delivery of a single food pellet. In addition, completion of the VR response requirement resulted in 1) the illumination of a red stimulus light for 1 s below the center response key, and 2) the initiation of a 10-s time-out period, during which the stimulus light illuminating the center response key was turned off and responding had no scheduled consequences. After monkeys received at least 50 food pellets per day for three consecutive days under the VR16 schedule, behavior was maintained on a second order schedule that consisted of two components, a VR and fixed ratio (FR). Under this schedule, completion of each VR schedule component resulted in the illumination of the red stimulus for 1 s below the center response key and initiation of the 10-s time-out, and this is designated as [VR:S]. However, a food pellet was delivered only after completion of a fixed number (or fixed ratio) of VR components. The FR component was gradually increased to 2 or 4, so that monkeys had to complete two or four VR components for each food pellet. The terminal second order schedule response requirements were designated as FR2 [VR 16:S] or FR4 [VR 16:S]. The final response requirement averaged 32 (range 26-39) or 64 (range 53-78) responses.

Testing Procedures. The effects of repeated treatments with saline and the high-efficacy µ-agonist fentanyl, the intermediate-efficacy µ-agonist morphine, and the low-efficacy µ-agonists nalbuphine and butorphanol were studied. Saline and each dose of each opioid agonist were examined for 7 consecutive test days. Saline and opioids were administered by i.v. injection through the second lumen of the double-lumen catheter. Injections were delivered every 20 min from 10:30 AM each day until 9:30 AM the next morning for a total of 3 inj/h and 69 inj/day. No injections were delivered between 9:30 AM and 10:30 AM, and during this period, monkeys received their morning ration of food, and their health status was evaluated by the technical staff. At the conclusion of each 7-day test period with an opioid agonist, the maintenance dose of cocaine (0.032 mg/kg/inj) and saline control treatment were reinstated for a period of at least 4 days and until the number of reinforcers per day maintained by cocaine and food returned to baseline levels. This interval between successive treatments was designed to reduce the possibility of carryover effects from one treatment condition to the next.

Data Analysis. The total numbers of injections or food pellets delivered per day were determined. Data for the first series of experiments were evaluated using a two-factor analysis of variance, with opioid dose and treatment day as the two factors. For the second series of experiments, data are expressed as the mean (±S.E.M.) numbers of injections per day and pellets per day for the 7 days of each test condition. Data were evaluated using a two-factor analysis of variance with cocaine dose and opioid dose as the two factors. A significant analysis of variance was followed by individual means comparison using Duncan's post hoc test. The criterion for significance was set at p < 0.05.

Cocaine Discrimination Procedures

Apparatus. Each monkey was housed individually in a well ventilated, stainless steel chamber (56 × 71 × 69 cm) equipped with an operant panel identical to the one described above. In addition, the response panel supported an externally mounted pellet dispenser (model G5310; Gerbrands) that delivered 1-g fruit-flavored food pellets (P.J. Noyes Company, Inc.) to a food receptacle mounted on the cage beneath the response panel. Operation of the response panels and data collection were accomplished with IBM-compatible computers and interface systems (MED Associates) located in a separate room.

Training Procedures. Drug discrimination procedures were identical to those used in our previous studies of the effects of opioids on cocaine discrimination (Negus et al., 1998). Discrimination sessions consisted of multiple cycles and were conducted 5 days/week. Each cycle consisted of a 15-min time-out period followed by a 5-min response period. During the time-out, all stimulus lights were off and responding had no scheduled consequences. During the response period, the right and left response keys were transilluminated red or green, and monkeys could receive up to 10 food pellets by responding under an FR30 schedule of food presentation. For three of the seven monkeys, the left key was illuminated green and the right key was illuminated red. For the other four monkeys, the colors of the response keys were reversed. The center key was not illuminated at any time, and responding on the center key had no scheduled consequences. If all available food pellets were delivered before the end of the 5-min response period, the stimulus lights transilluminating the response keys were turned off, and responding had no scheduled consequences for the remainder of that response period.

Testing Procedures. Once monkeys met criterion levels of cocaine discrimination, testing began. Test sessions were identical to training sessions except that responding on either key produced food, and cocaine, nalbuphine, or butorphanol was administered as described below. Two series of experiments were conducted to characterize the effects of nalbuphine and butorphanol administered alone or as pretreatments to cocaine. The effects of fentanyl and morphine on cocaine discrimination in this procedure have been described previously (Negus et al., 1998).

Data Analysis. Graphs for percentage of cocaine-appropriate responding and response rates were plotted as a function of the cumulative dose of test compound (log scale). The percentage of cocaine-appropriate responding for a given cycle was calculated and reported only if the monkey emitted enough responses to earn at least one food pellet (i.e., 30 response, equivalent to a response rate of 0.1 responses/s). In group graphs, data for percentage of cocaine-appropriate responding are plotted only if at least four of the seven monkeys met the response rate criterion.

Drugs

Cocaine HCl, fentanyl HCl, and morphine sulfate was obtained from the National Institute on Drug Abuse (Bethesda, MD) and were dissolved in sterile water. Nalbuphine HCl was purchased from Sigma/RBI (Natick, MA) and was also dissolved in sterile water. Butorphanol tartrate was used as the commercially available Torbutrol solution (Fort Dodge Animal Health, Overland Park, KS). All drug solutions were filter-sterilized using a 0.22-µm Millipore filter and stored in pyrogen-free vials. Doses were calculated using the salt forms of the drugs given above.

	Results

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Dose Dependence of µ-Agonist Effects on Cocaine- and Food-Maintained Responding. Figure 1 shows the mean effects of treatment with saline and the opioid agonists fentanyl, morphine, nalbuphine, and butorphanol on responding maintained by 0.01 mg/kg/inj cocaine and food pellets. During saline treatment, monkeys responded for approximately 70 to 80 cocaine injections per day and for 80 to 100 food pellets per day. All four opioid agonists produced a dose-dependent and significant decrease in cocaine self-administration. However, the selectivity of these effects depended on the efficacy of the µ-agonist.

View larger version (24K): [in this window] [in a new window]   Fig. 1.   Effects of µ-agonists on responding maintained by cocaine injections (0.01 mg/kg/injection; right) or food pellets (left). Abscissae, dose of the µ-agonist in milligrams per kilogram per hour. Bars over "Saline" show data collected during saline treatment. Ordinates, number of cocaine injections (maximum = 80) or food pellets (maximum = 100) delivered per day. Each bar shows mean data (±S.E.M.) for 7 consecutive days of treatment in four monkeys. Asterisks indicate effects significantly different from saline. , p < 0.05; , p < 0.01.

Time Course of µ-Agonist Effects on Cocaine- and Food-Maintained Responding. Figure 2 shows mean data for each of the 7 days of treatment with saline and with the highest dose of each of the µ-agonists. Monkeys responded for most of the food pellets and 0.01 mg/kg/inj cocaine injections throughout the 7 days of saline treatment. Cocaine self-administration was decreased during treatment with each of the µ-agonists. In general, peak decreases in cocaine self-administration were apparent by the 2nd day, and these decreases were sustained throughout the 7-day treatment period. The higher efficacy µ-agonists fentanyl and morphine also tended to decrease food-maintained responding, but the lower efficacy µ-agonists nalbuphine and butorphanol produced selective effects on cocaine self-administration with little or no change in food-maintained responding throughout the 7-day treatment period.

View larger version (44K): [in this window] [in a new window]   Fig. 2.   Time course of effects of saline (left) and the highest dose of each µ-agonist (right) on responding maintained by cocaine injections (0.01 mg/kg/injection) and food pellets. Abscissae, consecutive days of treatment. Ordinates, number of cocaine injections (left) or food pellets (right) delivered per day. Point shows mean data (±S.E.M.) from four monkeys. Data in the shaded regions on the far right show cocaine- and food-maintained responding during the 5 days after treatment with the highest dose of each µ-agonist (post-treatment days 1-5, P1-P5).

µ-Agonist Effects on Cocaine Self-Administration Dose-Effect Curve. The left panels of Figs. 3 (fentanyl and morphine) and 4 (nalbuphine and butorphanol) show cocaine self-administration dose-effect curves during saline treatment and during treatment with the µ-agonists. Data for responding maintained by food are shown in the right panels of Figs. 3 and 4. During saline treatment, monkeys responded at low levels for saline injections (points over Sal). Cocaine (0.001-0.1 mg/kg/inj) dose dependently maintained drug self-administration responding. The cocaine dose-effect curve had an inverted U-shape, and peak levels of cocaine self-administration occurred at unit doses of 0.01 to 0.032 mg/kg/inj. Monkeys responded at high, stable levels for food during availability of saline and cocaine doses up to 0.032 mg/kg/inj. Rates of food-maintained responding decreased to varying degrees across monkeys during availability of the high dose of 0.1 mg/kg/inj cocaine.

View larger version (36K): [in this window] [in a new window]   Fig. 3.   Effects of fentanyl and morphine on the cocaine self-administration dose-effect curve (left) and food-maintained responding (right). Abscissae, unit dose of cocaine in milligrams per kilogram per injection (log scale). Points above "Sal" show data obtained when saline was substituted for cocaine as the solution available for self-administration. Ordinates, number injections per day (left) and food pellets per day (right). Each point shows mean data (±S.E.M.) for 7 consecutive days of treatment in three monkeys except where indicated in parentheses. Filled points show effects significantly different from cocaine alone (p < 0.05).

View larger version (35K): [in this window] [in a new window]   Fig. 4.   Effects of nalbuphine and butorphanol on the cocaine self-administration dose-effect curve (left) and food-maintained responding (right). Other details as in Fig. 3

Effects of Nalbuphine and Butorphanol on Cocaine Discrimination. The effects of nalbuphine and butorphanol on cocaine discrimination were evaluated for comparison with their effects on cocaine self-administration. The effects of fentanyl and morphine on cocaine discrimination in this procedure have been described previously (Negus et al., 1998).

View larger version (32K): [in this window] [in a new window]   Fig. 5.   Effects of nalbuphine administered alone (left) or as a pretreatment to cocaine (right) in monkeys trained to discriminate cocaine from saline. Abscissae, dose of nalbuphine (left) or cocaine (right) in milligrams per kilogram (log scale). Ordinates, percentage of cocaine-appropriate responding (top) or response rate in responses per second (bottom). All dose-effect curves were determined in seven monkeys. Data were plotted in the top panel only if at least four of the seven monkeys met the response rate criterion of at least 0.1 responses/s. Thus, points in the top panels show mean data from four to seven monkeys. All points in the bottom panel show mean data from all seven monkeys. For clarity, error bars (S.E.M.) in the right panels are shown only for cocaine alone.

View larger version (33K): [in this window] [in a new window]   Fig. 6.   Effects of butorphanol administered alone (left) or as a pretreatment to cocaine (right) in monkeys trained to discriminate cocaine from saline. Other details as in Fig. 5.

	Discussion

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Effects of µ-Agonists on Cocaine Self-Administration. The high-efficacy µ-agonist fentanyl, the intermediate-efficacy µ-agonist morphine, and the low-efficacy µ-agonists nalbuphine and butorphanol all produced dose-dependent decreases in cocaine self-administration across a broad range of cocaine doses. These findings agree with previous reports that µ-agonists decreased cocaine self-administration by humans (Foltin and Fischman, 1994), rhesus monkeys (Mello et al., 1989; Carroll et al., 1992; Winger et al., 1992; Mello and Mendelson, 1995) and rodents (Carroll and Lac, 1992). The role of µ-agonist efficacy as a determinant of these effects has not been extensively examined. In a study that used procedures similar to those used herein, the intermediate-efficacy µ-agonist buprenorphine dose-dependently decreased cocaine self-administration, whereas the µ-antagonist naltrexone had little effect (Mello et al., 1990). Moreover, buprenorphine-induced decreases in cocaine self-administration were blocked by naltrexone (Mello et al., 1993b). These results suggested that some µ-agonist activity was required to produce robust decreases in cocaine self-administration. Similarly, Winger et al. (1992) examined the acute effects of a series of µ-opioids on complete cocaine self-administration dose-effect curves in rhesus monkeys. The µ-agonists nalbuphine, buprenorphine and heroin all dose-dependently decreased cocaine self-administration and produced downward shifts in the cocaine self-administration dose-effect curves, whereas the µ-selective opioid antagonist quadazocine had little effect on cocaine self-administration. Taken together with the results of the present study, these findings suggest that cocaine self-administration is decreased by µ-agonists with a wide range of efficacies at µ-opioid receptors.

Selectivity of µ-Agonist Effects on Cocaine Self-Administration. At least one dose of each µ-agonist produced a selective decrease in 0.01 mg/kg/inj cocaine self-administration without significantly altering behavior maintained by food presentation. This finding agrees with previous reports that µ-agonist effects on rates of operant responding may vary as a function of the reinforcer used to maintain responding (Katz and Goldberg, 1986; Mello et al., 1989). The low-efficacy µ-agonists nalbuphine and butorphanol produced the greatest decreases in cocaine self-administration across the broadest range of µ-agonist doses while producing the smallest effects on food-maintained responding. In contrast, the higher efficacy µ-agonists morphine and fentanyl selectively decreased cocaine self-administration across a relatively narrow range of doses, and higher doses produced pronounced undesirable effects, including sedation and significant decreases in food-maintained responding. These undesirable effects limited the range of high-efficacy µ-agonist doses that could be tested. These results support our hypothesis that opioids with lower efficacy at µ-receptor decrease cocaine self-administration more selectively than higher efficacy µ-agonists.

Effects of Withdrawal from µ-Agonist Treatment. After termination of chronic µ-agonist treatment, abstinence signs characteristic of µ-agonist withdrawal (Woods and Gmerek, 1985) were rarely observed (e.g., vomiting was observed in only one monkey after termination of treatment with the highest dose of fentanyl). In addition, cocaine self-administration recovered rapidly, and this finding is consistent with previous studies (Mello and Mendelson, 1995; Winger and Woods, 2001). However, termination of high-dose µ-agonist treatment often produced a transient decline in food-maintained responding, and decreases in food-maintained responding after termination of chronic opioid administration have been interpreted as a sensitive withdrawal sign indicative of physical dependence (Holtzman and Villarreal, 1973). These results suggest that µ-agonist doses that decreased cocaine self-administration in the present study may have produced modest levels of physical dependence.

Potential Role of -Receptor-Mediated Effects for Nalbuphine and Butorphanol. Nalbuphine and butorphanol produce agonist effects mediated primarily by µ-opioid receptors in rhesus monkeys (Gerak et al., 1994; Butelman et al., 1995). However, these compounds have only modest selectivity for µ- versus -receptors and may produce -receptor-mediated effects under some conditions. In vitro studies indicated that both compounds have relatively low efficacy at -receptors, and behavioral studies in rhesus monkeys found that irreversible blockade of µ-receptors unmasked weak -agonist effects of butorphanol but not of nalbuphine (Vivian et al., 1999). We reported previously that low-efficacy -ligands had little effect on cocaine self-administration (Mello and Negus, 2000), and as a result, it is unlikely that the low-efficacy actions of nalbuphine and butorphanol at -receptors contributed to their effects in the present study. However, intermediate- to high-efficacy -agonists do decrease cocaine self-administration in rhesus monkeys, and mixed action µ/-agonists produce greater decreases in cocaine self-administration with fewer undesirable effects than highly selective -agonists (Mello and Negus, 2000). Thus, we cannot exclude a role for the -receptor-mediated effects of nalbuphine and butorphanol in decreasing cocaine self-administration.

µ-Agonist Effects on Cocaine Discrimination. The low-efficacy µ-agonists nalbuphine and butorphanol substituted for cocaine in some monkeys and produced dose-dependent rate decreasing effects in all monkeys. When nalbuphine and butorphanol were administered as pretreatments to cocaine, the discriminative stimulus and rate-decreasing effects of the opioids and cocaine were approximately additive. Consequently, nalbuphine and butorphanol produced leftward shifts in the cocaine discrimination and rate suppression dose-effect curves. These results agree with a previous study from our laboratory, which found that the intermediate- to high-efficacy µ-agonists morphine and fentanyl also mimicked the discriminative stimulus effects of cocaine in some rhesus monkeys and produced approximately additive effects when administered in combination with cocaine (Negus et al., 1998). These findings in rhesus monkeys also agree with studies in humans, which found that both acute and chronic treatment with µ-agonists increased abuse-related subjective effects of cocaine (Foltin and Fischman, 1992, 1994; Foltin et al., 1995; Preston et al., 1996), even though cocaine self-administration was reduced (Foltin and Fischman, 1994). One implication of these findings is that µ-agonists may enhance some effects of cocaine while decreasing cocaine self-administration. A second implication of these findings is that decreases in cocaine self-administration produced by low- and high-efficacy µ-agonists do not result from a general blockade of the abuse-related behavioral effects of cocaine.

Clinical Implications. µ-Agonist-induced decreases in cocaine self-administration are concordant with the clinical finding that µ-agonists often decrease cocaine use by cocaine-dependent polydrug abusers (Kosten et al., 1989; Gastfriend et al., 1993; Strain et al., 1994; Schottenfeld et al., 1997; Borg et al., 1999). The extent to which these clinically observed decreases in cocaine use reflect a selective pharmacological effect of the opioid treatment medication on cocaine's reinforcing effects is unclear. Certainly, a number of other factors related to treatment, such as exposure to counseling, may have contributed to these effects. It is also important that cocaine abuse persists in many patients on opioid maintenance (Mello and Mendelson, 1995), and some patients may even initiate cocaine use while on treatment (Condelli et al., 1991; Borg et al., 1999). Finally, it should be noted that even for the low-efficacy µ-agonists, high doses were required to decrease cocaine self-administration relative to doses that are used clinically to produce analgesia (e.g., the lowest effective dose of butorphanol in the present study, 0.01 mg/kg/h, is equivalent to about 16 mg/day butorphanol in a 70-kg human). Nonetheless, the finding that µ-agonists decrease both cocaine self-administration in preclinical studies and cocaine use in many polydrug abusers suggests that opioid maintenance drugs may deserve careful consideration as candidate pharmacotherapies for cocaine abuse.