Behavioral maintenance of high concentrations of blood ethanol and physical dependence in the rat.

Rats maintained on an intermittent food schedule with an available ethanol solution drink to excess (13.1 grams of ethanol per kilogram of body weight, daily). Removal of ethanol produces symptoms of physical dependence including death from tonic-clonic seizures. Overindulgence in oral self-administration of an aqueous ethanol solution, resulting in unequivocal physical dependence, approximates a model of human alcoholism.

Use of in vivo apparent pA2 analysis in assessment of opioid abuse liability.

Abuse liability testing of opioid drugs was originally motivated by attempts to separate the analgesic effects of opioids from their likelihood for abuse. It has become apparent that the human population group likely to abuse opioids has little overlap with the population group requiring opioids to treat pain, therefore there is no longer a need to separate these two properties of opioids. This is fortunate, since, as reviewed here by Jim Woods and colleagues, the results of the plethora of studies that have attempted to distinguish these two properties in known opioids strongly indicate that they are inseparable. Evaluation of the abuse potential of novel opioids remains, however, critically important in deciding on governmental restrictions on their accessibility. In addition, opioid abuse liability testing contributes enormously to our understanding of the behavioral mechanism of action of these drugs, and in surprising and helpful ways has increased our appreciation of the various test systems used to garner information about them.

Reinforcing and discriminative stimulus effects of 1-benzylpiperazine and trifluoromethylphenylpiperazine in rhesus monkeys.

1-Benzylpiperazine (BZP) and 1-(3-trifluoromethylphenyl)piperazine (TFMPP) are two designer drugs that are often sold in combination tablets via the internet. The discriminative stimulus properties and reinforcing effects of these compounds have not previously been assessed in laboratory primates. In this regard, the reinforcing effects of BZP and TFMPP (alone, and in combination) were assessed via intravenous self-administration in rhesus monkeys previously trained to self-administer cocaine, while the discriminative stimulus effects of these compounds were determined in rhesus monkeys trained to discriminate amphetamine (AMPH) from saline. BZP was an effective reinforcer in self-administration tests, and appeared to induce long-lasting direct effects on behavior following sessions where BZP intakes were large. Additionally, BZP occasioned AMPH-appropriate responding in a dose-dependent manner, and produced full generalization in all monkeys tested. In contrast, TFMPP was not self-administered by any subjects and occasioned essentially no AMPH-appropriate responding at any dose tested. Non-contingent TFMPP administration had direct effects on behavior and abolished subsequent cocaine-maintained responding. Similarly, self-administration of various ratios of BZP:TFMPP combinations engendered less responding than did BZP alone. The present results suggest that BZP has abuse liability of the amphetamine type, but that such effects are not shared by TFMPP.

Intravenous self-administration studies with l-deprenyl (selegiline) in monkeys.

l-Deprenyl and its stereoisomer d-deprenyl did not maintain intravenous self-administration behavior in rhesus monkeys. In contrast, l-methamphetamine, the major metabolite of l-deprenyl, as well as the baseline drug, cocaine, maintained high rates of intravenous self-administration behavior. Treatment with l-deprenyl doses up to 1.0 mg/kg before self-administration sessions failed to alter self-administration of either cocaine or l-methamphetamine. Thus l-deprenyl did not appear to have cocaine- or methamphetamine-like reinforcing properties in monkeys and was ineffective in altering established patterns of psychomotor-stimulant self-administration behavior. These results support clinical findings that despite long-term use of l-deprenyl for the treatment of Parkinson's disease by large numbers of patients, no instances of abuse have been documented. l-Deprenyl has recently been suggested as a potential medication for the treatment of various types of drug abuse, including cocaine abuse, but its failure to produce selective effects in decreasing cocaine or methamphetamine self-administration behavior in the present experiments makes such an application seem unlikely.

Opioid and non-opioid effects of novel butyrophenone analogues.

Haloperidol, haloperidol propionate, and a haloperidol analogue N-3-(p-fluorobenzoyl) propyl-4-phenyl-4-propionyl-oxypiperidine (NIH 10495) were evaluated in several in vitro and in vivo tests of opioid effects. Haloperidol bound to opioid receptors with very low affinity and had no opioid agonist effects in the other test systems. Haloperidol propionate was 10 times less potent than NIH 10495 in the binding assay and in the smooth-muscle assay. Both of these haloperidol analogues decreased the rate and volume of respiration in air and in 5% CO2 with NIH 10495 being approximately 50 times more potent than haloperidol propionate. The NIH 10495, but not the haloperidol propionate, attenuated naltrexone-like discriminative stimulus effects in morphine-dependent withdrawn rhesus monkeys. Intravenously delivered NIH 10495 maintained higher rates of responding than did haloperidol propionate when evaluated for reinforcing effects. These drugs appear to have novel spectra of action that suggest possible value for this synthetic approach to the development of clinically useful analgesics and to the development of novel neuroleptics.

Discriminative stimulus effects of pentobarbital in rhesus monkeys: tests of stimulus generalization and duration of action.

Rhesus monkeys were trained to emit 20 or 30 consecutive responses on one lever following an IM injection of pentobarbital (10 or 18 mg/kg) and the same number of consecutive responses on another lever following an injection of saline. The required number of correct consecutive responses in both cases resulted in food delivery. When responding was reliably under the control of the presession injection, the ability of a variety of other compounds to produce pentobarbital-appropriate responding was examined. Diazepam, clobazam, methohexital, pentobarbital, and phenobarbital, given 10 or 20 min before the session, produced dose-related pentobarbital-appropriate responding in each monkey. Ethylketazocine and dextromethorphan produced responding primarily on the saline-appropriate lever, whereas codeine, cyclazocine, dextrorphan, and ketamine resulted in responding that was, on the average, intermediate between that appropriate for pentobarbital and that appropriate for saline. When tested at various times after their injection, methohexital (3.2 mg/kg) and pentobarbital (10 mg/kg) produced pentobarbital-appropriate responding within 10 min. Barbital (56 mg/kg) resulted in pentobarbital-appropriate responding only if at least 1 h intervened between the injection and the experimental session. The discriminative effects of methohexital, pentobarbital, and barbital lasted approximately 20-60, 120-240, and 480-720 min, respectively. The time-course of the discriminative stimulus effects of barbiturates in the rhesus monkey appears to parallel closely other pharmacological actions of these compounds.

Selective blockade of the discriminative stimulus effects of pentobarbital in pigeons.

The ability of CNS stimulants to block the discriminative effects of pentobarbital was studied in pigeons trained to discriminate IM pentobarbital (5 mg/kg) from saline. Pentobarbital, when administered alone, consistently produced greater than 90% pentobarbital-appropriate responding. The concomitant administration of pentobarbital and increasing doses of bemegride or pentylenetetrazol resulted in a dose-related decrease in pentobarbital-appropriate responses. In contrast, picrotoxin, another CNS stimulant, had little or no effect on pentobarbital-appropriate responding produced by pentobarbital.

Current benzodiazepine issues.

This article deals with some of the recent evidence bearing on the issues of the liability of benzodiazepines to lead to abuse, dependence, and adverse behavioral effects. Reviews of epidemiological, clinical and experimental literature indicated that the previous conclusion about abuse of these drugs still holds: the vast majority of the use of benzodiazepines is appropriate. Problems of nonmedical use arise nearly exclusively among people who abuse other drugs. Nevertheless, there are reasons for concern about patients who take benzodiazepines regularly for long periods of time. These drugs can produce physiological dependence when taken chronically, and although this does not appear to result in dose escalation or other evidence of "psychological dependence," physiological dependence can result in patient discomfort if drug use is abruptly discontinued. Also, physicians are currently prescribing shorter-acting benzodiazepines in preference to longer-acting benzodiazepines. The shorter-acting drugs can produce a more intense withdrawal syndrome following chronic administration. Furthermore, rates of use of benzodiazepines increase with age, and elderly patients are more likely than younger ones to take the drug chronically. The clearest adverse effect of benzodiazepines is impairment of memory. This, too, may be particular concern in older patients whose recall in the absence of drug is typically impaired relative to younger individuals, and who are more compromised following drug administration.

The effects of ethanol, phenobarbital, and baclofen on ethanol withdrawal in the rhesus monkey.

Physical dependence on ethanol was produced in four rhesus monkeys by IV ethanol administration every 8 h. Ethanol was administered on each occasion until the eyeblink reflex was lost. Evidence of physical dependence development, in the form of tremoring 8 h after an infusion, appeared on day 8 of chronic administration. Abrupt cessation of ethanol administration following 16 days of chronic administration was accompanied by moderate to severe tremoring, retching, vomiting, and one or more convulsions. Peak withdrawal occurred between 12 and 32 h after abrupt discontinuation of ethanol administration, and decreased over a period of 64-204 h. Ethanol dependence was then reinstated. Once every 3-4 days, ethanol was withheld for 16 h. Withdrawal signs were scored for the first 12 h of this period, and then a test dose of ethanol, phenobarbital, or baclofen was administered. Withdrawal or intoxication signs were scored over the next 4 h, at which time ethanol administration was resumed. Both ethanol and phenobarbital suppressed ethanol withdrawal signs in a dose-related manner, and produced dose-related intoxication. Baclofen was largely ineffective in reducing withdrawal-induced tremors, although it was capable of producing sedation of a different type than that produced by phenobarbitol and ethanol.

Observing responses maintained by stimuli associated with cocaine or remifentanil reinforcement in rhesus monkeys.

RATIONALE: The stimuli associated with drug reinforcement may be particularly relevant to drug abuse and relapse. OBJECTIVES: The study measured behavior maintained by conditioned reinforcing stimuli in an observing response procedure. METHODS: The experiment was conducted with rhesus monkeys in three stages: 1) discriminative control was established by reinforcing responding on one lever with either intravenous cocaine or remifentanil in the presence of one stimulus and extinguishing the response in the presence of another stimulus, 2) discriminative control was suspended by not presenting the stimuli, and 3) a final stage was implemented wherein the stimuli from the first stage were presented only when one or more responses were made on a second (observing) lever. RESULTS: Under FR1 conditions, observing responses were maintained at low rates, but increased markedly when the response requirement was increased. CONCLUSIONS: The procedure maintained observing responses quite well and may be useful to an analysis of conditioned reinforcement based on drug reinforcement.

Ethanol effects on self-administration of alfentanil, cocaine, and nomifensine in rhesus monkeys.

A common form of polydrug use is that of cocaine and ethanol. The identification of an ethanol-cocaine combination product, cocaethylene, with properties in common with cocaine, has led to speculation that this metabolite may contribute to the co-abuse of cocaine and ethanol. In order to determine whether ethanol pretreatments selectively altered cocaine's reinforcing potency, ethanol pretreatments were given to monkeys trained to press levers and receive IV infusions of several doses of cocaine or alfentanil. In addition, nomifensine, a drug which has a mechanism of action similar to cocaine's, was evaluated in the presence and absence of ethanol in monkeys with the cocaine baseline history. Ethanol, in doses ranging from 100 to 1780 mg/kg, given 10 min before the 130-min session, had no effect on responding maintained by alfentanil. These doses also had no significant effect on cocaine-maintained responding, although the potency of cocaine as a reinforcer was increased following administration of 1000 mg/kg ethanol in two of the four subjects. The potency of nomifensine as a reinforcer was significantly increased by 1000 mg/kg ethanol, but again, this enhancement was limited to the same two subjects. These data indicate that, in this paradigm, cocaethylene did not selectively modify cocaine's reinforcing potency, but there appear to be individual differences with respect to ethanol's ability to stimulate rates of drug-maintained responding.

Psychomotor stimulant effects of beta-phenylethylamine in monkeys treated with MAO-B inhibitors.

RATIONALE AND OBJECTIVE: Sufficiently high doses of beta-phenylethylamine (beta-PEA), a trace amine that is rapidly metabolized by monoamine oxidase-type B (MAO-B), can produce effects comparable to those of cocaine or methamphetamine (MA). The present experiments were conducted to study how the discriminative-stimulus (S(D)) and reinforcing-stimulus (S(R)) effects of beta-PEA in monkeys are modified by treatment with inhibitors of MAO-B [R-(-)-deprenyl and MDL 72974]. METHODS AND RESULTS: In studies of its S(D) effects, doses of beta-PEA up to 30 mg/kg engendered only sporadic responding on the drug-associated lever in squirrel monkeys that discriminated intramuscular injections of 0.3 mg/kg MA from vehicle whereas lower doses of 0.3-1.0 mg/kg beta-PEA produced full substitution when administered after either R-(-)-deprenyl or MDL 72974 (0.3 mg/kg). The MA-like S(D) effects of beta-PEA were attenuated by either dopamine D(1) or D(2) receptor blockers. In studies of its S(R) effects, high doses of beta-PEA maintained responding in two of three monkeys under a second-order fixed-interval schedule (3.0 or 10 mg/kg per injection) and two of three monkeys under a simple fixed ratio (FR) schedule (0.3-1.0 mg/kg per injection) of intravenous (i.v.) self-administration. MAO-B inhibition by R-(-)-deprenyl or MDL 72974 enhanced the S(R) effects of beta-PEA in all monkeys and, under the FR schedule, induced a 30-fold or greater leftward shift in the dose-response function for its i.v. self-administration. Based on time-course determinations, the enhanced S(R) effects of beta-PEA under the FR schedule were long-lasting and dissipated gradually over 3-7 days. CONCLUSIONS: These results show that inhibition of MAO-B enhances S(D) and S(R) effects of beta-PEA in monkeys, presumably by delaying its inactivation. MAO-B inhibition leading to increased levels of beta-PEA may be useful, alone or in combination with other therapeutic agents, in the pharmacological management of selected aspects of drug dependence.

Discriminative stimulus effects of pentobarbital in pigeons.

Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0--17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6--17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3--3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.

Glucocorticoid-reinforced responding in the rhesus monkey.

RATIONALE: Glucocorticoids have been reported to have rewarding effects in rats and may lead to drug-seeking behavior in humans under some circumstances. OBJECTIVES: The present study investigated whether glucocorticoids would be self-administered intravenously by rhesus monkeys (Macaca mulatta). METHODS: Ten monkeys, 7 male and 3 female, were maintained on a fixed ratio 10 (30 or 100), time-out 10-s schedule for 0.1 mg/kg methohexital or saline injections. Dexamethasone (0.03-0.3 mg/kg), methylprednisolone (0.1-1.0 mg/kg) and hydrocortisone (0.3-3.0 mg/kg) were periodically substituted for methohexital or saline. RESULTS: Dexamethasone (0.3 mg/kg) was self-administered by all of the male monkeys on the first, but not on subsequent occasions. It was hypothesized that suppression of hypothalamic-pituitary-adrenal (HPA) activity by these exogenous glucocorticoids following their first presentation may have interfered with their reinforcing effects on subsequent evaluation. Subsequently, plasma adrenocorticotropin and cortisol were measured in four male monkeys to ascertain that normal basal HPA activity had resumed prior to each glucocorticoid substitution. Of the ten monkeys that were tested, only one reliably self-administered dexamethasone, methylprednisolone and hydrocortisone, and he did so regardless of whether his basal HPA activity was suppressed. This monkey differed from some of the other monkeys both behaviorally and in his response to intravenous corticotropin releasing hormone. None of the three female monkeys that were tested with selected glucocorticoid doses showed any evidence of glucocorticoid reinforcement on any occasion. CONCLUSIONS: The results indicate that glucocorticoids were not reinforcing to the majority of monkeys in this study; nevertheless, large individual differences may exist in proclivity of monkeys to self-inject these compounds.

Methoclocinnamox: time course of changes in alfentanil-reinforced responding in rhesus monkeys.

RATIONALE: Methoclocinnamox (MC-CAM) possesses initial partial micro-opioid agonist activity with subsequent long-lasting micro-antagonist effects. This profile of activity is similar to that of buprenorphine, a compound with proposed use in the treatment of opioid abuse, suggesting a possible therapeutic use for MC-CAM as well. OBJECTIVE: The current study assessed the time course of the ability of MC-CAM and buprenorphine to antagonize the reinforcing effects of alfentanil and compared this with that of buprenorphine. METHODS: Rhesus monkeys self-administered a range of doses of alfentanil (0.03-1 microg/kg per injection) under a fixed-ratio 30, time-out 45 s schedule of i.v. drug delivery. MC-CAM was substituted for alfentanil on occasion, and a dose of 1.0 mg/kg MC-CAM or buprenorphine was given prior to sessions in which alfentanil was available. In the pretreatment studies, a wider range of alfentanil doses was utilized (0.03-30 microg/kg per injection). RESULTS: MC-CAM maintained self-administration behavior and was nearly equipotent with buprenorphine as a reinforcer in this paradigm. Both drugs, when given prior to a session in which alfentanil was available, produced a decrease in the reinforcing potency of alfentanil. The antagonist effects of the pretreatments were largest 30 min following administration and decreased over the next several days. The duration of MC-CAM's antagonism of alfentanil was approximately 4 days: the duration of buprenorphine as an antagonist was approximately 2 days. CONCLUSION: These data suggest that MC-CAM has a longer duration of antagonist effects than buprenorphine and it may therefore have an advantage in the treatment of opioid abuse.

Discriminative and reinforcing effects of brotizolam in rhesus monkeys.

The reinforcing and discriminative stimulus effects of brotizolam, a benzodiazepine-hypnotic, were evaluated in rhesus monkeys. In one experiment, separate groups of monkeys (N = 3 group) were trained to discriminate pentobarbital (10 mg/kg, IG) or d-amphetamine. (0.56-1.0 mg/kg, IG) from saline, in a discrete-trials avoidance/escape paradigm. Pentobarbital (5.6-10 mg/kg), diazepam (1.0-1.7 mg/kg), and brotizolam (0.3-1.7 mg/kg) resulted in 100% drug-lever responding in all three pentobarbital-trained monkeys. In d-amphetamine-trained monkeys brotizolam administration resulted only in saline-lever responding. In another experiment, monkeys were surgically prepared with indwelling intravenous catheters and lever pressing resulted in an injection of 0.1 mg/kg/injection sodium methohexital under a fixed-ratio 10 (FR 10) schedule. Pentobarbital (0.01-0.3 mg/kg/injection) and diazepam (0.003-0.10 mg/kg/injection) maintained responding above saline control levels when substituted for methohexital. Brotizolam (0.001-0.01 mg/kg/injection) resulted in more injections received compared to saline, but fewer injections compared to pentobarbital or diazepam. Thus, results from the present experiment suggest that brotizolam would have pentobarbital-like subjective effects. However, the abuse liability of brotizolam may be lower than that for diazepam.

Effect of ethanol and of noise on reaction time in the monkey: variation with stimulus level.

To determine whether the latency-increasing effects of ethanol were differential with respect to the intensity of the stimulus that initiated the response, three rhesus monkeys were trained on a behavioral task in which the latency of a simple motor response was measured following the onset of a pure tone stimulus. Following training, the animals were tested at a number of different tone intensities and functions relating latency to tone intensity were constructed. When these were stable, the animals were given ethanol in doses of 1.0-2.5 g/kg and the effects on response latencies to different tone intensities were determined. It was found that for all except the lowest stimulus levels, the effect of ethanol was dose-related, while for a given dose the effect was equal across intensity. These results indicate that the effects of ethanol in this situation are on response execution rather than stimulus detection. The effects of ethanol were compared to those of exposure to high intensity noise. This treatment, which affects primarily the inner ear, resulted in substantial increases in latency to low intensity tones, but little, if any, shift at high intensities.

Comparison of behavior maintained by infusions of eight phenylethylamines in baboons.

Doses of eight phenylethylamines were substituted for cocaine on a drug-maintained behavior baseline in baboons. Intravenous infusions of drug were contingent upon completion of 160 lever presses (a 160-response fixed-ratio schedule; FR 160). A 3-h time-out period followed each infusion, permitting a maximum of 8 infusions per day. Fenfluramine was the only drug that did not maintain self-infusion performance at any dose tested. d-Amphetamine was approximately 10 times more potent than phentermine, phenmetrazine or diethylpropion, and 20 to 30 times more potent than methylenedioxyamphetamine (MDA), clortermine or chlorphentermine, in maintaining self-infusion behavior. Some doses of d-amphetamine and phentermine produced a cyclic pattern of drug intake over days. Increasing self-infused doses of all drugs produced a substantial suppression of concurrent food-maintained behavior. There was no clear relation between the potency of the phenylethylamines in maintaining self-infusion performance and the potency in suppressing food-maintained behavior which indicates that different mechanisms may underlie the two effects. Examination of chemical structures indicates that substitution on the phenyl ring may decrease the potency of phenylethylamines in maintaining self-infusion behavior.

Naltrexone reduces ethanol- and sucrose-reinforced responding in rhesus monkeys.

These experiments evaluated the ability of naltrexone (NTX) to reduce selectively oral and i.v. ethanol-reinforced responding, and examined the ethanol-NTX interaction in terms of the competitive opioid antagonist property of NTX. Five rhesus monkeys self-administered ethanol or sucrose and concurrently available water. Ethanol concentration was varied from 0.25% to 8% (w/v). Naltrexone (0.032-0.32 mg/kg) or saline was given i.m. 30 min prior to some drinking sessions. NTX (0.32 mg/kg) reduced ethanol-reinforced responding at the concentration that maintained the most responding (1% or 2%). NTX (0.1 mg/kg) reduced ethanol-reinforced responding, both at a low ethanol concentration (0.25%) that produced little ethanol intake (g/kg), and at a higher concentration (4%) with an appreciable intake. Thus, NTX (0.1 mg/kg) shifted the ethanol concentration-consumption curve down, in an insurmountable manner. NTX (0.1 and 0.32 mg/kg) also reduced reinforced responding for sucrose 100 g/l. In another experiment, three rhesus monkeys were given opportunities to self-administer ethanol i.v. NTX (0.1 mg/kg) reduced the number of ethanol injections obtained by the monkeys at all ethanol doses tested (0.01, 0.032, and 0.1 g/kg per injection). The dose-effect curve was also shifted down. These results showed that NTX reduced behavior maintained by either ethanol or sucrose non-selectively. Furthermore, the ability of NTX to suppress ethanol-reinforced responding did not depend on the route of ethanol administration and was not overcome by increasing the concentration or dose per injection of ethanol.

Pharmacological profile of a potent, efficacious fentanyl derivative in rhesus monkeys.

The recent synthesis of fentanyl derivatives, some of which appear to have novel profiles of pharmacological effects, has provided compelling evidence that mu opioid efficacy might be altered systematically by modifications in the parent compound fentanyl. In the present study a new 4-(heteroanilido)-piperidine, compound 28, was studied for its effects in rhesus monkeys. In self-administration studies compound 28 maintained rates of lever pressing similar to those maintained by alfentanil; the reinforcing effects of compound 28 were attenuated by the opioid antagonist quadazocine. In drug discrimination studies compound 28 did not substitute for the kappa agonist ethylketocyclazocine and did substitute for the mu agonist alfentanil. In morphine-treated subjects discriminating between saline and naltrexone, compound 28 did not substitute for naltrexone; however, in morphine-abstinent subjects compound 28 reversed naltrexone lever responding. Moreover, this discriminative stimulus effect in morphine-abstinent subjects was antagonized by naltrexone and by quadazocine in a manner consistent with mu receptor mediation. Compound 28 also was an effective analgesic in a warm-water, tail-withdrawal procedure and it decreased markedly respiratory function. The analgesic effects as well as the respiratory depressant effects of compound 28 were antagonized by quadazocine. Together, these results show compound 28 to be a potent, efficacious mu agonist of similar potency to alfentanil. Large differences in apparent efficacy at mu receptors between compound 28 and another compound in this series (mirfentanil), clearly demonstrate that, within this chemical family, small chemical changes can confer significant differences in pharmacologic effect.