Effects of morphine alone and in combination with naloxone or d-amphetamine on shock-maintained behavior in the squirrel monkey

Key-pressing behavior in the squirrel monkey was maintained under an 8-min fixed-interval (FI) schedule of electric-shock delivery. The acute i.m. administration of morphine prior to a daily session decreased response rates at doses of 1.0–3.0 mg/kg but had little systematic effect on rate at doses of 0.03–0.3 mg/kg. When naloxone was administered concomitantly with morphine prior to a session, 0.01 mg/kg naloxone required a three-fold increase in the dose of morphine necessary to obtain decreased response rates, 0.1 mg/kg naloxone required a 30-fold increase in morphine, and 1.0 mg/kg required more than a 30-fold increase in morphine. Moreover, the administration of naloxone with morphine resulted in increased rates of responding at certain combinations of doses of the two drugs. The administration of d-amphetamine (0.03 or 0.1 mg/kg) alone increased mean response rates under the FI schedule; when combined with 0.03–0.3 mg/kg morphine the increases in responding were greater than obtained with d-amphetamine alone. The negative slope of the linear regression lines relating the effects of morphine to control rates of responding engendered under the FI schedule was decreased when morphine was combined with naloxone, but not with d-amphetamine. These results show that naloxone, but not d-amphetamine, can antagonize the response-rate decreasing effect of morphine when responding in the squirrel monkey is maintained by response-produced electric shock.     

Opioid receptor subtype-specific cross-tolerance to the effects of morphine on schedule-controlled behavior in mice

Key-press responding of mice was maintained under a fixed-ratio (FR) 30-response schedule of food presentation. Successive 3-min periods during which the experimental chamber was illuminated and the schedule was in effect were preceded by 10-min time-out (TO) periods during which all lights were out and responses had no scheduled consequences. Intraperitoneal (IP) injections of saline or of cumulative doses of drugs were given at the start of each TO period. Successive saline injections had little or no effect on response rates, whereas the -opioid agonists morphine (0.1–10.0 mg/kg) and levorphanol (0.1–3.0 mg/kg), the -opioid agonist ethylketazocine (0.03–3.0 mg/kg), the mixed -/-opioid agonist metkephamid (0.1–10.0 mg/kg), and the nonopioid dissociative anesthetic ketamine (1.0–100.0 mg/kg) generally produced dose-related decreases in response rates. Following chronic administration of morphine (100.0 mg/kg/6 h), tolerance developed to the effects of morphine on rates of responding. In addition, a comparable degree of cross-tolerance developed to the effects of levorphanol and metkephamid. On the other hand, there was no evidence of cross-tolerance to the effects of ethylketazocine or ketamine. These results are consistent with the evidence suggesting that different opioid agonists exert their behavioral effects through distinct classes of opioid receptors.     

Effects of selected opioid agonists and antagonists on DMT-and LSD-25-induced disruption of food-rewarded bar pressing behavior in the rat

Several opioid agonists and antagonists interact with N,N-dimethyltryptamine (DMT) and lysergic acid diethylamide-25 (LSD) in adult male Holtzman rats trained on a positive reinforcement, fixed ratio 4 (FR₄) behavioral schedule, i.e., a reward of 0.01 ml sugar-sweetened milk was earned on every fourth bar press. DMT (3.2 and 10.0 mg/kg) and LSD (0.1 mg/kg) given IP with 0.9% NaCl pretreatment, disrupted food-rewarded FR4 bar pressing. Animals were pretreated IP (10–15 min) with predetermined, behaviorally noneffective doses of morphine, methadone, naltrexone, and the (+)-and (-)-enantiomers of naloxone prior to receiving DMT or LSD. Dose-dependent effects were shown with opioid agonist pretreatment. Morphine (0.32–1.0 mg/kg) and methadone (0.32 mg/kg) significantly antagonized the bar pressing disruption induced by DMT and LSD. Larger doses of morphine (3.2 mg/kg) and methadone (1.0–3.2 mg/kg) potentiated only LSD-induced effects, with no effect on DMT-treated groups. The opioid antagonists (-)-naloxone and naltrexone potentiated the disruption of bar pressing induced by DMT and LSD. Failure of (+)-naloxone to potentiate the DMT effects was attributed to a stereospecific opioid antagonist effect of (-)-naloxone.     

Tolerance to the stimulant effects of morphine and pentazocine on avoidance responding in the rat

Dose-response curves were determined for the effects of morphine (0.3–10 mg/kg) and pentazocine (1.0–30 mg/kg) on continuous avoidance responding in the rat. Each dose of morphine was retested following 3 days of morphine administration. The pentazocine curve was redetermined after 3 days of treatment with either pentazocine or morphine. Upon initial testing, morphine and pentazocine both generated biphasic dose-response curves. Graded increases in response rate were produced by 0.3–3.0 mg/kg of morphine and by 1.0–10 mg/kg of pentacozine; behavior was disrupted by 10 mg/kg of morphine and by 30 mg/kg of pentazocine. The stimulant effects of the lower doses of morphine and pentazocine were markedly reduced by 3 days of drug treatment; the disruptive effect of the highest dose of each drug was similarly attenuated. These findings show that tolerance can develop to a stimulant component of action of morphine and pentazocine in the rat. The development of pentazocine cross-tolerance to morphine provides additional support for the view that a common mechanism mediates the effects of morphine and pentazocine on avoidance behavior.Publication No. 1203 of the Division of Basic Health Sciences of Emory University. This investigation was supported by USPHS Grant DA-00541.     

Characterization of the discriminative stimulus effects of centrally administered morphine in the rat

The discriminative stimulus effects of centrally administered morphine were characterized in rats trained to discriminate 3.0 mg/kg SC morphine from saline in a two-choice discrete-trial avoidance paradigm. The intracerebroventricular (ICV) administration of 0.3–10 g morphine engendered morphine-appropriate responding, morphine administered ICV being nearly 1000 times as potent as morphine administered SC. Cannula implantation itself did not affect the sensitivity of the rats to the discriminative effects of morphine. The onset of the discriminative stimulus effects of ICV morphine was not immediate; stimulus generalization comparable to that produced by 3.0 mg/kg morphine occurred 30–60 min after the injection of 1.0 or 10 g ICV morphine and persisted for 90 and 150 min, respectively. Naltrexone blocked the discriminative stimulus effects of 10 g ICV morphine in a dose-related manner. Complete antagonism of the stimulus effects of this dose of morphine was obtained with 0.01–0.03 mg/kg SC naltrexone. When administered centrally, the relatively lipid insoluble naltrexone methobromide completely antagonized the discriminative effects of 3.0 mg/kg morphine at a median effective dose of 0.3 g. In contrast, when injected systemically at a dose of 1.0 mg/kg (approximately 500 g), naltrexone methobromide failed to block the discriminative stimulus effects of either 10 g ICV morphine or the SC training dose. Thus, periventricular brain sites appear to be involved in mediating the discriminative stimulus effects of morphine in the rat.     

Effects of levo-alpha-acetylmethadol (LAAM) on morphine self-administration in the rat

Rats bearing cerebrocortical electrodes for recording the electroencephalogram (EEG) were rendered tolerant to and physically dependent on morphine and subsequently trained to self-administer morphine (10 mg/kg/injection) through a chronic intravenous cannula. Morphine was available for selfadministration 24 h/day. Once morphine intake had stabilized (10–12 injections/day), levo-alpha-acetylmethadol (LAAM) was administered noncontingently via a chronic intragastric (IG) cannula as a single daily dose of either 1 or 4 mg/kg. These morphine self-administering rats were maintained on daily LAAM treatment for 12 consecutive days. Analysis of the patterns of lever pressing, morphine self-injections, and sleepawake behavior revealed that daily IG administration of LAAM effectively suppressed morphine self-administration. The 1 mg/kg dose of LAAM reduced morphine intake by 30%–50%, while 4 mg/kg produced an 80%–90% decrease. The reduction in morphine self-administration occurred in the absence of overt signs of narcotic withdrawal, behavioral toxicity, or disruption of sleep-awake behavior in these rats. Termination of LAAM maintenance resulted in a gradual return of lever pressing and morphine intake to pre-LAAM levels.Preliminary report of this study appeared in The Pharmacologist 21, 226 (1979)     

Effects of chlordiazepoxide,morphine and amphetamine on responding suppressed by different levels of electric shock in the pigeon are rate dependent

In general, chlordiazepoxide (CDP) and amphetamine reduce high rates of responding and increase low rates (rate-dependent effect). However, unlike CDP, amphetamine does not typically increase low rates resulting from suppression of responding by noxious stimuli. In the present experiment, key pecking by pigeons was reinforced under a random ratio schedule of food presentation. This responding was then suppressed by stimuli correlated with electric shocks of varying intensity (2 or 4 mA) or reduced by the omission of the food (extinction). Treatment with CDP (0.3–10.0 mg/kg) and morphine (0.3–10.0 mg/kg) increased the rate of suppressed responding: lower rates being increased to a proportionately greater extent than high rates.d-Amphetamine (0.1–1.0 mg/kg) further reduced the rate of suppressed responding: the lower rates being reduced proportionately more than the higher rates. Thus the effects of all three drugs depended upon the control rates of responding, but the effects of amphetamine were the inverse of those of CDP and morphine. The effects of amphetamine on low, suppressed or punished response rates are therefore not an exception to the generality of rate-dependency, but a different aspect of the same principle — inverse rate-dependency.     

Effects of centrally acting beta adrenergic agonists on discrete trial conditioned avoidance behavior in rats

The acute effects of centrally acting beta adrenergic agonists on discrete trial conditioned avoidance responding in rats were examined. Clenbuterol (0.01–3.0 mg/kg), salbutamol (0.01–30 mg/kg), and prenalterol (30–300 mg/kg) suppressed avoidance responding in a dose-dependent manner at doses that did not produce escape failures. For comparative purposes, the effects of the tricyclic antidepressant desipramine (1.0–30 mg/kg) and the antipsychotic haloperidol (0.03–0.3 mg/kg) were similarly assessed. Both compounds suppressed avoidance responding in a dose-dependent manner. Only haloperidol (0.3 mg/kg) produced escape failures. Administered alone, the beta adrenergic antagonist propranolol (1.0 and 10 mg/kg) did not affect avoidance behavior. When administered prior to clenbuterol (0.1 mg/kg), salbutamol (1.0 mg/kg), or prenalterol (100 mg/kg), propranolol antagonized the beta adrenergic agonist-induced suppression of avoidance responding. The suppressive effect of desipramine (3.0 mg/kg) on avoidance performance only tended to be attenuated by propranolol. Propranolol had no effect on the ability of haloperidol (0.1 mg/kg) to reduce avoidance responding. These results suggest that the effects of the beta adrenergic agonists clenbuterol, salbutamol, and prenalterol on discrete trial avoidance behavior are mediated, in part, through agonist interactions with beta adrenergic receptors.     

Tolerance to behavioral effects of physostigmine under interval schedules of positive or negative reinforcement

The present experiments examined whether the rate and type of events maintaining responding help determine physostigmine's behavioral effects. The first two experiments examined the acute and chronic effects of physostigmine, respectively, on lever pressing of rats under variable-interval schedules of food presentation. The third examined the chronic effects of physostigmine on lever pressing under random-interval schedules of shock avoidance. Three different variable intervals (18, 56, and 180 s) and two different random intervals (20 and 60 s) were studied, each associated with a distinctive stimulus. Baseline rates of responding were directly related to the scheduled rate of food delivery or shock avoidance. Acute administration of 0.154–1.233 mol/kg (0.1–0.8 mg/kg) physostigmine sulfate produced monotonic decreases in overall response rate under all schedules of food presentation. Acute effects (per cent of control response rate) did not differ systematically under the various interval values. Large doses (i.e., 0.4 or 0.8 mg/kg) suppressed the rate of food delivery as well. When initially administered, 0.967 mol/kg (0.4 mg/kg) physostigmine salicylate also suppressed avoidance response rates and per cent shocks avoided. Tolerance developed to the effects of this dose of physostigmine salicylate on pellet or shock-avoidance frequency more rapidly than to effects on overall response rate. Tolerance to the latter developed only very gradually and could in the case of shock-avoidance response rates be considered partial at best. Tolerance was not affected by the scheduled rate of food or shock presentation. Blood acetylcholinesterase levels showed no recovery during chronic physostigmine. Tolerance is discussed in terms of the reinforcement-loss hypothesis.The views of the author(s) do not purport to reflect the position of the Department of the Army or the Department of Defense, (para 4-3, AR 360-5)     

Potentiation of disruptive effects of dextromethorphan by naloxone on fixed-interval performance in rats

A centrally acting antitussive agent dextromethorphan (DM) was tested to determine its possible interaction with naloxone in rats responding under a fixed-interval schedule of positive reinforcement. A sugar sweetened milk reward was used as a positive reinforcer. Under the same experimental conditions the effects of morphine alone and in combination with naloxone were also determined. Low dose DM (10 mg/kg) produced a slight increase, while higher doses (20–40 mg/kg) produced dose-dependent decreases in response rate. Morphine (0.3, 1.0 and 3.0 mg/kg) produced dose-dependent decreases in response rate. When doses of naloxone (0.1–1.0 mg/kg) were administered after the injection of DM the rate-decreasing effects of DM were potentiated even after the rate-increasing dose of naloxone (0.1 mg/kg) was used. When a dose of naloxone (0.1 mg/kg) was administered after the injection of morphine the rate-decreasing effects of morphine were markedly antagonized, i.e., the morphine dose-response curve was shifted to the right. The observed potentiation of DM disruption by naloxone on fixed-interval performance in rats is consistent with findings showing that naloxone potentiates the disruptive behavioral effects of a number of drugs that are psychotomimetic in man.     

Anxiolytic-like effects of morphine and buprenorphine in the rat model of fear-potentiated startle: tolerance,cross-tolerance,and blockade by naloxone

Rationale Morphine and buprenorphine have analgesic and anxiolytic-like properties. While their analgesic effects have been well characterized, their anxiolytic-like properties have not. Objectives Effects of acute morphine and buprenorphine on the expression of acoustic fear-potentiated startle (FPS) and naloxone pretreatment were assessed. Effects of chronic morphine and buprenorphine on tolerance, cross-tolerance, and withdrawal were also examined. Materials and methods Fear-conditioned rats were given subcutaneous drug treatment immediately before testing for FPS. Experiment 1, rats were administered morphine (0.03, 0.25, 0.63, 2.5, or 10 mg/kg) or buprenorphine (0.004, 0.0075, 0.015, 0.03, or 0.25 mg/kg). Experiment 2, rats were given saline or naloxone (0.5 mg/kg) and 5min later given saline, morphine (2.5 mg/kg), or buprenorphine (0.03 mg/kg). Experiment 3, rats received once-daily injections of saline, morphine (10 mg/kg), or buprenorphine (0.25 mg/kg) for 7 days. Immediately before testing, saline-treated rats were given saline, morphine (2.5 mg/kg), or buprenorphine (0.03 mg/kg), morphine-treated rats were given morphine (2.5 mg/kg) or buprenorphine (0.03 mg/kg), and buprenorphine-treated rats were given buprenorphine (0.03 mg/kg) or morphine (2.5 mg/kg). Tolerance and cross-tolerance in analgesia were assessed via the tail-flick test, as were naloxone-precipitated withdrawal. Results Morphine and buprenorphine had parallel dose–response curves in blocking FPS, with buprenorphine 40 times more potent than morphine. Naloxone reversed these effects. Morphine and buprenorphine showed tolerance and cross-tolerance in their anxiolytic-like and analgesic effects. Chronic buprenorphine produced less withdrawal than chronic morphine. Conclusions Cross-tolerance between morphine and buprenorphine suggests a common receptor mediating their anxiolytic-like and analgesic effects.     

Morphine effects on activity and pain reactivity of developing mice with or without late prenatal oxazepam exposure

Locomotor activity in a Varimex apparatus, hotplate responding, and morphine effects (1 and 10 mg/kg IP) were assessed in 14-, 21-, 28-, and 70-day old mice. The development of hot-plate responding consisted mainly of a progressive increase of latencies and a parallel reduction of sensitivity to morphine. Morphine depressed activity at 14 days at the lower dose, had no effect at 21 days, and produced an adult-like hyperactivity at 28 days (10 mg/kg). Prenatal oxazepam (15 mg/kg, given per os twice daily on days 12–16 of pregnancy) did not influence hot-plate responding and morphine analgesia at any of the test ages. By contrast, the data on activity, besides replicating the response reduction at 14 days observed previously in an open-field test (Alleva et al. 1985), showed a delayed appearance of morphine hyperactivity in oxazepam mice.A preliminary account of some of the present data was given at the Inaugural Meeting of the European Behavioural Pharmacology Society, Antwerp (Belgium), 2–5 July 1986 (Alleva et al. 1986)     

Kappa antagonist properties of buprenorphine in non-tolerant and morphine-tolerant rats

Buprenorphine was evaluated for its ability to act as a kappa opioid antagonist in rats responding under a fixed-ratio 30 schedule of food presentation both before and after the induction of morphine tolerance. Before the induction of morphine tolerance, both buprenorphine and the selective kappa agonist bremazocine decreased rates of responding in a dose-dependent manner, and buprenorphine (0.03 and 0.3 mg/kg) failed to antagonize bremazocine's rate-decreasing effects. Following the induction of morphine tolerance, the bremazocine dose-effect curve was unaffected, but a profound cross-tolerance developed to buprenorphine. Furthermore, buprenorphine (0.03, 0.3 and 1.0 mg/kg) produced a dose-dependent antagonism of the rate-decreasing effects of bremazocine in the morphine-tolerant rats. These results support the hypothesis that buprenorphine has antagonist activity at kappa opioid receptors.     

Situational specificity of tolerance to decreased operant responding by morphine andl-nantradol

In one experiment, key pressing of rats was maintained under a fixed-ratio schedule of food presentation in a first daily session in one environmental situation, and interruption of a photobeam was maintained under a continuous shock avoidance schedule in a second daily session in another environmental situation. After receiving acute injections of the cannabinoidl-nantradol (0.01–0.3 mg/kg), rats received daily administration of a rate-decreasing dose of the drugafter the second session, thenbefore the second session, and thenbefore the first session. Tolerance that developed to decreased avoidance responding in the second daily session did not extend to decreased fixed-ratio responding in the first daily session, but was specific to circumstances coinciding with the pharmacological actions ofl-nantradol. In a second experiment, lever pressing of squirrel monkeys was maintained under an identical fixed-interval schedule of food delivery in two separate daily sessions in different experimental situations. After receiving once-weekly acute injections of morphine (0.3–3.0 mg/kg), monkeys received daily administration of a rate-decreasing dose of morphine in a counter-balanced orderbefore each session. Just as for experiment 1, tolerance that developed in the environment coinciding with the pharmacological actions of morphine did not immediately generalize to operants in the other environmental situation. Instead, tolerance depended on both pharmacologic action as well as concurrently operating behavioral processes.Animals used in this study were maintained in accordance with guidelines of the Animal Care Committee of the Worcester Foundation for Experimental Biology and of the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education and Welfare, Publication Number (NIH)85-23, revised 1985     

Discriminative stimulus properties of cocaine, alone and in combination with buprenorphine, morphine and naltrexone

Rats were trained to discriminate a dose of 10.0 mg/kg cocaine from saline. During substitution tests, both cocaine (5.6–10.0 mg/kg) and d-amphetamine (1.0–3.0 mg/kg) produced greater than 80% responding on the cocaine-appropriate lever. In contrast, buprenorphine (0.03–0.56 mg/kg), morphine (0.3–10.0 mg/kg) and naltrexone (1.0–10.0 mg/kg) failed to substitute for the cocaine stimulus, up to doses that substantially decreased rate of responding. When the cocaine dose-effect curve was redetermined in the presence of selected doses of buprenorphine, the amount of cocaine-appropriate responding following a low dose of cocaine (1.0 mg/kg) was increased slightly whereas cocaine-appropriate responding following higher doses of cocaine (3.0 and 5.6 mg/kg) was reduced slightly. Responding following the training dose of cocaine (10.0 mg/kg) was not changed. These results indicate that buprenorphine produced only small alterations in cocaine's discriminative stimulus effects and that the nature of these alterations differed depending on the dose of cocaine examined.     

Opioid agonist and antagonist behavioural effects of buprenorphine.

1 The agonist and antagonist effects of a range of buprenorphine doses (0.08-20 mg/kg) were studied on the responding of pigeons under a multiple fixed-ratio, fixed-interval schedule of grain presentation. Various doses (0.02-10 mg/kg) of buprenorphine were also tested in pigeons trained to discriminate between injections of 0.05 mg/kg of fentanyl and injections of distilled water. 2 Buprenorphine, over a broad dose range (0.08-5 mg/kg), increased the rates of responding in the fixed-interval component of the multiple schedule and disrupted patterning of responding within the fixed-interval, without affecting fixed-ratio responding even at a dose of 40 mg/kg. The effects of some of the high doses on fixed-interval responding were still evident one and two days after buprenorphine injection. 3 Doses of buprenorphine which produced increases in fixed-interval responding were also effective as antagonists of the behavioural depression produced by 40 mg/kg of morphine, and were discriminated as fentanyl-like by pigeons trained to discriminate between injections of fentanyl and injections of water. 4 These results show that buprenorphine produces marked agonist and antagonist effects over an extremely broad dose range without producing behavioural depressant effects.     

Behavioral effects of cocaine and its interaction with d-amphetamine and morphine in rats

Drugs of abuse are commonly co-abused, and frequently these combinations produce effects which cannot be predicted by studying the effects of the individual drugs. To investigate the behavioral interactions which occur following combinations of cocaine plus amphetamine or cocaine plus morphine, rats were trained to respond under a differential reinforcement of low rates (DRL) schedule (10-14 sec). Cocaine (0.1-10 mg/kg) and d-amphetamine (0.1-3 mg/kg) decreased the percentage of reinforced responses (efficiency) at doses which had no effect on overall rate of responding. Following moderate doses of either drug, the interresponse time (IRT) distribution showed an increase in the percentage of shorter (less than 10 sec) IRT's. Morphine (0.1-10 mg/kg) also decreased efficiency, but the decrease which occurred was only observed at doses which also decreased overall response rates. As might be expected, the IRT distribution for morphine showed a dose-related increase in the percentage of long IRT's (greater than 14 sec). When doses of morphine which had no significant effect when administered alone (1 or 3 mg/kg) were combined with cocaine, the cocaine dose-response curve for efficiency was shifted down and to the left and response rates were increased. Analysis of the IRT distribution showed that the combination of an ineffective dose of cocaine, 1 mg/kg, plus 3 mg/kg morphine produced a shift in the IRT distribution to the left (an increase in the percentage of short IRT's). When cocaine was combined with 0.3 mg/kg d-amphetamine, a dose which had no effect when given alone, no significant interactions were observed on efficiency or overall rate of responding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Generalization of [DAla2]-enkephalinamide but not of substance P to the morphine cue

Rats were trained to discriminate morphine (7.5 mg/kg, IP) from saline in a two bar positively reinforced lever pressing paradigm on a FR4 schedule. Morphine (IP) showed a naloxone reversible dose-related generalization to the training dose. [DAla²]-Methionine enkephalinamide (DAE) at 1 mg/kg and Substance P (SP) at 0.1 and 0.25 mg/kg showed vehicle appropriate responding after IP injection. DAE (5 mg/kg) disrupted responding completely; SP (0.5 and 0.1 mg/kg) disrupted responding in 50% of the rats. The disruption caused by IP injection of DAE was not naloxone reversible. Intraventricular injection of morphine (5 μg/rat) and DAE (5 μ/rat) produced generalization to the opiate cue. The effect of DAE was reversed by naloxone (1 mg/kg, SC). SP (500 and 750 ng/rat, IVT) produced saline-like responding; 1 μg/rat disrupted responding completely. These data demonstrate that morphine and enkephalin, but not Substance P, share similar discriminative properties.     

Naloxone effects on schedule-controlled behavior in morphine-pelleted rats

The effects of morphine pellet implantation and naloxone administration were examined in rats lever pressing under inter-response time schedules of food presentation. Subcutaneous implantation of a morphine pellet initially decreased lever-pressing rates. Tolerance to this effect developed within 3–4 days. Naloxone (0.25–1.0 mg/kg) decreased response rates in morphine-pelleted rats in a dose-dependent and time-dependent manner. All doses of naloxone severely decreased rates of lever pressing on days four to nine post-pellet. This rate-decreasing effect persisted 7–17 days for 0.25 mg/kg naloxone, 9–22 days for 0.50 mg/kg, and 13–28 days for 1.0 mg/kg. Decreases in response rate were due to an increased frequency of long pauses and not to marked shifts in the temporal patterning of those lever presses that did occur. Changes in response rate after naloxone were accompanied by body weight loss. Area values summarizing the naloxone-induced changes in response rate or body weight over time after pellet implantation increased as a function of naloxone dose. Naloxone (0.25–1.0 mg/kg) did not alter performance by placebo-pelleted rats.     

Dose- and time-dependent effects of narcotic analgesics on intracranial self-stimulation in the rat

Rats were trained to bar-press in order to obtain electrical stimulation of the medial forebrain bundle through chronically implanted electrodes. Dose-response and time-effect curves were determined for morphine (1.0–30 mg/kg), levorphanol (0.1 to 3.0 mg/kg), methadone (0.1–3.0 mg/kg), meperidine (1.0–30 mg/kg), oxymorphone (0.03–1.0 mg/kg), and d-amphetamine (0.1–3.0 mg/kg). Dose-response and time-effect curves were also determined for morphine (1.0–30 mg/kg) in rats that had received multiple injections of morphine over a period of 3 days. All of the narcotic analgesics produced dose-related decreases in responding; the durations of these decreases were also dose-related. The relative potencies of the five narcotic analgesics with respect to the rate-decreasing effects for self-stimulation responding were: oxymorphone > levorphanol > methadone > morphine > meperidine. In morphine-tolerant rats the rate-decreasing effects of morphine on responding for self-stimulation were attenuated. These findings suggest that narcotic analgesics from diverse chemical families have a similar, predominantly depressant, effect on self-stimulation behavior and that the relative potencies of a series of narcotics for this effect are similar to those demonstrated for other properties of these drugs.