Quantification of the morphine reversal activity of opioid agonists/antagonists and naloxone by using a rabbit tooth pulp procedure

The rabbit tooth pulp procedure was used to determine the potencies and durations of morphine reversal by naloxone, buprenorphine, nalbuphine, butorphanol, and pentazocine. Cumulative doses (mg/kg) required to double the number of morphine-depressed respirations per minute (RPM) (ED 2 X) and to reduce morphine-elevated lick/chew (L/C) volts by one-half (ED 1/2) were determined. These doses were naloxone 0.003, 0.013; buprenorphine 0.030, 0.130; nalbuphine 0.130, 0.520; butorphanol 0.120, 0.630; pentazocine 1.10, 0.150. The antinociceptive effects of these compounds were compared by determining the cumulative dose required to achieve the highest percentage maximum possible effect (% MPE) as determined by the elevation of lick/chew threshold volts from control volts in morphine-free rabbits: naloxone 6% at 0.0005 mg/kg; buprenorphine 69% at 0.075 mg/kg; nalbuphine 32% at 0.150 mg/kg; butorphanol 32% at 0.150 mg/kg, and pentazocine 12% at 1.55 mg/kg. The durations (min) of reversal of morphine RPM and morphine L/C volts were also determined: naloxone 33, 30; buprenorphine 240, 240; nalbuphine 120, 120; butorphanol 90, 45; pentazocine 60, 15. It is suggested that the rabbit tooth pulp assay is a sensitive and reliable assay to evaluate and quantitate compounds for opioid agonist/antagonist activity.     

Interactions between H1-antagonists and opioids: a drug discrimination study

We previously demonstrated that combination of opioids, pentazocine and dihydrocodeine, with the histamine H₁-receptor antagonists tripelennamine and chlorpheniramine could enhance their rewarding effects in rats. In the present study, the effects of combined treatment with opioids and H₁-antagonists on discriminative stimulus effects were examined in rats trained to discriminate between cocaine (10 mg/kg) or morphine (3.0 mg/kg) and saline, since it is believed that discriminative stimulus effects of abused drugs are related to their rewarding effects. Tripelennamine and chlorpheniramine, but not pentazocine or dihydrocodeine, generalized to the discriminative stimulus effects of cocaine. Pentazocine (3.0 mg/kg) and dihydrocodeine (5.6 mg/kg) significantly potentiated the cocaine-like discriminative stimulus effects of low doses of tripelennamine and chlorpheniramine, respectively. On the other hand, pentazocine and dihydrocodeine, but not tripelennamine or chlorpheniramine, generalized to the discriminative stimulus effects of morphine. Neither 1.0 or 3.0 mg/kg tripelennamine nor chlorpheniramine affected the morphine-like discriminative stimulus effects of pentazocine and dihydrocodeine, respectively. These results suggest that the potentiation of the cocaine-like discriminative stimulus effects of H₁-antagonists by opioids may be involved in the enhanced rewarding effects of combinations of opioids and H₁-antagonists. Received: 10 September 1996/Final version: 27 December 1996     

Morphine training dose: A determinant of stimulus generalization to narcotic antagonists in the rat

Rats were trained to discriminate between saline and either 1.75 or 5.6 mg/kg of morphine in a two-choice discrete-trial avoidance paradigm. Both groups of rats generalized completely to higher doses of morphine as well as to profadol and pentazocine, analgesics with narcotic antagonist properties. The dose of each test drug required to elicit drug-appropriate responding was about one-half log-unit higher in the rats trained with 5.6 mg/kg of morphine than in the rats trained with 1.75 mg/kg. Rats trained with the lower dose of morphine also generalized completely to the narcotic antagonist nalbuphine and to the non-opioid drug d-amphetamine, and generalized partially to the narcotic antagonist cyclazocine. In contrast, rats trained with the higher dose of morphine showed only partial generalization to nalbuphine and virtually none to cyclazocine and d-amphetamine. The degree of stimulus generalization to the narcotic antagonists and to d-amphetamine in the two groups of rats corresponds well with the known similarities and differences between the syndromes of subjective effects engendered by these drugs and morphine in man. These results indicate that systematic variation of the morphine training dose can facilitate characterization of the discriminative stimulus properties of narcotic antagonist analgesics and enhance the value of drug discrimination procedures as a model for predicting the subjective effects of these drugs.     

Substitution and primary dependence studies in animals

The mixed agonist-antagonist analgesics buprenorphine, butorphanol, nalbuphine, pentazocine and picenadol were compared to the prototype mu and kappa agonists morphine and Mr 2033, respectively, in the following tests in rhesus monkeys: overt behavioral effects upon acute administration in drug-naive animals; discriminative stimulus properties in monkeys trained to respond to either etorphine or ethylketazocine; self-administration of the test agent relative to codeine; single dose suppression and precipitation in withdrawn and non-withdrawn morphine-dependent monkeys, respectively; and primary addiction studies in drug-naive animals. Whereas both buprenorphine and nalbuphine precipitate withdrawal in morphine-dependent monkeys, withdrawal following chronic administration of buprenorphine resulted in no observable signs of abstinence, while nalbuphine withdrawal was similar to that seen in morphine-dependent monkeys. Butorphanol, pentazocine and picenadol all produced mild dependence of the kappa-type; that is, natural withdrawal behavior similar to that seen following chronic Mr 2033 administration.     

Evaluation of the discriminative stimulus effect of an enkephalin analog, EK-399, in the rat]

Four groups of rats were trained to discriminate between the no-drug conditions (saline, s.c.) and the effect of s.c. injection of the novel enkephalin analog Tyr-D-Met (O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399, 1 mg/kg), morphine (3 mg/kg), ethylketocyclazocine (EKC, 0.3 mg/kg) or N-allylnormetazocine (NANM, 3 mg/kg) in a two-lever choice, water reinforced procedure. All groups of animals acquired the ability to discriminate EK-399, morphine, EKC or NANM from saline. Naloxone (0.03-0.3 mg/kg, s.c.) completely antagonized the discriminative stimulus effects of EK-399, morphine and EKC, but not that of NANM. In stimulus generalization tests, morphine (10 mg/kg) and buprenorphine (0.03 mg/kg), mu-opioid receptor agonists, completely substituted for EK-399 in groups trained with EK-399, whereas EK-399 (0.1-3 mg/kg) only partially substituted for morphine in rats trained with morphine. EKC (0.01-0.1 mg/kg), a kappa-opioid receptor agonist, partially substituted for EK-399, and EK-399 (0.1-3 mg/kg) partially substituted for EKC. NANM (0.3-10 mg/kg), a sigma-receptor agonist, partially substituted for EK-399, but EK-399 (0.1-3 mg/kg) did not substitute for NANM. These results suggest that the discriminative stimulus effect of EK-399 in rats mainly involves mu-opioid receptor-mediating action and also involves, to a lesser extent, other receptor (probably delta-opioid receptor)-mediating actions.     

Sensitization and tolerance to the discriminative stimulus effects of mu-opioid agonists

The discriminative stimulus effects of several μ-opioid agonists were examined under conditions of opioid sensitization or tolerance, i.e., before and after 1-week SC infusions of naloxone or μ-opioid agonists. Rats were trained to discriminate 3.0 mg/kg morphine from saline using a two-lever, discrete trial, shock-avoidance/escape procedure. The rats generalized completely to morphine, fentanyl, meperidine, buprenorphine, and etorphine, and partially to pentazocine. A 7-day infusion of naloxone (0.3 mg/kg per h) potentiated the discriminative stimulus effects of all of these drugs. The magnitude of the increased potency varied indirectly with the efficacy of the μ-opioid agonists; potency ratios (pre-infusion ED₅₀/post-infusion ED₅₀) ranged from 1.58 (etorphine) to 3.58 (pentazocine). Stimulus generalization to morphine, fentanyl, and meperidine also was examined following infusions of equieffective doses of each of these three drugs. Differences among drugs were generally small, and failed to reach statistical significance. Nonetheless, the induction of μ-opioid tolerance did seem to vary with the efficacy of the three μ-opioid agonists. Thus, meperidine (6.25 mg/kg per h), which has the lowest efficacy of the drugs infused, produced the greatest shift to the right of the stimulus-generalization curves of these three drugs; the post-meperidine PR ranged between 0.40 and 0.61. Fentanyl (0.1 mg/kg per h), a drug with a higher efficacy at μ-opioid receptors, did not produce tolerance to the discriminative stimulus effects of morphine, fentanyl, or meperidine; potency ratios ranged from 0.50 to 0.75. Potency ratios for buprenorphine, etorphine, fentanyl, meperidine, and morphine after 7-day morphine infusions (0.75 mg/kg per h) ranged from 0.38 (buprenorphine) to 0.80 (etorphine). Morphine induced significant tolerance only to the discriminative stimulus effects of fentanyl. Our results suggest that different cellular mechanisms underlie the development of tolerance and sensitization to the discriminative stimulus effects of μ-opioid agonists.     

Discriminative stimulus effects of nalbuphine in nontreated and morphine-treated pigeons.

In the present study, the stimulus effects of the low efficacy agonist nalbuphine were examined under two conditions: nontreated and morphine treated. In the first experiment, five pigeons were trained to discriminate among 3.2 mg/kg morphine, 5.6 mg/kg nalbuphine, and saline. Nalbuphine produced nalbuphine-like responding. Low doses of morphine produced nalbuphine-like responding, whereas high doses produced morphine-like responding. Naltrexone produced saline-like responding and reversed the stimulus effects produced by the training doses of morphine and nalbuphine. Five different pigeons were treated daily with 10 mg/kg morphine (i.m.) and trained 6 h later to discriminate among 10 mg/kg morphine, 1.0 mg/kg nalbuphine and saline. In these pigeons, morphine produced morphine-like responding and nalbuphine produced nalbuphine-like responding. Morphine abstinence produced nalbuphine-like responding that was reversed by morphine. Additionally, naltrexone produced nalbuphine-like responding. These data suggest that the discrimination between morphine and nalbuphine in the nontreated and morphine-treated pigeons may be based on the relative efficacy differences between morphine, a higher efficacy mu-agonist, and nalbuphine a lower efficacy mu-agonist.     

Social and environmental influences on opioid sensitivity in rats: importance of an opioid’s relative efficacy at the mu-receptor

Rationale Evidence indicates that social and environmental enrichment can influence the functional maturation of the central nervous system and may affect an organism’s sensitivity to centrally acting drugs. Objective The purpose of the present study was to examine the effects of social and environmental enrichment on sensitivity to mu-opioids possessing a range of relative efficacies at the mu-receptor. Methods Rats were obtained at weaning (21 days) and divided into two groups immediately upon arrival. Isolated rats were housed individually in opaque laboratory cages with no visual or tactile contact with other rats; enriched rats were housed socially in groups of four in large cages and given various novel objects on a daily basis. After 6 weeks under these conditions, the effects of morphine, levorphanol, buprenorphine, butorphanol, and nalbuphine were examined in the warm-water, tail-withdrawal procedure and the place-conditioning procedure. Results In the tail-withdrawal procedure, isolated and enriched rats did not differ in sensitivity to morphine (1.0–30 mg/kg) and levorphanol (0.3–10 mg/kg), but enriched rats were more sensitive to buprenorphine (0.03–3.0 mg/kg), butorphanol (0.3–30 mg/kg), and nalbuphine (0.3–30 mg/kg). In drug combination tests, butorphanol and nalbuphine antagonized the effects of morphine in isolated rats under conditions in which they produced high levels of antinociception in enriched rats. In the place-conditioning procedure, doses of 10 morphine and 3.0 levorphanol established a place preference in both groups of rats, whereas doses of 0.3 buprenorphine, 3.0 butorphanol, and 10 nalbuphine established a place preference only in enriched rats. Conclusions These findings may be taken as evidence that enriched rats are more sensitive than isolated rats to the effects of lower-efficacy mu-opioids and that social and environmental enrichment leads to functional alterations in opioid receptor populations.     

The µ opioid irreversible antagonist beta-funaltrexamine differentiates the discriminative stimulus effects of opioids with high and low efficacy at the μ opioid receptor

 The purpose of the present study was to determine the relative intrinsic efficacy of various opioids using the irreversible μ opioid antagonist beta-funaltrexamine (βFNA). To this end, pigeons were trained to discriminate 3.0 (n=6) or 1.8 (n=1) mg/kg morphine from distilled water in a two-key, food-reinforced, drug discrimination procedure. The μ opioids fentanyl, l-methadone, buprenorphine, butorphanol, nalorphine, nalbuphine and levallorphan, as well as the δ opioid BW373U86, substituted completely for the morphine stimulus. The stimulus effects of morphine were antagonized (i.e., produced a significant increase in the ED₅₀ value) by a 10 mg/kg but not a 5 mg/kg dose of βFNA. Antagonist effects of βFNA were observed following a 2-h pretreatment, but not following 26-, 50-, 74-, 98- or 146-h pretreatments. The stimulus effects produced by fentanyl, l-methadone and buprenorphine were not antagonized by doses of βFNA as high as 20, 10 and 10 mg/kg, respectively. The lowest dose of βFNA required to antagonize the stimulus effects of butorphanol was 10 mg/kg, whereas the effects of nalorphine, nalbuphine and levallorphan were antagonized by a dose of βFNA as low as 5 mg/kg. The δ opioid BW373U86 substituted for the morphine stimulus, and this effect was not antagonized by 10 mg/kg βFNA. The pkB values for naloxone (1.0 mg/kg) against the stimulus effects of fentanyl (6.70) and morphine (6.52) were considerably higher than that for BW373U86 (4.60), indicating further that the morphine-like stimulus effects produced by BW373U86 were not mediated by activity at the μ opioid receptor. These findings indicate that the strategy of irreversible antagonism can be used effectively to differentiate opioids with varying degrees of intrinsic efficacy at the μ opioid receptor in a pigeon drug discrimination procedure. In particular, the ranking of these drugs by relative intrinsic efficacy at the μ opioid receptor is: l-methadone=fentanyl≥buprenorphine≥morphine≥ butorphanol>nalorphine=nalbuphine=levallorphan. Additionally, the short-acting effect of βFNA in the pigeon suggests that the recovery of μ opioid receptor function varies across species. Received: 19 August 1997 / Final version: 28 March 1998     

Tolerance and cross-tolerance to morphine-like stimulus effects of µ opioids in rats

 The purpose of these experiments was to examine the relationship of agonist relative efficacy to the pattern of tolerance and cross-tolerance to the morphine-like stimulus effects of three opioid agonists. Rats were trained to discriminate 3.2 mg/kg morphine from saline under fixed-ratio 15 schedule of food reinforcement. Morphine, nalbuphine, and fentanyl produced dose-dependent increases in morphine-like stimulus effects and decreases in response rates. Repeated treatment with 20 mg/kg per day morphine increased the ED₅₀ for stimulus control by fentanyl, morphine, or nalbuphine two-, four-, or 40-fold, respectively. Repeated treatment with 64 mg/kg per day nalbuphine increased the ED₅₀ for stimulus control for morphine by two-fold, but lower or higher treatment doses had no significant effect. Treatment with 100 mg/kg per day nalbuphine increased the ED₅₀ for nalbuphine by six-fold. Repeated treatment with 0.22 mg/kg per day fentanyl increased the ED₅₀ for stimulus control by fentanyl or morphine by approximately two-fold. Comparisons among treatment conditions suggested that magnitude of tolerance to morphine-like stimulus effects did not vary as an inverse function of the relative efficacy of the agonist used for repeated treatment. Rather repeated morphine and fentanyl treatments produced comparable tolerance, whereas repeated nalbuphine treatment did not evoke substantial tolerance. Comparisons within treatment conditions, however, suggested that magnitude of tolerance may vary inversely with relative efficacy of the agonist tested for morphine-like stimulus effects. During treatment with morphine or fentanyl, greater tolerance was observed to the morphine-like stimulus effects of the lower efficacy agonist relative to the higher efficacy agonist. Received: 17 September 1996 / Final version: 13 March 1997     

Morphine-like stimulus effects in the monkey: opioids with antagonist properties

The discriminative stimulus properties of opioids with a wide spectrum of agonist and antagonist properties were evaluated in squirrel monkeys trained to discriminate between morphine and saline in a two-choice discrete-trial avoidance task. Stimulus control was considered to be established when the monkeys reliably completed at least 22 trials of a 25-trial session on the lever appropriate for the drug state. Tests of stimulus generalization were conducted with compounds that were previously shown in the rat to produce discriminative stimulus effects that are: (a) morphine-like (profadol, WY-16,225, pentazocine, butorphanol, nalmexone); (b) cyclazocine-like (cyclazocine, ketocyclazocine, levallorphan); (c) neither morphine-like nor cyclazocine-like (nalbuphine and nalorphine). Profadol and WY-16,225 were equipotent with morphine in producing morphine-like stimulus effects. Naloxone antagonized the morphine-appropriate responding produced by all three compounds, but 10 times more naloxone was needed to block the stimulus effects of WY-16,225 than to block those of either morphine or profadol consistent with the known antagonist properties of WY-16,225. None of the other drugs produced complete morphine-like stimulus control of behavior but, with the exception of nalorphine, the highest dose of each resulted in about half of the trials being completed on the morphine-appropriate choice lever. These results confirm the heterogeneous nature of the discriminative stimulus effects of opioids with mixed agonist and antagonist properties and indicate the importance of interspecies comparisons.     

Opioid agonist-antagonist drugs in acute and chronic pain states.

The agonist-antagonist opioid analgesics are a heterogeneous group of drugs with moderate to strong analgesic activity comparable to that of the pure agonist opioids such as codeine and morphine but with a limited effective dose range. The group includes drugs which act as an agonist or partial agonist at one receptor and an antagonist at another (pentazocine, butorphanol, nalbuphine, dezocine) and drugs acting as a partial agonist at a single receptor (buprenorphine). These drugs can be classified as nalorphine-like or morphine-like. Meptazinol does not fit into either classification and occupies a separate category. Pentazocine, butorphanol and nalbuphine are weak mu-antagonists and kappa-partial-agonists. All three drugs are strong analgesics when given by injection: pentazocine is one-sixth to one-third as potent as morphine, nalbuphine is slightly less potent than morphine, and butorphanol is 3.5 to 7 times as potent. The duration of analgesia is similar to that of morphine (3 to 4 hours). Oral pentazocine is closer in analgesic efficacy to aspirin and paracetamol (acetaminophen) than the weak opioid analgesics such as codeine. Neither nalbuphine nor butorphanol is available as an oral formulation. At usual therapeutic doses nalbuphine and butorphanol have respiratory depressant effects equivalent to that of morphine (though the duration of such effects with butorphanol may be longer). Unlike morphine there appears to be a ceiling to both the respiratory depression and the analgesic action. All of these 3 drugs have a lower abuse potential than the pure agonist opioid analgesics such as morphine. However, all have been subject to abuse and misuse, and pentazocine (but not the others) is subject to Controlled Drug restrictions. Buprenorphine is a potent partial agonist at the mu-receptor, and by intramuscular injection is 30 times as potent as morphine. A ceiling to the analgesic effect of buprenorphine has been demonstrated in animals and it is also claimed in humans. However, there are no reliable data available to define the maximal dose of buprenorphine in humans. A practical ceiling exists for sublingual use in that the only available formulation is a 2 micrograms tablet and few patients will accept more than 3 or 4 of these in a single dose. The duration of analgesia is longer than that of morphine, at 6 to 9 hours. There have been suggestions that buprenorphine causes less respiratory depression than morphine, but viewed overall it appears that in equianalgesic doses the 2 drugs have similar respiratory depressant effects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Discriminative stimulus properties of the mixed agonist-antagonist pentazocine in the rat using two-choice discrete-trial avoidance paradigm

The discriminative stimulus effects of pentazocine were evaluated in the rat trained to discriminate 3.0 mg/kg of pentazocine from vehicle in a two-choice discrete-trial avoidance paradigm. The rats used could discriminate 3.0 mg/kg of pentazocine from vehicle within 20 sessions after the start of discrimination training. The stimulus effects lasted 30 to 90 min and disappeared thereafter except for one rat in which the discriminative effects lasted 30 to 150 min. Pentazocine produced dose-dependent stimulus effects at 0.3 to 3.0 mg/kg doses. The stimulus effects of pentazocine were fully reversed by higher doses of naltrexone. Butorphanol, nalorphine, morphine, levorphanol, SKF 10,047, and methamphetamine generalized to pentazocine cue. However, ethylketocyclazocine, dextrorphan or pentobarbital did not produce stimulus effects in common with pentazocine. These results suggest that the discriminative stimulus effects of pentazocine (3.0 mg/kg) are mediated through an opioid but non-mu and nonspecific mechanism.     

Discriminative stimulus effects of spiradoline,a kappa-opioid agonist

This study represents the initial step in assessing the discriminative effects of spiradoline (U62,066), a potent congener of the selective kappa-opioid agonist, U50,488. Separate groups of rats were trained to discriminate between SC injections of saline and either 3.0 mg/kg spiradoline or 3.0 mg/kg morphine in a discrete-trial shock-avoidance/escape procedure. Spiradoline-trained rats generalized completely to U50,488 (ED₅₀s for spiradoline and U50,488 were 0.66 and 8.71 mg/kg, respectively), but selected the choice lever appropriate for saline in generalization tests with graded doses of morphine, phencyclidine, and agonist-antagonist opioids with varying degrees of kappa activity, ethylketocyclazocine, nalorphine, and butorphanol. Morphine-trained rats did not generalize to spiradoline. Naltrexone (0.01 or 0.1 mg/kg) blocked surmountably the discriminative effects of both spiradoline and morphine, but was approximately 10-fold less potent against spiradoline. These results indicate that the discriminative effects of spiradoline are mediated by kappa-opioid receptors; meaningful mu-opioid and PCP/sigma components of action were not in evidence. The potency and apparent pharmacological selectivity of spiradoline suggest the potential value of this drug for studying kappa-opioid-mediated stimulus control of behavior.     

Contribution of individual differences to discriminative stimulus, antinociceptive and rate-decreasing effects of opioids: importance of the drug's relative intrinsic efficacy at the mu receptor

Rats were trained to discriminate 3.0mg/kg morphine from water in a standard two-lever drug discrimination procedure and tested in a hot water tail-withdrawal procedure. When tested with morphine, fentanyl, buprenorphine and butorphanol, individual animals showed a three- to ten-fold difference in the lowest dose that substituted completely for morphine, whereas 30- to 1000-fold differences were obtained with nalbuphine and levallorphan, respectively. Across repeated determinations, the dose-effect curves for morphine and nalbuphine remained relatively stable within an individual, suggesting that the profound individual differences with nalbuphine were not a consequence of variability in the dose-effect curve. In addition, despite the extremely shallow group dose-effect curves obtained with nalbuphine and levallorphan, intermediate levels of drug-appropriate responding were not evidenced in individual animals. In the tail withdrawal procedure, the doses of morphine and fentanyl required to produce the maximal levels of antinociception varied by approximately three-fold across individual rats. With butorphanol and nalbuphine, differences across animals were greater than 30-fold and 300-fold, respectively, whereas with levallorphan, substantial individual differences were observed in the maximal level of antinociception. Further analyses indicated that animals sensitive to the stimulus effects of nalbuphine and levallorphan were also sensitive to the antinociceptive effects of nalbuphine, levallorphan and butorphanol. In contrast to the individual differences obtained with the stimulus and antinociceptive effects of these opioids, the potency of these drugs for decreasing rate of responding was similar across animals. These findings indicate that the relative efficacy of an opioid at the mu receptor is an important determinant of individual differences in responsiveness to its stimulus and antinociceptive effects, but not to its rate-decreasing effects.     

Further characterization of the discriminative stimulus effects of spiradoline

The results of a previous study in rats indicated that spiradoline has pharmacologically selective discriminative effects that are mediated by kappa-opioid receptors. However, the training dose, 3.0 mg/kg, increased response latencies, suggesting that it was relatively high. The current study was performed to characterize further the discriminative effects of spiradoline by using a lower training dose, 1.0 mg/kg, and testing a larger number of drugs for generalization with spiradoline. Rats were trained in a discrete-trial avoidance/escape procedure to discriminate 1.0 mg/kg spiradoline, SC, from saline in an average of 19.7 sessions; response latencies after saline and spiradoline were not different from each other. The rats generalized dose dependently and completely to other kappa-opioid agonists that have relatively high efficacy: ethylketocyclazocine, U69,593, and U50,488. They generalized partially to ketocyclazocine, (-)-N-allylnormetazocine, and DuP 747, and not at all to cyclazocine, butorphanol, nalorphine, and pentazocine, discriminable opioids that have relatively low efficacy at kappa-opioid receptors, or to morphine and dextromethorphan, discriminable drugs that do not act at kappa-opioid receptors. The discriminative effects of spiradoline were unaffected by the mu-opioid antagonist beta-funaltrexamine, but were blocked completely for at least 4 weeks by the kappa-opioid antagonist nor-binaltorphimine. Thus, spiradoline-like stimulus control of behavior remains kappa-opioid selective, and continues to have a high efficacy requirement even at a training dose that does not impair performance.     

Narcotic discrimination in pigeons: antagonism by naltrexone

In pigeons trained to discriminate between morphine (10 mg/kg) and saline, both morphine and ethylketazocine produced dose-related morphine-appropriate responding. The maximum effect produced by meperidine, however, was only 60% of that produced by morphine or ethylketazocine. Naltrexone (0.1-1.0 mg/kg) produced dose-related shifts to the right in the dose-response curves for the discriminative stimulus and rate-decreasing effects of morphine and ethylketazocine without affecting the response produced by meperidine. Thus, in contrast to the effects observed in other species, morphine and ethylketazocine produce similar discriminative effects in the pigeon. In addition, the morphine-like discriminative effects and the rate-decreasing effects of meperidine in the pigeon are not mediated by the naltrexone-sensitive mechanisms which mediate these effects of morphine or ethylketazocine.     

Self-administration of nalbuphine,butorphanol and pentazocine by morphine post-addict rats

The purpose of the study was to define possible self-administration of nalbuphine, butorphanol and pentazocine by morphine post-addict rats. Rats were prepared with permanent EEG and EMG electrodes and indwelling IV cannulae ,made tolerant to and physically dependent on morphine, then trained to lever press for morphine IV self-injections on a fixed ratio (FR) 20 schedule of reinforcement. Rats were then spontaneously withdrawn from morphine. When these morphine post-addict rats were returned to the experimental cages three to four weeks later, they were found to reestablish self-administration of morphine as well as to establish self-administration of nalbuphine, butorphanol and pentazocine. Suppression of REM sleep for at least 30 min was apparent following self-injections of these agents. After the stabilization of self-injection patterns, withdrawal from morphine and pentazocine was found to be associated with intense abstinence symptoms. However, withdrawal from nalbuphine and butorphanol was not. It can be concluded that while drug-seeking behavior for the above narcotics in morphine post-addict rats was analogous as measured by self-administration, nalbuphine and butorphanol appeared to produce lower levels of physical dependence.     

Mu-opioid component of the ethylketocyclazocine (EKC) discriminative stimulus in the rat

The opioid receptor selectivity of the EKC discriminative stimulus was characterized in Fischer rats trained to discriminate 0.3 mg/kg EKC (SC) from saline in a twochoice discrete-trial avoidance paradigm. The putative kappa-opioid receptor agonists EKC and U50,488H completely generalized with the EKC aue at doses of 0.3 and 10 mg/kg, respectively. The putative mu-opioid receptor agonists morphine (M) and fentanyl also dose-dependently generalized with the EKC stimulus. The generalization of M with EKC was not symmetrical, EKC and U50,488H produced little or no M-appropriate responding in rats trained to discriminate 3.0 mg/kg M (SC) from saline. This generalization pattern may reflect a lack of opioid receptor selectivity of the EKC stimulus. However, distinct muopioid and kappa-opioid components of the EKC cue could be identified using graded doses of naloxone in EKC-trained rats. The discriminative effects of morphine and fentanyl were blocked completely by doses of 0.1–1.0 mg/kg naloxone, whereas doses of naloxone 3–10 times greater were necessary to block the discriminative effects of EKC and U50,488H. These results suggest that EKC produces a complex discriminative stimulus with mu-opiod and kappa-opioid components that can be separated using antagonists such as naloxone.     

Subjective, psychomotor, and physiological effects of cumulative doses of mixed-action opioids in healthy volunteers

RATIONALE: Conducting complete dose-response evaluations of multiple drugs in a single within-subjects experiment is very time-consuming when a complete session is required for evaluation of each dose. OBJECTIVE: To evaluate a within-session cumulative-dosing procedure as a potentially efficient method for conducting dose-response evaluations of mixed-action opioids. METHODS: Fifteen healthy volunteers received intravenous injections of saline, butorphanol, nalbuphine, pentazocine, or morphine in a randomized, double-blind, crossover design. Subjects received one injection per hour for the first 4 h, and a 3-h recovery period followed. Saline was injected first, then saline or increasing doses of each drug (except pentazocine, see below) were administered every hour for the next 3 h. The absolute doses per injection were morphine and nalbuphine 2.5, 5, and 10 mg/70 kg, butorphanol 0.5, 1, and 2 mg/70 kg, and pentazocine 7.5, 15, and 0 mg/70 kg. (The highest dose of pentazocine was omitted because of the risk of dysphoria and psychotomimesis). These injections resulted in cumulative doses of morphine or nalbuphine 2.5, 7.5, and 17.5 mg/70 kg, butorphanol 0.5, 1.5, and 3.5 mg/70 kg, and pentazocine 7.5 and 22.5 mg/70 kg. Mood, psychomotor performance, and vital signs were assessed. RESULTS: Effects of all opioids were similar, with some exceptions. Butorphanol had the strongest effects on psychomotor performance and some subjective effects. Morphine was associated with delayed or prolonged side effects. CONCLUSIONS: Orderly dose-response functions and replication of results of single-dosing studies confirmed that the cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects.