Biomedical subjects

M J Picker

Publications and source records attributed to M J Picker.

At least 37 records · Page 2Linked to original sources

PubMed1998

Drug discrimination history: pigeons trained to discriminate opioids with activity at different receptor types.

In pigeons (Columba livia; N = 5) trained to discriminate the mu (mu) opioid butorphanol from saline, various mu (morphine, fentanyl) but not kappa (kappa; bremazocine, U50,488, U69,593) opioids produced at least 80% drug-appropriate responding. Subsequently, pigeons were retrained to discriminate the kappa opioid bremazocine from saline; in this condition, both mu and kappa opioids produced at least 80% drug-appropriate responding, naloxone was more potent as an antagonist of the butorphanol stimulus, and chronic bremazocine treatment selectively produced tolerance to the bremazocine stimulus. Although butorphanol can function as a kappa antagonist, the effects produced by combinations of butorphanol and bremazocine during training with bremazocine were generally effect-additive. The findings indicate that the mechanisms underlying the stimulus effects of mu opioids are not altered by subsequent training with a kappa opioid. Conversely, a history of discrimination training with a mu opioid does not alter the discriminative control produced by kappa opioids during subsequent training with a kappa opioid.

Animals↗

PubMed1998

Delta opioid-like discriminative stimulus effects of mu opioids in pigeons discriminating the delta opioid BW373U86 from saline.

The purpose of this experiment was to examine the substitution patterns produced by opioids with activity at the mu receptor in pigeons trained to discriminate the delta opioid BW373U86 from saline. A low dose of naltrindole (0.1 mg/kg) produced at least a 16-fold rightward shift in the dose-effect curve for the stimulus effects of BW373U86 (yielding a pK(B) = 7.9), whereas a relatively high dose of naloxone (1.0 mg/kg) produced only a 2-fold rightward shift (yielding a pK(B) = 5.6). The delta opioid SNC80 and the mixed mu/kappa opioids ethylketocyclazocine and ketocyclazocine substituted completely for the BW373U86 stimulus. Various opioids with activity at the mu receptor (levallorphan, [-]-cyclazocine, [-]-n-allylnormetazocine, morphine, butorphanol, nalbuphine, [+]-propoxyphene, etorphine, fentanyl) substituted partially for the BW373U86 stimulus. There was no relationship between the substitution patterns produced by these opioids and their relative intrinsic efficacy at the mu receptor, their relative selectivity for the mu receptor or their relative affinity for the delta receptor. Naloxone (1.0 mg/kg) was considerably more effective than naltrindole (0.1 mg/kg) in antagonizing the substitution patterns produced by etorphine, ethylketocyclazocine, ketocyclazocine and butorphanol, suggesting that these effects were not mediated by activity at the delta receptor. There was no evidence that these opioids antagonized the BW373U86 stimulus, suggesting that they were not functioning as low efficacy agonists at the delta receptor. The kappa opioids bremazocine and U50,488, as well as the non-opioids cocaine and pentobarbital, failed to produce appreciable levels of BW373U86 responding. The present findings indicate that in pigeons mu opioids most likely produce delta-like discriminative stimulus effects by activation of mu rather than delta or kappa receptors.

Animals↗

PubMed1997

Tolerance and cross tolerance to the accuracy- and rate-decreasing effects of mu opioids in rats responding under a fixed-consecutive-number schedule.

The purpose of the present investigation was to examine the development of tolerance to the effects of morphine and other mu opioids in rats responding under a fixed-consecutive-number (FCN) schedule of food presentation. To this end, five rats were trained under an FCN schedule and subsequently tested with a variety of mu opioids both before and during chronic exposure to a 0.4 mg/ml morphine drinking solution. Morphine, fentanyl, buprenorphine, butorphanol and nalbuphine produced dose-dependent decreases in both accuracy and response rate when tested prior to the chronic regimen. In most instances, doses of these drugs that decreased accuracy also decreased response rate. During chronic treatment, tolerance developed to the effects of morphine and cross-tolerance was conferred to the effects of fentanyl, buprenorphine and butorphanol. A greater degree of tolerance was conferred to the effects of butorphanol than to the other opioids examined, and the degree of tolerance conferred to butorphanol's rate-decreasing effects was greater than the degree of tolerance conferred to its accuracy-decreasing effects. Doses of naloxone that had no effect prior to morphine treatment produced large decreases in accuracy and response rate when tested during the chronic regimen. In contrast to the other opioids examined, the potency of nalbuphine was not altered by chronic morphine administration. These data emphasize the importance of both pharmacological and procedural variables in the development of tolerance and cross tolerance to the behavioral effects of opioids.

Animals↗

PubMed1997

Discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine: cross-substitution by mu and delta opioid agonists.

The purpose of this investigation was to evaluate the discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine. In pigeons trained to discriminate 1.7 mg/kg dezocine from saline, a series of opioids with activity at the mu opioid receptor substituted completely for the dezocine stimulus with a rank order of potency similar to that obtained in other assays sensitive to the effects of mu agonists (i.e., fentanyl >[-]-cyclazocine >buprenorphine = butorphanol >l-methadone >nalbuphine >[-]-metazocine >morphine). (-)-N-allylnormetazocine and (+)-propoxyphene substituted partially for the dezocine stimulus, an effect obtained even when tested up to doses that suppressed responding. Naloxone (0.1 - 10 mg/kg) antagonized the stimulus effects of dezocine, (+)-propoxyphene and fentanyl in a dose-related manner, whereas doses of naloxone that antagonized fentanyl's rate-decreasing effects failed to antagonize the rate-decreasing effects of dezocine and (+)-propoxyphene. A 10-mg/kg dose of the mu-selective, noncompetitive antagonist beta-funaltrexamine was more effective against the stimulus effects of dezocine and nalbuphine than against morphine and fentanyl. As was observed with naloxone, beta-funaltrexamine failed to antagonize dezocine's rate-decreasing effects. The delta agonists BW373U86 and SNC80 substituted partially for the dezocine stimulus, and these effects were reversed by doses of the delta-selective antagonist naltrindole (0.1 and 1.0 mg/kg) that had no effect on the dezocine stimulus. Naltrindole also antagonized the rate-decreasing effects produced by BW373U86 and SNC80, but not those of dezocine. The kappa agonists bremazocine, spiradoline, U50,488 and U69,593 failed to substitute for the dezocine stimulus. The kappa-selective antagonist norbinaltorphimine (1.0 mg/kg) failed to antagonize dezocine's stimulus or rate-decreasing effects. The present findings indicate that dezocine shares similar stimulus effects with both mu and delta agonists, its stimulus effects are reversed by mu-selective antagonists, and its rate-decreasing effects are not mediated by activity at mu, kappa or delta opioid receptors.

Analgesics, Opioid↗

PubMed1997

Discriminative stimulus effects of opioids in pigeons trained to discriminate fentanyl, bremazocine and water: evidence of pharmacological selectivity.

The purpose of the present investigation was to examine the discriminative stimulus effects of opioids with activity at mu and kappa opioid receptors, in pigeons trained to discriminate the mu opioid fentanyl, the kappa opioid bremazocine and water in a three-choice discrimination task. The apparent pkB values obtained for naloxone as an antagonist of the stimulus effects of fentanyl were higher than those obtained against the bremazocine stimulus. The mu opioids morphine and l-methadone substituted for the fentanyl stimulus, the kappa opioids U50,488 and U69,593 substituted for the bremazocine stimulus, and the non-opioid pentobarbital failed to substitute for either the fentanyl or bremazocine stimulus. A series of opioids with activity at both the mu and kappa opioid receptor sites, including nalorphine, butorphanol, buprenorphine, nalbuphine, ethylketocyclazocine, (-)-ketocyclazocine, (-)-n-allylnormetazocine (NANM) and levallorphan, produced high levels of substitution for the fentanyl stimulus without producing appreciable levels of substitution for the bremazocine stimulus. At doses that did not substitute for the fentanyl stimulus, (-)-NANM, levallorphan, nalorphine and nalbuphine partially antagonized the bremazocine stimulus (i.e. produced responding on the water key). Butorphanol and buprenorphine also antagonized the bremazocine stimulus, although this effect was evidenced only at doses that substituted for the fentanyl stimulus. In contrast, even when tested up to doses that markedly decreased rates of responding, ethylketocyclazocine and (-)-ketocyclazocine failed to antagonize the bremazocine stimulus. The present findings indicate that in this three-choice task the fentanyl-like substitution patterns produced by opioids with activity at both the mu and kappa opioid receptors are similar to those reported in pigeons trained to discriminate either fentanyl or bremazocine from saline (i.e. two-choice tasks). In this task, however, the level of kappa antagonist activity evidenced by these opioids was considerably less than that obtained in pigeons trained to discriminate bremazocine from saline.

Analgesics↗

PubMed1996

Effects of the delta opioid against BW373U86 in pigeons trained to discriminate fentanyl, bremazocine and water in a three-choice drug discrimination procedure.

The delta opioid agonist BW373U86 was examined alone and in combination with mu agonists in pigeons trained to discriminate the mu agonist fentanyl (0.056 mg/kg), the kappa agonist bremazocine (0.017 mg/kg), and distilled water in a three-choice drug discrimination procedure. BW373U86 (0.01-10 mg/kg) produced a dose-dependent increase in fentanyl-appropriate responding and complete generalization to fentanyl in four of five subjects. BW373U86 did not elicit bremazocine-appropriate responding in any of the subjects. Fentanyl-appropriate responding elicited by BW373U86 was antagonized by the delta selective antagonist naltrindole (0.1-10 mg/kg) but not by the mu selective antagonist naloxone (0.1-30.0 mg/kg). When BW373U86 was administered in combination with the mu agonists fentanyl, morphine and nalbuphine, a low dose of BW373U86 (0.01 mg/kg) that elicited primarily water-appropriate responding when administered alone did not produce a significant change in the ED50 values for fentanyl, morphine or nalbuphine. Higher doses of BW373U86 (0.1-1.0 mg/kg) increased levels of fentanyl-appropriate responding elicited by low doses of fentanyl, morphine and nalbuphine to levels similar to those produced by BW373U86 alone. These results indicate that BW373U86 shares discriminative stimulus properties with the mu agonist fentanyl in pigeons, possibly by acting at delta opioid receptors. However, BW373U86 does not potentiate the discriminative stimulus effects of mu agonists or share discriminative stimulus effects with the kappa agonist bremazocine.

Analgesics↗

PubMed1996

Discriminative-stimulus effects of morphine in combination with alpha- and beta-noradrenergic agonists and antagonists in rats.

Studies have shown that the noradrenergic system is involved in the analgesic effects of opioids and in the expression and development of physical signs of opioid withdrawal. The purpose of the present experiment was to determine if the noradrenergic system was involved in the discriminative effects of morphine in rats trained to discriminate 5.6 mg/kg morphine from saline under a fixed-ratio schedule of food presentation. A range of doses of morphine (0.3-10.0 mg/kg) produced dose-dependent increases in morphine-appropriate responding without substantial decreases in response rate. Several experiments were conducted to determine whether a number of noradrenergic agonists and antagonists 1) substitute for morphine or 2) alter the discriminative-stimulus effects of morphine when administered concurrently. The alpha 2 agonist clonidine (0.003-0.1 mg/kg), the alpha 1 antagonist prazosin (0.1-10.0 mg/kg), the alpha 2 antagonist yohimbine (0.1-10.0 mg/kg), the beta 2 agonist salbutamol (0.03-10.0 mg/kg), and the beta antagonist propranolol (1.0-10.0 mg/kg), neither substituted for morphine nor altered the discriminative-stimulus effects of morphine when administered in combination. These data suggest that the noradrenergic system is not involved in the discriminative-stimulus effects of 5.6 mg/kg morphine in rats.

Adrenergic Agents↗

PubMed1996

Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists.

The discriminative stimulus effects of butorphanol were examined in separate groups of pigeons trained to discriminate either a low (0.1 mg/kg), medium (1.0 mg/kg) or high (5.6 mg/kg) dose of butorphanol from saline. The mu-selective opioid antagonist naloxone was considerably more potent than the delta-selective opioid antagonist naltrindole in antagonizing the effects of butorphanol. In each of the training dose groups, the mu opioid agonists morphine, l-methadone and fentanyl, as well as buprenorphine, (-)-pentazocine, nalbuphine, (-)-metazocine and nalorphine, substituted completely for the butorphanol stimulus. The rank order of potency for these compounds in substituting for the butorphanol stimulus was similar across training dose groups and similar to those reported in studies in which fentanyl or morphine were used as training stimuli. (-)-N-allylnormetazocine (NANM) and levallorphan substituted completely for the butorphanol stimulus in the low-dose group, and substituted partially for and antagonized partially the butorphanol stimulus in the medium- and high-dose groups. The kappa opioid agonists spiradoline, bremazocine, U50,488 and U69,593 substituted partially for butorphanol in the low-dose group, an effect that was not reversed by naloxone. In the medium- and high-dose groups, these kappa opioid agonists produced predominantly saline-appropriate responding. The delta opioid agonist BW373U86 substituted completely for butorphanol in the low-dose group, and naltrindole was more potent than naloxone in antagonizing these effects. In the medium- and high-dose groups, BW373U86 substituted partially for the butorphanol stimulus. Unlike the substitution patterns produced by the mu, kappa and delta opioid agonists, the sigma/phencyclidine compounds (+)-cyclazocine and (+)-NANM and the barbiturate pentobarbital produced predominantly saline-appropriate responding in all training dose groups. The present findings suggest that opioids with agonist activity at mu, kappa and delta opioid receptors share similar stimulus effects with a low training dose of butorphanol, whereas only opioids with agonist activity at the mu opioid receptor share stimulus effects with a medium and high training dose of butorphanol.

Analgesics, Opioid↗

PubMed1995

Discriminative stimulus effects of the 5HT1A agonist 8-OH-DPAT: attenuation by mu but not by kappa opioids.

The ability of mu and kappa opioids to alter the discriminative-stimulus and rate-decreasing effects of the 5-HT1A receptor agonist 8-OH-DPAT was examined in rats trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8-OH-DPAT from water using a two-lever food-reinforced drug discrimination procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488 and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when tested up to doses that substantially reduced rates of responding. During antagonism tests, selected doses of the mu opioids, morphine and fentanyl, administered at various pretreatment times, attenuated the stimulus effects of both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect curve that were partially surmountable and naltrexone-reversible. In contrast to the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of dose or pretreatment time. The rate-decreasing effects of 8-OH-DPAT were not altered substantially by either the mu or kappa opioids examined. The present study demonstrates that the stimulus effects, but not the rate-decreasing effects, of 5-HT1A receptor agonists can be modulated by mu opioids, whereas neither of these effects are changed by kappa opioids.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1994

Pharmacological analysis of the rate-decreasing effects of mu and kappa opioids in pigeons.

The present study investigated the rate-decreasing effects of several mu (morphine and l-methadone) and kappa (bremazocine, U69,593 and U50,488) opioid agonists in pigeons. Mu and kappa agonists were examined alone, in combination with naltrexone or the mu-selective opioid antagonist, beta-funaltrexamine (beta-FNA), and in pigeons treated chronically with U50,488. Naltrexone was equipotent in shifting the morphine, l-methadone and bremazocine dose-effect curves to the right, but was less potent in shifting the U69,593 dose-effect curve and did not shift the U50,488 dose-effect curve. Beta-FNA shifted the l-methadone dose-effect curve to the right but did not shift the bremazocine, U69,593 or U50,488 dose-effect curves. Pigeons that developed tolerance to U50,488 following daily administration were cross-tolerant to bremazocine but not to l-methadone. Taken together, these experiments indicate that the rate-decreasing effects of morphine and l-methadone are mediated by mu opioid receptors, whereas the rate-decreasing effects of bremazocine, U69,593 and U50,488 in pigeons differ depending on the pharmacological procedures used to assess their effects.

Animals↗

PubMed1994

Discriminative stimulus and response rate-decreasing effects of kappa opioids: antagonism by naloxone.

The present study examined the discriminative stimulus and response rate-decreasing effects of kappa opioids in pigeons trained to discriminate a 0.017 mg/kg dose of bremazocine from saline. Bremazocine, spiradoline, CI977, U69,593 and U50,488 substituted completely for the bremazocine stimulus in a dose-dependent and naloxone-reversible manner. Apparent pA2 values (range, 6.01-6.81) of naloxone against the discriminative stimulus effects of these kappa opioids were smaller than those reported previously in the pigeon for naloxone against the discriminative stimulus effects of various mu opioids. Bremazocine, CI977, spiradoline and U69,593 also decreased rate of responding in a dose-dependent and naloxone-reversible manner. The apparent pA2 values (range, 6.25-6.44) for naloxone against the rate-decreasing effects of bremazocine, CI977 and U69,593 were not different from the apparent pA2 values for naloxone against their discriminative stimulus effects. An apparent pA2 for naloxone against the rate-decreasing effects of spiradoline could not be determined due to the shallow slope of the Schild plot. Although the rate-decreasing effects of U50,488 were antagonized by naloxone, the degree of antagonism was small and not dose-dependent. These findings indicate that the discriminative stimulus and rate-decreasing effects of some kappa opioids are mediated by similar mechanisms and that a non-opioid mechanism may contribute to the rate-decreasing effects of spiradoline and U50,488.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1994

Discriminative stimulus effects of phencyclidine: pharmacologically specific interactions with delta 9- and delta 8-tetrahydrocannabinol.

Rats were trained to discriminate a dose of 1.75 mg/kg phencyclidine (PCP) from saline. During substitution tests, both PCP (0.3-10.0 mg/kg) and the non-competitive NMDA antagonist, MK-801 (0.01-0.3 mg/kg) substituted for the PCP stimulus in a dose-dependent manner. In contrast, delta 9-tetrahydrocannabinol (delta 9-THC, 0.1-5.6 mg/kg) and delta 8-tetrahydrocannabinol (delta 8-THC, 0.3-5.6 mg/kg) failed to substitute for the PCP stimulus, up to doses that substantially decreased rate of responding. However, both delta 9-THC and delta 8-THC partially attenuated the discriminative stimulus effects of the PCP training dose. Furthermore, a dose of 3.0 mg/kg delta 9-THC shifted the PCP dose-effect curve for discriminative stimulus effects to the right and shifted the PCP dose-effect curve for rate of responding to the left. The attenuation of the PCP stimulus by delta 9-THC lacked a strong dose-dependent relationship and was observed both at doses which did not alter rate of responding, as well as at doses which substantially decreased rate. In contrast to the effects observed with delta 9-THC and delta 8-THC, morphine, d-amphetamine and chlordiazepoxide failed to attenuate the discriminative stimulus effects of PCP, even at doses that markedly decreased rate of responding. The present findings suggest that delta 9-THC and delta 8-THC alter the discriminative stimulus effects of PCP in a pharmacologically specific manner.

Animals↗

PubMed1994

Kappa agonist and antagonist properties of mixed action opioids in a pigeon drug discrimination procedure.

Previous investigations indicate that mixed action opioids (i.e., opioids with activity at a combination of opioid receptor sites or a combination of opioid and nonopioid sites) often possess kappa-like stimulus effects in the rat and monkey, but mu-like stimulus effects in pigeons. In the present investigation, the kappa agonist and antagonist actions of a series of mixed action opioids were examined in pigeons trained to discriminate a 0.017-mg/kg dose of the kappa agonist bremazocine from saline. The mixed-action opioids (-)-n-allylnormetazocine, (-)-cyclazocine, (-)-metazocine, levallorphan, buprenorphine, nalbuphine, butorphanol and nalorphine failed to substitute for the bremazocine stimulus. When administered in combination with the training dose of bremazocine, each of these opioids produced a dose-related antagonism of the bremazocine stimulus. With the exceptions of butorphanol and (-)-metazocine, the antagonist effects of these opioids were surmountable. Buprenorphine, (-)-n-allylnormetazocine and levallorphan produced their kappa antagonist effects at doses approximately 2 to 3 log units lower than those that decreased rates of responding when these opioids were administered alone, whereas approximately 1 log unit separated the kappa antagonist and rate-decreasing effects of nalorphine, nalbuphine and (-)-cyclazocine. In contrast, the kappa antagonist effects of butorphanol and (-)-metazocine were observed only at doses of markedly decreased response rates. A somewhat different profile was obtained with ethylketocyclazocine and ketocyclazocine in that these mixed action opioids produced partial substitution for and partial antagonism of the bremazocine stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Serotonin involvement in the discriminative stimulus effects of kappa opioids in pigeons.

The purpose of the present study was to examine the role of serotonin (5HT) in the discriminative stimulus effects of kappa opioids. Pigeons were trained to discriminate 5.6 mg/kg of the kappa opioid, U50,488, from water. During substitution tests, both U50,488 and another kappa opioid, spiradoline, produced > 80% responding on the U50,488-appropriate key. In contrast, the non-opioid compound, phencyclidine and several serotonergic compounds failed to substitute for the U50,488 discriminative stimulus across a wide range of doses. During combination tests, the selective 5HT1A agonist, 8-OH-DPAT (0.001-3.2 mg/kg), dose-dependently attenuated the discriminative stimulus effects of 5.6 mg/kg U50,488 and 3.2 mg/kg spiradoline. This effect was reversed by the 5HT1A antagonist, NAN-190 (0.01-1 mg/kg), in a dose-dependent manner. Buspirone (0.01-10 mg/kg), a 5HT1A partial agonist, also attenuated the discriminative stimulus effects of the training dose of U50,488 but ipsapirone, another 5HT1A partial agonist, did not. Ketanserin, a 5HT2 antagonist, and MDL72222, a 5HT3 antagonist, attenuated the effects of U50,488, whereas the 5HT1B,1C agonist, mCPP, and the 5HT2 agonist, DOI, did not. Depletion of 5HT with p-CPA also attenuated U50,488's discriminative stimulus effects. Taken together, the results suggest that serotonin release is an important component in the discriminative stimulus effects produced by kappa opioids; however, the effects of DOI and mCPP alone suggest that activation of post-synaptic 5HT receptors is not sufficient to produce the full spectrum of kappa opioid discriminative stimulus effects.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1993

Agonist and antagonist effects of mixed action opioids in the pigeon drug discrimination procedure: influence of training dose, intrinsic efficacy and interanimal differences.

The stimulus effects of selective, high efficacy mu opioids and mixed action opioids with varying degrees of intrinsic efficacy at the mu receptor were examined in pigeons trained to discriminate between saline and either 0.056 (low) or 0.18 (high) mg/kg of fentanyl. The stimulus profiles produced by the various opioids could be separated into three groups: 1) opioids that substituted completely for both training doses of fentanyl, with steep slopes and little interanimal differences in the lowest dose (lowest discriminable dose) that produced complete substitution (fentanyl, morphine and l-alpha-acetylmethadol); 2) opioids that substituted completely for the low training dose and produced high levels of substitution for the high training dose, with relatively shallow slopes and interanimal differences in the lowest discriminable dose (butorphanol, buprenorphine, ethylketocyclazocine, ketocyclazocine, proxorphan, (-)-pentazocine and (-)-metazocine); and 3) opioids that substituted completely for the low training dose, with relatively shallow slopes and large interanimal differences in the lowest discriminable dose. Each of these opioids also antagonized the high-dose fentanyl stimulus with large interanimal differences in the lowest antagonist dose (nalbuphine, nalorphine, (-)-cyclorphan, (-)-cyclazocine, (-)-n-ally-normetazocine and levallorphan). These patterns of substitution and antagonism most likely reflect differences in the intrinsic efficacy of these drugs at the mu receptor, with low intrinsic efficacy associated with shallow dose-effect functions, large interanimal differences in the drug's lowest discriminable dose and low levels of substitution for the high-dose fentanyl stimulus. During antagonism tests with naloxone, two patterns were observed: 1) opioids against which naloxone had apparent pA2 values of approximately 7.0, with little interanimal differences and with the slopes of the Schild plots approximating -1.0 (fentanyl and morphine) and 2) opioids against which naloxone had apparent pA2 values an order of magnitude higher, with large interanimal differences and with the slopes of Schild plots being relatively shallow (butorphanol, nalbuphine, nalorphine and levallorphan). The present findings emphasize the importance of training dose, intrinsic efficacy and interanimal differences when analyzing drug discrimination data.

Animals↗

PubMed1992

Delta 9-tetrahydrocannabinol interactions with phencyclidine and ethanol: effects on accuracy and rate of responding.

The effects of delta 9-tetrahydrocannabinol (delta 9-THC) in combination with phencyclidine (PCP) or ethanol were examined in rats responding under a fixed-consecutive-number schedule of food presentation. Under this schedule, a minimum of 13 consecutive responses on one lever followed by one response on another lever produced food. When administered alone, PCP (0.1-10.0 mg/kg) and delta 9-THC (0.1-5.6 mg/kg), but not ethanol (0.3-1.7 g/kg), decreased accuracy. PCP, delta 9-THC, and ethanol alone all produced dose-dependent decreases in rate of responding. A dose-effect curve for PCP or ethanol was then redetermined in combination with selected doses of delta 9-THC (0.125-1.75 mg/kg) and the data were analyzed according to the effect-addition and dose-addition models of additivity. When administered in combination, delta 9-THC produced dose-dependent leftward shifts in the PCP dose-effect curves for both accuracy and rate of responding. The interactions for PCP + delta 9-THC combinations were effect-additive for accuracy. In contrast, the type of interaction obtained for PCP + delta 9-THC combinations on rate of responding depended upon the particular doses combined, as well as on the model used to analyze the interactions. According to the effect-addition model, these interactions were additive at low doses of delta 9-THC and supraadditive at the highest dose. However, according to the dose-addition model the interactions at the higher doses of delta 9-THC were infraadditive. Delta 9-THC also shifted the ethanol dose-effect curve for rate of responding to the left but did not alter the ethanol dose-effect curve for accuracy. The interactions for ethanol + delta 9-THC combinations were effect-additive for accuracy and both effect- and dose-additive for rate of responding. The present investigation clearly illustrates the importance of examining an extensive range of dose combinations on different behavioral measures, as well as the use of appropriate analyses in studies designed to evaluate the interactions between drugs.

Animals↗

PubMed1992

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 level. 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.

Animals↗

PubMed1992

Intermediate efficacy mu opioids: examination of their morphine-like stimulus effects and response rate-decreasing effects in morphine-tolerant rats.

The present study examined the effects of morphine, the intermediate efficacy mu opioids (-)-pentazocine, (-)-metazocine, proxorphan, levallorphan, (-)-NANMY (N-allylnormetazocine) and (-)-cyclazocine, and the mu antagonist naloxone 1) in rats responding under a FR (fixed-ratio) 30 schedule before, during and after a chronic morphine regimen, and 2) in rats trained to discriminate 10.0 [10-MS (morphine sulfate)] or 3.0 mg/kg (3-MS) of morphine from saline. Under the FR30 schedule, chronic administration of morphine produced tolerance to morphine's rate-decreasing effects and conferred cross-tolerance to (-)-metazocine, proxorphan and (-)-pentazocine. However, the effects of these intermediate efficacy mu opioids could be differentiated from those of morphine on the basis of their 1) shallow dose-effect curves, and 2) large differences in the degree to which tolerance developed in individual rats. In the drug discrimination procedure, (-)-metazocine, proxorphan and (-)-pentazocine produced high levels of substitution for the 3-MS stimulus and intermediate levels for the 10-MS stimulus. In contrast to the pattern of substitution observed with morphine in the 10-MS group, the effects of these drugs were characterized by 1) shallow dose-effect curves, 2) large individual differences in the lowest dose of each drug that substituted completely for the 10-MS stimulus and 3) the failure to obtain complete substitution for the 10-MS stimulus in all of the rats tested. The behavioral profile obtained with the intermediate efficacy mu opioids (-)-NANM, levallorphan and (-)-cyclazocine was indicative of opioids with intrinsic efficacy lower than that of (-)-pentazocine, (-)-metazocine and proxorphan. Under the FR30 schedule, chronic administration of morphine produced an enhanced sensitivity to the rate-decreasing effects of (-)-NANM and levallorphan but not (-)-cyclazocine. In the drug discrimination procedure, (-)-NANM, levallorphan and (-)-cyclazocine produced high levels of substitution for the 3-MS stimulus and low levels for the 10-MS stimulus. Like naloxone, these drugs produced a dose-related attenuation of the 10-MS stimulus. The results of the present study suggest that the relative order of intrinsic efficacy among the opioids tested is: morphine > (-)-metazocine = (-)-pentazocine = proxorphan > (-)-cyclazocine = levallorphan = (-)-NANM > naloxone.

Animals↗