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Biomedical subjects

M J Picker

Publications and source records attributed to M J Picker.

At least 55 records · Page 3Linked to original sources
PubMed1991

Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation.

If different populations of opioid receptors mediate the actions of mu and kappa opioid agonists, then tolerance induced by the chronic administration of a mu agonist should confer cross-tolerance to other mu agonists but not necessarily to those compounds whose effects are mediated by the kappa receptor. This hypothesis was evaluated in the present investigation by examining the effects of the mu agonists morphine, l-methadone and fentanyl, the kappa agonists U50,488 and bremazocine, and the mixed kappa/mu agonist ethylketocyclazocine in rats responding under a fixed-ratio 30 schedule of food presentation before, during and after exposure to a regimen of chronic morphine administration. For comparison, naloxone was evaluated as a representative mu antagonist and the phenothiazine chlorpromazine as a control drug. During all phases of the experiment, each of these compounds produced dose-related decreases in rate of responding. During the daily administration of 40 mg/kg morphine, tolerance developed to the rate-decreasing effects of morphine, l-methadone and fentanyl, and an enhanced sensitivity to the effects of naloxone. In contrast to the effects obtained with these mu opioids, there was no evidence that chronic morphine administration produced tolerance or enhanced sensitivity to the rate-decreasing effects of U50,488, bremazocine, ethylketocyclazocine and chlorpromazine. The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Cross-tolerance and enhanced sensitivity to the response rate-decreasing effects of opioids with varying degrees of efficacy at the mu receptor.

The purpose of the present experiment was to determine whether the effects of opioids with varying degrees of efficacy at the mu receptor are differentially altered in morphine-tolerant pigeons. To this end, dose-effect curves were determined for high, intermediate, and low efficacy mu agonists in pigeons responding under a schedule of food presentation prior to, during, and after exposure to a regimen of chronic morphine administration. In pigeons treated with 56 mg/kg/daily morphine, the dose-effect curves for the rate-decreasing effects of the high-efficacy mu agonists morphine and fentanyl were shifted to the right of their prechronic positions (i.e., tolerance). A small degree of tolerance was also conferred to the intermediate-efficacy mu agonists (-)-pentazocine and (-)-metazocine, but not to nalbuphine or butorphanol. In contrast to the effects obtained with these mu agonists, the chronic morphine regimen shifted the dose-effects curves of the mu antagonist naloxone and the low-efficacy mu agonists nalorphine and levallorphan to the left of their prechronic positions (i.e., enhanced sensitivity). These findings demonstrate that morphine tolerance confers cross-tolerance to other high efficacy mu agonists, enhanced sensitivity to mu antagonists and low efficacy mu agonists, and little or no cross-tolerance to intermediate efficacy mu agonists. Disadvantages of using schedule-controlled responding to examine the effects of intermediate efficacy mu agonists are discussed.

Animals↗
PubMed1991

Interactions between the discriminative stimulus effects of mu and kappa opioid agonists in the squirrel monkey.

A series of mu and kappa opioid agonists with varying degrees of selectivity were evaluated for their agonist and antagonist effects in squirrel monkeys trained to discriminate either the selective mu agonist fentanyl or the selective kappa agonist U50,488 from water. In the fentanyl-trained monkeys, fentanyl, as well as the less selective mu agonists buprenorphine and (-)-metazocine, produced dose-dependent and complete substitution for the training stimulus. U50,488 produced neither agonist nor antagonist effects in the fentanyl-trained monkeys, but the less selective kappa agonists bremazocine and tifluadom generally produced either agonist or antagonist effects, depending on the monkey tested. In the U50,488-trained monkeys, U50,488, bremazocine and tifluadom all produced a dose-dependent and complete substitution for the training stimulus. Fentanyl produced neither agonist nor antagonist effects in the U50,488-trained monkeys, but buprenorphine and (-)-metazocine antagonized the discriminative stimulus effects of U50,488. The inability of the selective mu agonist fentanyl and the selective kappa agonist U50,488 to antagonize each other's discriminative stimulus effects suggests that the stimulus effects mediated by mu and kappa opioid receptors in squirrel monkeys do not interact with a common biologic substrate. Rather, these results suggest that the stimulus effects mediated by mu and kappa receptors function independently of one another. Interactions involving the less selective mu agonists buprenorphine and (-)-metazocine, or the less selective kappa agonists bremazocine and tifluadom, can be explained on the basis of the low receptor selectivity of these drugs.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Acute and chronic morphine administration: effects of mixed-action opioids in rats and squirrel monkeys responding under a schedule of food presentation.

The effects of several opioid compounds were examined in rats and squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation. In rats, dose-effect curves were determined before and after acute pretreatment with 5.6 mg/kg of morphine 5 to 6 hr before the session, as well as during and after the termination of a chronic regimen in which rats received 30.0 mg/kg/day of morphine. In monkeys, dose-effect curves were determined before, during and after the termination of a chronic regimen in which monkeys received 6.0 mg/kg/day of morphine. In morphine-pretreated rats, dose-effect curves for the opioid antagonists naloxone, naltrexone and diprenorphine shifted to the left of those determined when rats were not morphine-pretreated; whereas those for the mu-opioid agonists morphine and I-methadone and mixed-action opioids nalorphine, nalbuphine, butorphanol, pentazocine and bremazocine were unaltered. During chronic morphine administration in rats, dose-effect curves for morphine and butorphanol shifted to the right; whereas the dose-effect curves for naloxone and nalorphine shifted to the left of those determined when rats were not treated with morphine. The effects of pentazocine, nalbuphine, bremazocine and the kappa-opioid agonist U50,488 were unaltered in morphine-maintained rats. In morphine-maintained monkeys, the dose-effect curves for morphine and I-methadone shifted to the right; whereas those for naloxone, nalorphine and nalbuphine shifted to the left of the prechronic dose-effect curves. Dose-effect curves for butorphanol, pentazocine and U50,488 were unaltered. Overall, these results suggest that the chronic morphine administration procedure can be used to distinguish opioid compounds based upon their relative mu agonist and antagonist activity.

Animals↗
PubMed1990

Interactions between mu and kappa opioid agonists in the rat drug discrimination procedure.

The present study was designed to explore the nature of the interaction between mu and kappa opioid agonists in the rat drug discrimination procedure. In rats trained to discriminate the kappa agonist U50,488 (5.6 mg/kg) from water, the other kappa agonist bremazocine substituted completely for the U50,488 training stimulus, and the additional kappa agonist tifluadom substituted in three of five of rats tested. In contrast, the mu agonists morphine, fentanyl, and buprenorphine produced primarily vehicle-appropriate responding. When morphine, fentanyl, and buprenorphine were combined with the training dose of U50,488, all three mu agonists reduced U50,488-appropriate responding. In rats trained to discriminate the mu agonist morphine (10.0 mg/kg) from saline, the other mu agonists morphine and buprenorphine all substituted in a dose-dependent manner for the morphine training stimulus, whereas U50,488, bremazocine, and tifluadom produced primarily vehicle-appropriate responding. When combined with the training dose of morphine, bremazocine antagonized morphine's discriminative stimulus effects, whereas U50,488 and tifluadom had no effect. The barbiturate pentobarbital neither substituted for, nor antagonized, the discriminative stimulus effects of either U50,488 or morphine. These results suggest that mu agonists and kappa agonists produce interacting effects in the drug discrimination procedure in rats.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

Butorphanol's efficacy at mu and kappa opioid receptors: inferences based on the schedule-controlled behavior of nontolerant and morphine-tolerant rats and on the responding of rats under a drug discrimination procedure.

The purpose of the present investigation was to characterize the mu agonist and kappa antagonist effects of the mixed opioid agonist/antagonist butorphanol. To this end, the effects of butorphanol were examined: 1) alone and in combination with the kappa agonist bremazocine in nontolerant and morphine-tolerant rats responding under a fixed-ratio 30 (FR30) schedule of food presentation, and 2) in rats trained to discriminate 10 mg/kg morphine from saline. Prior to the induction of morphine tolerance, morphine, bremazocine and butorphanol produced dose-dependent decreases in rate of responding under the FR30. In these nontolerant rats, butorphanol failed to antagonize bremazocine's rate-decreasing effects. During the chronic morphine regimen, the dose-effect curve for morphine was shifted to the right of its prechronic position by approximately 0.9 log units, whereas the bremazocine curve was not altered substantially. The butorphanol dose-effect curve, in contrast, was shifted to the right and flattened such that doses which eliminated responding in nontolerant rats, as well as doses approximately 1.0 log unit higher, had no effect on responding. In these morphine-tolerant rats, butorphanol produced a dose-dependent antagonism of bremazocine's rate-decreasing effects. In rats trained to discriminate morphine from saline, butorphanol substituted completely for the morphine stimulus. Unlike morphine, which produced its stimulus effects only at doses that decreased rate of responding, butorphanol substituted for the morphine stimulus at doses that had little or no effect on rate of responding.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1990

Opioid agonists/antagonists in morphine-tolerant squirrel monkeys.

The mu-opioid agonist morphine, the opioid antagonist naloxone and the isomers of the mixed action opioids, cyclazocine, n-allylnormetazocine, and pentazocine were examined in squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation. Dose-effect curves for all drugs were obtained prior to, during, and following a chronic regimen in which monkeys received 6 mg/kg/day of morphine. When compared to the dose-effect curves obtained prior to the chronic regimen, the morphine dose-effect curve obtained during the chronic regimen was shifted to the right 0.5-1.0 log unit, whereas the naloxone dose-effect curve shifted over 3 log units to the left. No changes were observed between the prechronic and chronic dose-effect curves for (+)-cyclazocine, (+)-n-allylnormetazocine, and (+)- or (-)-pentazocine. The (-) isomers of n-allylnormetazocine and cyclazocine shifted 0.6-1.7 log units to the left. These results suggest that the (-) isomers of cyclazocine and n-allylnormetazocine have mu antagonist properties which are revealed during chronic morphine administration.

Analgesics, Opioid↗
PubMed1990

Discriminative stimulus properties of U50,488 and morphine: effects of training dose on stimulus substitution patterns produced by mu and kappa opioid agonists.

By using a two-lever drug discrimination task, four groups of rats were trained to discriminate either a low (3.0 mg/kg) and a high (5.6 mg/kg) training dose of the kappa opioid agonist U50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl] benzeneacetamine methanesulfonate hydrate] or a low (3.0 mg/kg) and a high (10 mg/kg) training dose of the mu opioid agonist morphine from water. The stimulus effects of the high training dose of U50,488 were shared by the kappa agonists bremazocine and ethylketocyclazocine (i.e., these drugs produced at least 80% drug-appropriate responding), but not by the mu agonists morphine, fentanyl and l-methadone or the nonopioid compounds d-amphetamine, pentobarbital and phencyclidine. Conversely, the stimulus effects of the high training dose of morphine were shared by other mu agonists, but not by the kappa agonists or the nonopioid compounds examined. Similarities in the stimulus effects of morphine and U50,488 occurred, however, when mu and kappa agonists were examined in rats trained to discriminate relatively low training doses of morphine or U50,488 from water. At the low training dose of morphine, complete substitution was obtained with the mu agonists tested as well as the kappa agonist ketocyclazocine. In these rats, intermediate (approximately 70% drug-appropriate responding) levels of substitution were obtained with the kappa agonists bremazocine and ethyylketocyclazocine. Similarly, at the low training dose of U50,488 both the mu and kappa agonists examined substituted completely. Asymmetrical substitution occurred between U50,488 and morphine at the low training doses, with morphine substituting completely for the low training dose of U50,488 and U50,488 failing to substitute for the low training dose of morphine. The rank order of potency for naloxone as an antagonist of the stimulus effects of morphine and U50,488 was; 3.0 mg/kg of morphine greater than 10 mg/kg of morphine greater than 3.0 mg/kg of U50,488 = 5.6 mg/kg of U50,488. The present results indicate that training dose is an important determinant of the different levels of cross-substitution obtained between mu and kappa agonists, and that a greater pharmacological specificity of drug-induced discriminative stimuli can be obtained when relatively high training doses of mu and kappa opioid agonists are used to establish the discrimination.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation.

The effects of various mu and kappa opioid agonists were evaluated in three squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation before, during and after a regimen of chronic morphine administration. Initially, dose-effect curves for the mu opioid agonists morphine and l-methadone, the kappa opioid agonists U50,488 and tifluadom, the mixed mu/kappa opioid agonist ethylketocyclazocine, and the non-opioid compound pentobarbital were determined in non-tolerant squirrel monkeys. Subsequently, monkeys were administered up to 3.0 mg/kg of morphine twice daily for 8-9 weeks, which resulted in a 1/2 to 3/4 log unit shift to the right of the morphine dose-effect curve relative to its prechronic position. During the chronic morphine regimen, the l-methadone dose-effect curve shifted to the right approximately 3/4 log unit, while the U50,488 and pentobarbital dose-effect curves did not change. In contrast, the ethylketocyclazocine and tifluadom dose-effect curves shifted to the left approximately 1/4 and 3/4 log unit, respectively. The lack of cross-tolerance between mu and kappa agonists in morphine-tolerant squirrel monkeys observed in the present study provides further support for the differentiation of mu and kappa agonists. The occurrence of leftward shifts in the dose-effect curves of some opioid compounds with kappa agonist activity during the regimen of chronic morphine administration suggests that morphine tolerance modulates their

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

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.

Animals↗
PubMed1989

Opioid-like discriminative stimulus properties of benzomorphans in the pigeon: stereospecificity and differential substitution patterns.

Pigeons were trained to discriminate the kappa-opioid agonist bremazocine (BREM) or the mu-opioid agonist fentanyl (FENT) from water. During tests of stimulus substitution, FENT and BREM failed to substitute for each other. The (-)-isomers of cyclazocine, pentazocine and ketocyclazocine substituted for the FENT but not the BREM stimulus. The (+)-isomers of these compounds, as well as the isomers of nallylnormetazocine, failed to substitute for either the FENT or BREM stimulus. In FENT- and BREM-trained pigeons, the (-)-isomers of cyclazocine, pentazocine, nallylnormetazocine and ketocyclazocine were more potent than their respective(+)-isomers in decreasing rates of responding. These results indicate that in the pigeon there is an isomeric separation of the discriminative stimulus properties of cyclazocine, pentazocine and ketocyclazocine and that the FENT-like stimulus effects of these drugs reside in their (-)-isomers. In addition, the present findings establish further that the classification of the discriminative stimulus effects of mu and kappa opioid compounds in the pigeon differ from those in rat and monkey.

Analgesics↗
PubMed1989

Molindone: effects in pigeons responding under conditional discrimination tasks.

Pigeons were trained to respond under three conditional discrimination procedures; 1) a fixed-consecutive-number procedure with (FCN 8-SD) and without (FCN 8) an added external discriminative stimulus, 2) a delayed matching-to-sample (DMTS) procedure using 0-sec, 2-sec and 8-sec delay intervals, and 3) a repeated acquisition of behavioral chains (RA) procedure using a four-link response chain with three stimulus keys. The atypical neuroleptic agent molindone decreased accuracy under the FCN 8 at doses that had no effect on accuracy under the FCN 8-SD. Under the DMTS procedure, molindone-induced decreases in accuracy were directly related to the delay interval, with the largest relative decrements obtained at the 8-sec delay and the smallest at the 0-sec delay. Under the RA procedure, molindone decreased accuracy at doses that had little or no effect on the number of correct responses emitted. Relative to control values, molindone-induced decreases in accuracy were smallest under the DMTS and FCN 8-SD procedures and largest under the FCN 8 and RA procedures. The differential effects obtained with molindone under each of these procedures illustrate the need to employ a variety of assays when determining the behavioral actions of neuroleptics. In addition, this battery of behavioral tests may provide a useful tool for assessing the different neurochemical actions of neuroleptic compounds.

Animals↗
PubMed1989

Differential cross-tolerance to opioid agonists in morphine-tolerant pigeons responding under a schedule of food presentation.

Effects of the opioid agonists morphine, l-methadone, ethylketazocine, U50,488 [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide methanesulfonate hydrate], cyclazocine and bremazocine, and the nonopioid chlorpromazine were determined in pigeons responding under a fixed-ratio 30 schedule of food presentation before, during and after chronic morphine administration. Before chronic morphine administration, all drugs produced dose-dependent decreases in response rates. After daily administration of up to 56 mg/kg of morphine for 7 weeks, dose-effect curves for the mu agonists morphine and l-methadone, as well as the mu/kappa agonist ethylketazocine shifted to the right approximately 1 1/4, 3/4 and 1/2 log units, respectively. In contrast, dose-effect curves for the mixed agonist/antagonists cyclazocine and bremazocine each shifted to the left approximately 3/4 log unit, whereas dose-effect curves for the kappa agonist U50,488 and the nonopioid chlorpromazine did not shift during chronic morphine administration. Dose-effect curves for all drugs except bremazocine returned to their prechronic positions within the period 3 to 8 weeks after termination of chronic morphine administration. The present study demonstrates that repeated administration of morphine produces tolerance to its rate-decreasing effects as well as cross-tolerance selective to other opioids possessing mu agonist properties. The cross-tolerance to ethylketazocine observed in morphine-tolerant pigeons corroborates studies of the discriminative stimulus effects of ethylketazocine in pigeons, suggesting that in this species ethylketazocine possesses predominantly mu agonist properties.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Discriminative stimulus effects of mu and kappa opioids in the pigeon: analysis of the effects of full and partial mu and kappa agonists.

Pigeons were trained to discriminate a dose of either 0.01 mg/kg of bremazocine or 0.05 mg/kg of fentanyl from water using a two-key drug discrimination procedure. During tests of substitution, the selective kappa-opioid agonists bremazocine, U50, 488 and tifluadom substituted for the bremazocine stimulus, whereas the less selective kappa-opioid agonists ethylketocyclazocine, levallorphan, proxorphan and nalorphine substituted for the fentanyl stimulus. The full mu-opioid agonists fentanyl, morphine, I-methadone and levorphanol, as well as the partial agonists nalbuphine, butorphanol and buprenorphine, substituted for the fentanyl stimulus. Compounds with partial-opioid agonist effects, namely nalbuphine, butorphanol, buprenorphine, proxorphan, levallorphan and nalorphine, produced 50% fentanyl-appropriate responding at doses 25 to 369.2 times smaller than the doses required to decrease response rates to 50% of control values. In contrast, the full mu-opioid agonists fentanyl, morphine, I-methadone and levorphanol produced 50% fentanyl-appropriate responding at doses only 1.3 to 10.9 times smaller than those required to decrease response rates by 50%. During tests of antagonism, both naloxone and Mr2266 produced a dose-dependent attenuation of the stimulus effects of bremazocine and fentanyl, whereas beta-funaltrexamine antagonized the stimulus effects of fentanyl but not bremazocine. Although bremazocine has been reported to have mu-opioid antagonist effects, it failed to antagonize the stimulus effects of the training dose of fentanyl. The present investigation establishes further that pigeons can discriminate selective kappa-opioid agonists from mu-opioid agonists and that in pigeons the classification of numerous opioid compounds on the basis of their kappa-like or mu-like stimulus effects differ from those in rat and monkey. In addition, under the drug discrimination procedure the actions of compounds classified as partial-opioid agonists can be differentiated from those of full mu-opioid agonists on the basis of the ratio of the dose required to engender fentanyl-like stimulus effects to the dose required to reduce response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

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