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S S Negus

Publications and source records attributed to S S Negus.

63 records · Page 4Linked 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

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↗
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

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

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↗
PubMed1988

Kappa antagonist properties of buprenorphine in the shock titration procedure.

Buprenorphine produced a dose-dependent antagonism of the selective kappa opioid agonist U50,488 in squirrel monkeys responding under the shock titration procedure. In one group of four monkeys, 0.003-0.01 mg/kg buprenorphine produced dose-dependent rightward shifts in the individual U50,488 dose-effect curves and increased the A50 value for U50,488 more than 2-fold in each monkey. Furthermore, 0.01 mg/kg buprenorphine antagonized a maximally effective dose of U50,488 in these monkeys. Buprenorphine (0.01-0.1 mg/kg) also produced rightward shifts in the group U50,488 dose-effect curve for a second group of three monkeys. Buprenorphine's antagonism of U50,488 was probably not a consequence of any mu opioid antagonist properties of buprenorphine in this procedure since (1) buprenorphine produced an inconsistent antagonism of the selective mu agonist fentanyl, and (2) the selective mu antagonist beta-funaltrexamine did not antagonize U50,488. These results support the hypothesis that buprenorphine has kappa antagonist activity in the shock titration procedure.

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