Ineffectiveness of cholecystokinin in impairing runway performance.

We compared changes in runway performance by rats for sucrose reward following injections of the synthetic C-terminal octapeptide of cholecystokinin (CCK-8) with those seen after variations in food deprivation and injections of lithium chloride. No effects on running for either 10% or 30% sucrose were found following 0.5 to 4.0 micrograms/kg of CCK-8, though such doses suppressed 30-min sucrose intake up to 53%. Statistically reliable slowing of running for 10% sucrose was observed on two series of tests after 8.0 micrograms/kg of CCK-8. Running for 30% sucrose was not significantly affected by this dose. The general ineffectiveness of CCK-8 for producing decrements in running spread contrasts with significantly reduced performance after either reductions in food deprivation (21 h vs 12 and 3 h) or injections of 75 mg/kg lithium chloride. These results suggest that the mode of action of CCK-8 in reducing food intake is different than that produced by changes in hunger or by non-specific interference with motivation by malaise. The finding that CCK-8 can substantially reduce consumption with no apparent changes in appetitive motivation is consistent with the hypothesis that this substance acts only late in the meal to prematurely trigger satiety.

Does midazolam inhibit the development of acute tolerance to the analgesic effect of alfentanil?

Alfentanil-midazolam analgesic interactions were studied in rats with continuous infusions or bolus injections of the drugs. Analgesia was determined by measuring the threshold of motor response to noxious pressure. The continuous constant-rate infusion of alfentanil demonstrated that after an initial peak, the analgesia profoundly declined due to the development of acute tolerance. When alfentanil (250 micrograms.kg-1.h-1) was given together with midazolam (3 mg.kg-1.h-1), the decline in the analgesic effect of alfentanil was attenuated. Following the 4 h period of the constant-rate (250 micrograms.kg-1.h-1) infusion of alfentanil, when acute tolerance was already developed, midazolam (3 mg.kg-1) given as a bolus injection enhanced the alfentanil-induced anesthesia. At the same time, when alfentanil was given as a bolus injection (30 micrograms.kg-1) with or without midazolam (3 mg.kg-1) also by bolus injection, no changes were seen to indicate an enhancement of the analgesic effect of alfentanil by midazolam. The results suggest that midazolam attenuates the development of acute tolerance to the analgesic effect of alfentanil.

The dietary status of "new" vegetarians.

A study of fifty well educated young adults, average age twenty-eight years, living in a metropolitan area of New England, who were followers of Zen macrobiotics, revealed that none was below his/her desirable weight although all were at the limit of the normal range. Average triceps skinfold thickness of the men and women fell in the 15th percentile, while arm circumference for members of both sexes was in the 5th percentile (24). Their ten-day dietary records indicated that the base of their diet was grains interspersed with a wide variety of vegetables, fish, cheese, and eggs and that nutrient intakes of the adults were limiting in energy, calcium, and riboflavin--and additionally in iron for the women. Improvement in the nutritional value could be achieved by greater consumption of foods common to macrobiotic dietary practices. Calcium and energy intakes of ten young children were low, especially for a period of rapid growth and development. Because of the bulk necessary to achieve nutritional adequacy with respect to calcium, increasing the children's consumption of macrobiotic food would not be advisable. Consequently, it is suggested that milk be included in their diets.

Reserpine-induced changes in anesthetic action of fentanyl.

The effect of prior administration of reserpine on fentanyl dose-response curves for loss of the righting reflex and prevention of purposeful movement response to noxious stimulation was studied in rats. It was found that reserpine (5 mg X kg-1, 3 h before the tests) antagonized the effect of fentanyl on purposeful movement response to the tail clamp and, at the same time, strengthened its effect on the righting reflex. As a result, reserpine pretreatment reversed the order of fentanyl potency regarding these two effects. Reserpine changed fentanyl ED50 values for the purposeful movement response from 8.2 to 20.3 micrograms X kg-1 (P less than 0.0001) and for the righting reflex from 20.5 to 13.7 micrograms X kg-1 (P less than 0.0001). The results suggest that reserpine dissociates the analgesic action of fentanyl from its anesthetic action, defined as a loss of the righting reflex. This may be regarded as an indication that the analgesic action of narcotics may not adequately reflect their anesthetic potency.

Training non-psychologists in the treatment of sexual dysfunction with special reference to the training of marriage guidance counsellors.

This paper describes a study in which marriage guidance counsellors were trained in the treatment of sexual difficulties. This study is discussed in the wider context of the literature concerned with training issues in the treatment of sexual function problems. The results of the training programme give clear evidence that non-professionals can be trained to produce results similar to those of a professional and it is argued that issues discussed in the literature concerning the training of professionals in the treatment of sexual difficulties are also applicable to non-professionals.

DNA variation in tissue-culture-derived rice plants.

Regenerants of rice were examined by RFLP analysis to determine the occurrence and extent of somaclonal variation. DNA polymorphisms were observed both among plants regenerated from different callus cultures as well as among sibling plants derived from a single callus. Regardless of the basal medium, a higher degree of genetic instability was found among plants regenerated from callus cultures maintained for longer incubation periods (67 days) than among those from shorter incubation periods (28 days). Detailed analysis showed that in several regenerants, there was a close correlation among those plants exhibiting DNA rearrangements and those with apparent methylation changes. Such alterations were observed with both structural and housekeeping genes.

RFLP analysis of Zea mays callus cultures and their regenerated plants.

Tissue culture of the Zea mays inbred line A188 resulted in the regeneration of plants having a high level of phenotypic variation compared to seed-grown control plants. To determine how such variation was induced and whether this could be related to specific in vitro culture methods, callus cultures were established and maintained on different, commonly used culture media. Plants were regenerated and the genomic DNA of callus cultures and regenerants analysed for RFLP differences. The results show that regardless of the gene probe used, callus formation resulted in significant deviations from the DNA pattern normally found in seed-grown control plants. Alterations in gene copy number also occurred. As differentiation and organogenesis began, the level of DNA variation fell, and most of the regenerated plants showed a genetic similarity to the controls; those with RFLP differences were the somaclonal variants.

Locomotor activity after recovery from hypnosis: midazolam-morphine versus midazolam.

This study was performed to test the hypothesis that sedation after recovery from pharmacologic hypnosis is less pronounced if hypnosis is induced with a midazolam-morphine combination compared with midazolam administered alone. Loss of the righting reflex was used as an index for the hypnotic effect and reduction of locomotor activity as an index for the sedative effect. One group of rats received midazolam (20 mg/kg i.v) and another group an equipotent (in relation to the hypnotic ef.fect) combination of midazolam (4 mg/kg i.v.) and morphine (1.3 mg/kg i.v.). The duration of loss of the righting reflex in the midazolam and midazolam-morphine groups was 30 +/- 3 and 28 +/- 2 min, respectively (mean +/- SE). The difference between the groups in locomotor activity after recovery from hypnosis was very pronounced. The locomotor activity in the midazolam-morphine group at 1 and 2 h was seven and five times greater, respectively, than in the midazolam group (P < 0.005). The profound difference in locomotor activity for the two treatment groups was explained on the basis of the difference in the outcomes of midazolam-morphine interactions with regard to hypnosis (synergism) and sedation (summation). When the animals recovered from hypnosis, the synergism of the drug interaction ceased to be a contributing factor.

Sedative and hypnotic midazolam-morphine interactions in rats.

The midazolam-morphine interactions in relation to the sedative effect and in relation to the hypnotic effect were studied in rats. Two series of experiments (sedative and hypnotic) were performed. In the sedative series, doses that inhibited locomotor activity to 10% or more of the control level were determined when the agents were given singly or in combination. Dose-response curves were determined with a probit procedure. The ED50 values of both agents and their combination were compared with algebraic (fractional) and isobolographic analyses in one subseries of experiments. The effect of a small fixed dose of morphine (1/10 of ED50 value for the sedative effect) on the slope of the sedative dose-response curve for midazolam was determined in the other subseries. In the hypnotic series of experiments, doses (ED50) that blocked the righting reflex with drugs given separately and in combination were determined by a probit procedure and, as in the sedative series, compared with algebraic (fractional) and isobolographic analyses. Sedative interaction between midazolam and morphine was found to have a tendency for synergism (interaction coefficient of 1.56, P greater than 0.05) with decreased individual variability in the sedative response to the combination. Hypnotic midazolam-morphine interaction was highly synergistic with the interaction coefficient of 3.70 (P less than 0.0001). A difference in the outcomes of midazolam-morphine interaction regarding sedation and hypnosis suggests that underlying mechanisms for these two effects are different; therefore, they should not be regarded as only increasing depths of the same action.

Magnitude of acute tolerance to opioids is not related to their potency.

It was suggested that for a given analgesic effect, more potent opioids may produce smaller degrees of tolerance than those with lower analgesic potency. The use of opioids with high analgesic potency to reduce the rate of tolerance development would be an important therapeutic consideration. This study tested the hypothesis that the degree of acute tolerance to the analgesic effect of opioids is inversely related to their potency. In the experiments on rats, the analgesic effects of morphine, alfentanil, and sufentanil given by a continuous 8-h infusion at a constant rate, were determined by measuring the threshold of motor response to noxious pressure on the tail. The comparative degree of acute tolerance was determined on the basis of the decline in the level of analgesia at the end of the infusion period. Morphine 4 mg.kg-1.h-1, alfentanil 0.45 mg.kg-1.h-1, and sufentanil 0.0085 mg.kg-1.h-1 caused approximately similar increases in the pain threshold. The peak of analgesia could not be maintained; it declined by 74 +/- 6% (P less than 0.0001) with morphine, 86 +/- 6% (P less than 0.0001) with alfentanil, and 92 +/- 2% (P less than 0.0001) with sufentanil. The results indicate that the infusion of alfentanil and sufentanil, which differ from morphine by higher analgesic potency (by 10-fold and more than 100-fold, respectively), results in a decline in the degree of analgesia during infusion similar to that of morphine. These data reject the hypothesis that the magnitude of acute tolerance to the analgesic action of opioid drugs following their systemic administration is inversely related to their potency.

Morphine and fentanyl anesthetic interactions with diazepam: relative antagonism in rats.

The anesthetic effects of morphine-diazepam and fentanyl-diazepam combinations as characterized by abolition of the movement response to noxious stimulation were studied in rats to test the hypothesis of antagonistic interactions between the components of these combinations. Noxious pressure on the tail was used to induce the response. Dose-effect curves were constructed for the drugs given alone and in combination. With the use of probit procedure ED50 values for single drugs and their combinations were determined, and the interactions were analyzed with algebraic (fractional) and isobolographic methods. It was found that both morphine and fentanyl have a less than additive (antagonistic) interaction with diazepam. In combination the sum of fractional doses was higher than a single-drug fractional dose, 1.67 versus 1.00 (P less than 0.05) for morphine-diazepam and 1.61 versus 1.00 (P less than 0.05) for fentanyl-diazepam. The observed antagonism is a relative one that does not increase the requirement for one agent upon the addition of another agent.

An investigation into the role of 5-Azacytidine in tissue culture.

A major problem associated with cereal biotechnology remains the extreme difficulty of reliably and efficiently regenerating plants from protoplasts. Because of the assumed inverse correlation between levels of the modified nucleotide 5-methylcytosine in a gene and the degree of transcription, we report here on experiments to determine whether exposure of maize and tobacco cultures to the 5-methylcytosine analogue 5-Azacytidine (5-Azt) induces gene de-methylation and, as such, enhances tissue culture response, for example by increasing protoplast division frequency. The results show that whilst 5-Azt may be of use in expanding leaf areas capable of producing callus as well as increasing the amount of callus produced, in all other aspects 5-Azt is strongly inhibitory to growth at all but the lowest concentrations. Molecular analysis shows that no readily discernible changes in gene methylation status can be found, regardless of 5-Azt concentration or the gene probe used. Differences can, however, be found in methylation status between callus and developmentally determined tissues, irrespective of 5-Azt treatment. The results suggest that, apart from a very limited role, 5-Azt has no obvious use in tissue culture.

Pentobarbital-morphine anesthetic interactions in terms of intensity of noxious stimulation required for arousal.

BACKGROUND: Previous reports suggest that the outcome (synergism, antagonism, summation) of opioid-barbiturate interactions may depend on the depth of anesthesia. One aim of the present study was to determine whether pentobarbital, alone and in combination with morphine, blocks awakening caused by noxious stimulation in a dose-related manner: the more intense the noxious stimulation, the more pentobarbital is required to suppress the response. A second aim of the study was to determine whether the pentobarbital-morphine anesthetic interaction depends on the depth of anesthesia measured in terms of intensity of noxious stimulation required for behavioral arousal (recovery of the righting reflex). METHODS: Experiments were performed on rats, with the measure of anesthetic effect being suppression of the righting reflex. The noxious stimulus was pressure on the tail at four levels of intensity: 0.0, 0.25, 2.5, and 3.3 kg, generated with an Analgesy-Meter. Pentobarbital and morphine were injected intravenously via chronically implanted catheters. Dose-response curves for pentobarbital given alone and in combination with morphine were determined (by probit analysis) separately for each of the pressure levels. RESULTS: Pentobarbital, alone and in combination with morphine, blocked awakening caused by noxious stimulation of different intensities in a dose-related fashion so that more anesthetic was required to block awakening with more intense stimulation. The pentobarbital ED50 values were: 12.0, 19.5, 22.7, and 24.3 mg/kg for 0.0, 0.25, 2.5, and 3.3 kg pressure, respectively. The addition of morphine (1 mg/kg) reduced the pentobarbital ED50 values for 0.0, 0.25, and 2.5 kg pressure by 34% (P < 0.0001), 39% (P < 0.0001), and 21% (P < 0.005), respectively. No change was seen in the pentobarbital ED50 value at the maximal (3.3 kg) pressure level. CONCLUSIONS: The results suggest that the depth of anesthesia can be measured in terms of intensity of noxious stimulation required for arousal and that the outcome of barbiturate-opioid anesthetic interaction depends on the depth of anesthesia.