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PubMed1988

Ketamine- and morphine-induced analgesia and catalepsy. I. Tolerance, cross-tolerance, potentiation, residual morphine levels and naloxone action in the rat.

The effects of ketamine and morphine on pain perception and catalepsy were compared in rats. Analgesia, as measured by the latency to withdrawal of the tail from a 55 degrees C water bath (tail-flick latency difference, TFLD), was produced by both ketamine and morphine, but at widely different doses, and in each case the effect was reversed by naloxone. Catalepsy, measured by the duration of loss of righting reflex (DLRR) in catatonic animals, was induced by larger doses of both ketamine and morphine and in each case was reduced by a larger dose of naloxone. DLRR and TFLD tolerance developed rapidly and with a similar time course after daily doses of ketamine or morphine. Rats tolerant to the DLRR effect of ketamine showed cross-tolerance to morphine. Rats tolerant to the DLRR effect of morphine did not show cross-tolerance to ketamine when administered the following day; instead, these rats showed potentiation of the ketamine-induced DLRR. The degree of potentiation noted 24 hr after a single or multiple daily doses of 45 mg/kg of morphine is the same as that seen when 2 mg/kg of morphine is given simultaneously with ketamine. The residual brain level of morphine 24 hr after 45 mg/kg is similar to the level 1 hr after a 2-mg/kg dose. The augmented ketamine response in morphine-tolerant rats is postulated to be a result of residual morphine still present in the brain 24 hr after the last DLRR-inducing dose of morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1988

Tolerance and cross-tolerance to the discriminative stimulus properties of fentanyl and morphine.

The investigation tested the hypothesis that tolerance would develop to the discriminative stimulus properties of fentanyl upon discontinuation of discrimination training and injection of fentanyl in doses larger than the training dose. Rats were trained to discriminate an injection of fentanyl, 0.04 mg/kg, from saline using a two-lever choice procedure with food as a reinforcer. Given acutely, morphine substituted for fentanyl and was 100-times less potent. Subsequently, training was stopped, and fentanyl, 0.08 mg/kg, was injected every 12 hr for 1 week. This procedure did not produce tolerance nor did tolerance occur when fentanyl, 0.16 mg/kg every 24 hr, was continued for an additional week. In contrast, a dose of morphine (8.0 mg/kg) that was equated for efficacy to the 0.08-mg/kg dose of fentanyl produced both tolerance to the morphine stimulus and cross-tolerance to the fentanyl stimulus after 3 to 4 days of administration. In an additional experiment, the time course for detection of fentanyl was found to be significantly shorter than the time course for the detection of morphine. These results suggest that the present, as well as a previous, report of failure to find tolerance to the stimulus properties of fentanyl is perhaps attributable to fentanyl's brief duration of action. To test this hypothesis, 16 rats were trained to discriminate fentanyl, 0.04 mg/kg, and dose-effect data were obtained for the generalization of fentanyl and the substitution of morphine for this discriminative stimulus. Subsequently, training was stopped and fentanyl was injected for 4 days in a design that called for injection of 0.12 mg/kg every 6 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

The effect of long-term glibenclamide treatment on glucose tolerance, insulin secretion and serum lipids in subjects with impaired glucose tolerance.

The effects of glibenclamide plus diet (n = 27) or diet alone (n = 18) on glucose tolerance, insulin secretion and serum lipids in non-obese subjects with normal or low insulin responses and impaired glucose tolerance (IGT) has been followed up for two years. Glucose tolerance and insulin secretion were characterized by means of a glucose infusion test consisting of an initial injection of 0.33 g glucose/kg body weight followed by 12 mg/kg body weight/min for 2 h. Dietary treatment did not improve glucose tolerance in normal and low insulin-responders. Glibenclamide plus diet succeeded in improving glucose tolerance only in low insulin responders whereas glucose tolerance remained unchanged in normal insulin responders. There was a significant decrease in fasting and glucose-stimulated insulin levels after two years of glibenclamide treatment in both the normal and low insulin-responders. The body weight was not altered. Triglyceride and cholesterol levels both decreased. In summary, the present study failed to demonstrate an increase in insulin secretion under chronic administration of glibenclamide in subjects with IGT independent of the type of insulin response. From the practical point of view, glibenclamide is of benefit in the treatment of non-obese subjects with IGT and relative insulin deficiency.

Adult↗
PubMed1996

In vivo depletion of free thiols does not account for nitroglycerin-induced tolerance: a thiol-nitrate interaction hypothesis as an alternative explanation for nitroglycerin activity and tolerance.

The present study investigates the effects of thiol-depleting/ modifying agents on the activity of and tolerance to nitroglycerin (GTN), sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) in an in vivo rat model. Rats were treated with either vehicle (control), GTN (before and after induction of tolerance), diethyl maleate (a thiol-depleting agent) or N-ethylmaleimide (a thiol-modifying agent). The effects of GTN, SNP and SNAP on vascular cyclic GMP levels were investigated before and after each treatment. In addition, plasma and tissue thiol concentrations were measured in the same tissues as used for the determination of cyclic GMP in aorta and inferior vena cava after single and serial i.v. bolus doses of each drug. Depletion of free thiols (glutathione and cysteine) was not found to accompany tolerance development in GTN-treated tolerant rats or to significantly enhance tolerance development or augment its magnitude in diethyl maleate-treated rats. When rats were pretreated with a low single dose of N-ethylmaleimide, where no significant changes in vascular free thiols were observed, significant reduction in GTN- and SNP-induced, but not SNAP-induced, vascular cyclic GMP production was obtained. Considering the differential effects of diethyl maleate (mainly free thiol depletion) and N-ethylmaleimide (mainly proteinous thiol-alkylation) on vascular thiols, these results indicate that depletion of sulfhydryl groups other than those from free glutathione and cysteine seems to be involved in the mechanisms defining GTN and SNP (but not SNAP) action and tolerance. Here we propose that SNAP may act either directly by nitrosation of the heme moiety of the enzyme or via an S-enzyme-S-drug transnitrosation reaction, whereas GTN and SNP actions are mediated by the formation of S-nitrosothiol on the enzyme itself, rather than by activation of the enzyme by free S-nitrosothiols.

Animals↗
PubMed1976

The existence of tolerance to and cross-tolerance between d-amphetamine and methylphenidate for their effects on milk consumption and on differential-reinforcement-of-low-rate performance in the rat.

Administration of d-amphetamine (2.5 mg/kg) or methylphenidate (20 mg/kg) decreased milk consumption in rats. When these drugs were administered daily, tolerance developed to this effect over the course of 20 days. Cross-tolerance to the effects on milk consumption occurred between d-amphetamine and methylphenidate over a 4-fold range of dose of both drugs. Administration of d-amphetamine (1.5 mg/kg) or methylphenidate (10 mg/kg) disrupted responding under differential-reinforcement-or-low-rate (DRL) contingencies. Both drugs increased response rate, decreased frequency of reinforcement and shifted the mode of the inter-response time distribution to the left. When the drugs were administered daily, tolerance developed to all these effects over the course of 20 days. Cross-tolerance to the effects on DRL behavior occurred between d-amphetamine and methylphenidate over a 4-fold range of dose of both drugs. Daily administration of d-amphetamine (2.5 mg/kg) but not of methylphenidate (20 mg/kg) resulted in decreased norepinephrine (NE) levels in brain; the decreased norepinephrine levels, which occur with repeated d-amphetamine administration, are believed to result from the storage in noradrenergic neurons of p-hydroxynorephedrine, a metabolite of d-amphetamine. Radioactivity was not detectable in brain 24 hours after the last of 15 daily doses of radiolabeled methylphenidate. These results suggest that d-amphetamine, but not methylphenidate, is metabolized to a compound which is stored in noradrenergic neurons. The existence of behavioral cross-tolerance between d-amphetamine and methylphenidate is therefore inconsistent with the hypothesis that tolerance to the behavioral effects of d-amphetamine is due to the metabolism of d-amphetamine to p-hydroxynorephedrine, a false transmitter in noradrenergic neurons.

Animals↗
PubMed1999

Acid tolerance induced by metabolites and secreted proteins, and how tolerance can be counteracted.

Several metabolites and salts including glucose, L-glutamate, L-aspartate, FeCl3, KCl and L-proline induce acid tolerance at neutral external pH (pHo) in log phase Escherichia coli. For induction by glucose and L-glutamate, the processes are independent of integration host factor (IHF), H-NS, CysB, ferric uptake regulator (Fur) and RelA. For most of the above, tolerance does not appear if induction occurs and NaCl, sucrose, SDS or DOC are present. For several responses, cAMP inhibits induction. For many established acid tolerance and sensitization processes, including those tolerance responses switched on at pH 5.0 and by glucose, glutamate or aspartate, induction is associated with secretion of extracellular induction proteins. These proteins bring about the response if added to organisms under normally non-inducing conditions. Secreted components also influence inherent acid tolerances and sensitivities. Analysis of some established tolerance responses indicates that induction is a two-stage process, secreted extracellular proteins playing an obligate role in induction. For example, the functioning of the acid-induced medium protein(s) is essential for acid habituation at pHo 5.0. It seems likely that such two-stage mechanisms are essential for many inducible processes in bacteria.

Acids↗
PubMed2001

Tolerance to the analgesic effect of buprenorphine, butorphanol, nalbuphine, and cyclorphan, and cross-tolerance to morphine.

PURPOSE: The increased use of opioids in the chronic treatment of pain, especially with oncologic patients, encourages the search for drugs with potent analgesic activity, but with minimal induced tolerance and cross-tolerance to morphine. METHODS: Four agonist-antagonist opioid derivatives (buprenorphine, butorphanol, nalbuphine, and cyclorphan) were examined. Tolerance to the analgesic effect of the four drugs and their cross-tolerance effects with morphine were evaluated in ICR albino mice by the "hot plate method". Measurements of the analgesic effect were taken before and after chronic treatment (of 14 days duration) with these drugs, as well as morphine. RESULTS: All tested drugs produced tolerance after 14 days of treatment. Chronic treatment with morphine reduced the effects of nalbuphine and cyclorphan, but not those of buprenorphine and butorphanol. After 14 days treatment with buprenorphine and cyclorphan, the analgesic action of morphine was reduced, but this reduction did not occur after butorphanol and nalbuphine treatments. CONCLUSION: Of the four agonist-antagonists tested, butorphanol seems to be least likely to produce cross-tolerance with morphine.

Journal Article↗
PubMed1991

Selenium tolerance, salt tolerance, and selenium accumulation in tall fescue lines.

High levels of soil salinity and Se concentration are coexisting problems in the San Joaquin Valley, California. Tall fescue is a potentially useful crop plant for land management in soils containing elevated concentrations of Se and salinity. Information regarding its physiological mechanism and genetic variation of Se accumulation in this species is scant. Thirteen tall fescue (Festuca arundinacea Schreb.) lines were examined for Se and salt tolerances and Se accumulation in nutrient solution culture. Genetic variation of both Se and salt tolerances was detected among six American cultivars and seven worldwide tall fescue lines. Selenium tolerance and salt tolerance are independent of each other and are negatively correlated with tissue Se and salt concentrations. These relationships suggest that an exclusion mechanism is responsible for the tolerance. This diversity of Se and salt tolerance and Se accumulation among the tall fescue lines is important for the application of this species for land management.

Genotype↗
PubMed2006

Introgression of a novel salt-tolerant L-myo-inositol 1-phosphate synthase from Porteresia coarctata (Roxb.) Tateoka (PcINO1) confers salt tolerance to evolutionary diverse organisms.

We have previously demonstrated that introgression of PcINO1 gene from Porteresia coarctata (Roxb.) Tateoka, coding for a novel salt-tolerant L-myo-inositol 1-phosphate synthase (MIPS) protein, confers salt tolerance to transgenic tobacco plants (Majee, M., Maitra, S., Dastidar, K.G., Pattnaik, S., Chatterjee, A., Hait, N.C., Das, K.P. and Majumder, A.L. (2004) A novel salt-tolerant L-myo-inositol-1-phosphate synthase from Porteresia coarctata (Roxb.) Tateoka, a halophytic wild rice: molecular cloning, bacterial overexpression, characterization, and functional introgression into tobacco-conferring salt-tolerance phenotype. J. Biol. Chem. 279, 28539-28552). In this communication we have shown that functional introgression of the PcINO1 gene confers salt-tolerance to evolutionary diverse organisms from prokaryotes to eukaryotes including crop plants albeit to a variable extent. A direct correlation between unabated increased synthesis of inositol under salinity stress by the PcINO1 gene product and salt tolerance has been demonstrated for all the systems pointing towards the universality of the application across evolutionary divergent taxa.

Adaptation, Physiological↗
PubMed2005

Freezing tolerance in two Norway spruce (Picea abies [L.] Karst.) progenies is physiologically correlated with drought tolerance.

The goal of the present study was to investigate whether seedlings of Norway spruce (Picea abies [L.] Karst.) from a frost tolerant progeny (P2), were more drought tolerant than seedlings from a less frost tolerant progeny (P1). Progenies differing in freezing tolerance were identified by exposing seedlings in autumn in a large-scale trial to temperatures from -11 to -15 degrees C and scoring the degree of needle injury. Seedlings from P1 and P2 were grown from seeds for about 1 year under controlled conditions in a climatized growth room and were exposed to drought stress by withholding water for about 3 weeks. Drought caused reductions in biomass in both progenies but to a stronger extent in P1 than in P2. Seedlings of P2 were able to fully maintain root biomass. They also showed less water loss in different tissues. Decreases in quantum yield efficiency of photosystem II of dark-adapted plants occurred several days later in P2 than in P1. New proteins of molecular masses of 24.3 and 25.5 kDa appeared during drought stress. Since they occurred in both progenies a role of these proteins in progeny-related differences in drought performance is unlikely. Progeny 2 contained inherently higher superoxide dismutase and lower peroxidase activities than progeny 1. In conclusion, freezing and drought-tolerance respective -sensitivity were co-occurring traits in the spruce progenies studied here. Pre-existing high activities of enzymes protecting against oxidative stress in seedlings may have contributed to increase stress tolerance in P2 compared with P1.

Adaptation, Physiological↗
PubMed2004

Selection of acid tolerant bifidobacteria and evidence for a low-pH-inducible acid tolerance response in Bifidobacterium longum.

Acidity is an environmental condition commonly encountered by lactic acid bacteria and bifidobacteria in the gastrointestinal tract and fermented foods. In the present study, 22 strains of Bifidobacterium were screened for acid tolerance in artificial gastric juice (AGJ, pH 3.0) and fermented milk. AGJ tolerance was found to be strain-specific, with a pronounced variation among the strains. Several strains with a high survival rate in AGJ that belonged to Bifid. longum, Bifid. breve and Bifid. adolescentis were selected. Among them, only strain BL1 of Bifid longum was found to possess a high survival rate in fermented milk during refrigerated storage. Strain BL1 exhibited a survival rate of more than 25% in AGJ at pH 3.0 for 2 h and maintained a viable cfu level of more than 10(8) per gram of product in fermented milk (pH 4.6) under refrigerated conditions for 2 weeks. The acid tolerance of strain BL1 was found to depend on the final growth pH (<4.5). Rapid loss of acid tolerance was observed when the cells were shifted from acid to neutral conditions by addition of NaOH. Strain BL1 cells were able to maintain much higher intracellular pH under acid conditions, in comparison with those of AGJ sensitive mutant (BL1-S) or cells that lost acid tolerance following pH shifting from acid to neutral conditions. These results suggested that a cytoplasmic pH homeostasis system may function in the acid tolerance response in this strain.

Animals↗
PubMed1999

Role of the thymus in transplantation tolerance in miniature swine: II. Effect of steroids and age on the induction of tolerance to class I mismatched renal allografts.

BACKGROUND: Recent studies in young (5-7 months) miniature swine have demonstrated that the thymus is involved in the rapid induction of stable tolerance to class I mismatched renal allografts after a 12-day course of Cyclosporine (CyA). Because both steroids and age are known to influence the structure and function of the thymus, we have now studied the effects of these two parameters on tolerance induction in this model. MATERIALS AND METHODS: In young swine, the administration of methylprednisolone (MP) during the standard tolerance-inducing regimen (a 12-day course of CyA) produced severe renal dysfunction and acute cellular rejection histologically. However, the renal allografts recovered and were accepted for >100 days with histological evidence of chronic rejection. To test the effect of age, two relatively old swine (55 and 71 months) received transplants of class I mismatched renal allografts and the standard 12-day course of CyA. One animal rejected the allograft acutely on postoperative day 22, and the second also rejected, but more slowly, with manifestations of chronic rejection. CONCLUSION: These findings suggest that both MP and old age interfere with the induction of stable tolerance in a fashion similar to the previously described effect of thymectomy. These results may have important implications for the mechanism of thymic-dependent tolerance, for the use of steroids in clinical protocols for the induction of allograft tolerance, and for the application of such protocols to adult patients.

Animals↗
PubMed2004

How do crop plants tolerate acid soils? Mechanisms of aluminum tolerance and phosphorous efficiency.

Acid soils significantly limit crop production worldwide because approximately 50% of the world's potentially arable soils are acidic. Because acid soils are such an important constraint to agriculture, understanding the mechanisms and genes conferring tolerance to acid soil stress has been a focus of intense research interest over the past decade. The primary limitations on acid soils are toxic levels of aluminum (Al) and manganese (Mn), as well as suboptimal levels of phosphorous (P). This review examines our current understanding of the physiological, genetic, and molecular basis for crop Al tolerance, as well as reviews the emerging area of P efficiency, which involves the genetically based ability of some crop genotypes to tolerate P deficiency stress on acid soils. These are interesting times for this field because researchers are on the verge of identifying some of the genes that confer Al tolerance in crop plants; these discoveries will open up new avenues of molecular/physiological inquiry that should greatly advance our understanding of these tolerance mechanisms. Additionally, these breakthroughs will provide new molecular resources for improving crop Al tolerance via both molecular-assisted breeding and biotechnology.

Aluminum↗
PubMed1993

Physiological responses of freeze-tolerant and -intolerant frogs: clues to evolution of anuran freeze tolerance.

Freeze tolerance in the wood frog, Rana sylvatica, is promoted by multiple, integrated physiological responses to ice forming within body tissues. By analyzing the freezing responses of the sympatric, but freeze intolerant, leopard frog (R. pipiens), we sought clues to the evolution of anuran freeze tolerance. Physiological responses critical to R. sylvatica's freeze tolerance, such as the synthesis and distribution of the cryoprotectant glucose, protective dehydration of organs, and deferred cardiac failure, were present, but comparatively less pronounced, in R. pipiens. Both species were innately tolerant of hyperglycemia. Glucose supplements did not enhance the freezing viability of R. pipiens, although in vitro tests of cryoprotectant efficacy revealed that glucose and glycerol provided comparable protection to erythrocytes of both species. We conclude that the evolution of freeze tolerance in R. sylvatica is not only promoted by its desiccation tolerance and the fortuitous biophysical consequences of freezing (e.g., exothermic induction of cardioacceleration and moderation of cooling rate) but also involves a progressive enhancement of fundamental physiological stress responses.

Acclimatization↗
PubMed1995

The effects of dopamine agonists on rotational behavior in non-tolerant and caffeine-tolerant rats.

Tolerance develops to caffeine-induced stimulation of both locomotor activity and rotational behavior. The role of dopamine in tolerance to the locomotor stimulant effects of caffeine has been documented. However, the role of dopamine in caffeine-induced turning behavior remains to be elucidated. Therefore, the present study determined the role of dopamine receptors in tolerance to caffeine-induced rotational behavior. Rats with a unilateral lesion of the nigrostriatal tract, induced by 6-hydroxydopamine (6-OHDA), were treated chronically with either caffeine (1.0mg/ml) or with drug-free tap water, by a method of scheduled access. Agonists with and without selectivity for dopamine receptor sub-types were tested in both groups of rats (nonselective: apomorphine, d-amphetamine; D1 selective: SKF-38393, SKF-77434; D2 selective: R(-)-propylnorapomorphine (NPA), quinpirole). All drugs produced dose-dependent increases in turning that, with the exception of quinpirole, were comparable in both groups. Quinpirole produced a smaller effect in rats treated with caffeine than in control rats. Thus, there was significant cross-tolerance only to the effects of quinpirole. The concurrent administration of SKF-38393 with NPA produced a synergistic interaction on rotational behavior in control rats, to which cross-tolerance did not develop in caffeine-treated rats. In contrast to what occurs with locomotor activity, in control rats the selective D1 dopamine receptor antagonist SCH 23390 completely blocked SKF-38393-induced turning behavior and the selective D2 dopamine receptor antagonist eticlopride partially attenuated this effect. NPA-induced turning behavior was blocked only by eticlopride; SCH 23390 was without effect. Both SCH 23390 and eticlopride blocked d-amphetamine-induced rotational behavior. The results of this study suggest that D1 dopamine receptors are not involved in tolerance to caffeine-induced rotational behavior. The role of D2 dopamine receptors in this effect is unresolved. Results obtained from rotational behavior studies generally do not parallel those obtained from locomotor activity studies, suggesting that different mechanisms underlie the effects of caffeine on these two behaviors.

Journal Article↗
PubMed1976

Studies on tolerance. I. The role of the interval between doses on the development of tolerance to morphine.

The effect of varying the interval between doses on the rate of development of tolerance to a series of injections of morphine was studied in two strains of rats. Morphine sulfate injections (15 mg/kg s.c.) were given at intervals of 1, 2, 3, 7, 10, 14 or 21 days to adult male Wistar/Furth or Wistar-Lewis rats and drug effect was measured by means of the hot-plate assay technique. A diminution of morphine effect on the second or subsequent injections of drug was considered to be the result of the development of tolerance. Little or no tolerance was observed with the Wistar/Furth animals when a second injection or morphine was administered 7 days after the first, although there was marked tolerance when there were shorter or longer intervals between the first two injections. Subsequent injections of morphine sulfate, given to the animals at the predetermined intervals, resulted in wiping out out the differences between all interval groups, with the exception of the 1-day group, by the fifth injection. Although the differences between the 7-day and longer or shorter intervals were not as great with the Wistar-Lewis animals, they were significant and may reflect a slightly different rate of tolerance development in the latter strain. These observations are consistent with the hypothesis that there may be two types of tolerance, one appearing very rapidly, the other taking a longer period of time to develop.

Animals↗
PubMed1975

Kinetics of the reactive cell clones after immunosuppression and induction of tolerance. II. Different recovery of 19 S and 7 S plaque-forming cells after induction of tolerance.

By the aid of two alkylating agents (cyclophosphamide (CP) and 036.5122, (Asta), applied after a single dose of antigen, tolerance to sheep red blood cells (SRBC), has been induced in NMRI mice. Duration and characteristics of recovery were followed by a second antigenic challenge at various time intervals and by determination of 19 S and 7 S plaque-forming cells (PFC) 4 days later. During recovery from the tolerant state two phases of responsiveness could be differentiated: an early phase with no or markedly reduced numbers of total PFC, all of them being of the IgM type; a later phase with a steady increase in total PFC up to normal values, paralleled by an increase in the proportion of 7 S PFC finally reaching 90% of total PFC. In comparison with CP, recovery from tolerance induced by equitoxic doses of 5122 were delayed and modified. Even after 8 weeks, total PFC to SRBC were still depressed, and the ratio 19 S/7 S PFC resembled neither a typical primary nor secondary pattern. It is concluded that CP-mediated immunological tolerance is followed spontaneously by the establishment of a memory state. This observation, in agreement with findings of other authors, is interpreted as the expression of an established B cell memory compartment during the period of deficient T cell activity. The long-lasting modification of specific responsiveness after 5122 indicates a profound disturbance of the potency to recover from the impact of this alkylating agent, the biological base of which is as yet unidentified. It is suggested that observation of the characteristic features during the recovery phase from tolerance may help to clarify the nature of the defect in specific responsiveness.

Animals↗