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At least 19 recordsLinked to original sources
PubMed1992

Rapid tolerance and cross-tolerance as predictors of chronic tolerance and cross-tolerance.

Hypothermia and motor impairment (tilt-plane) tests were used to assess the phenomenon of rapid tolerance to ethanol and cross-tolerance to various alcohols, benzodiazepines, and barbiturates that differ in lipid:water partition coefficients. The hypothermic and motor impairment responses to ethanol were significantly reduced on day 2 in rats receiving ethanol (2 doses of 2 g/kg each for the hypothermia test and 2.3 and 1.7 g/kg for the tilt-plane test) 24 and 22 h earlier compared to the control group pretreated with saline. Ethanol pretreatment resulted in rapid cross-tolerance, on both tests, to the various alcohols (n-propanol, n-butanol, and t-butanol) and the benzodiazepines (chlordiazepoxide, diazepam, oxazepam, and flurazepam) tested. Ethanol pretreatment also conferred clear rapid cross-tolerance to barbital and phenobarbital, but did not result in rapid cross-tolerance to pentobarbital, secobarbital, amobarbital, or thiopental. The results on rapid cross-tolerance on both tests seen in these studies parallel the results obtained in chronic tolerance and cross-tolerance studies reported recently. These results suggest that rapid tolerance and cross-tolerance can be used as predictors of chronic tolerance and cross-tolerance.

Alcohols↗
PubMed1990

Tolerance to the respiratory actions of opiates: withdrawal tolerance and asymmetrical cross-tolerance.

Cross-tolerance to the respiratory depression induced by i.c.v. [D-Ala2,D-Leu5]enkephalin (DADLE) and by s.c., i.c.v. and i.v. morphine was studied in anesthetized rats that had been rendered tolerant to s.c. sufentanil (4 micrograms/h per 7 days). Tolerance induced by i.c.v. sufentanil was also compared during withdrawal and its absence. Tolerance was evaluated by estimation of the changes in both the maximum attained reduction of respiratory frequency (Emax) and the area under the time-course curve for the effects (AUC). In contrast to the failure to develop tolerance, as estimated with the Emax, after i.c.v. sufentanil in the absence of abstinence (tolerance index: 1.1), rats displayed significant degrees of cross-tolerance to i.c.v. morphine (3.6), i.c.v. DADLE (4.3) and s.c. morphine (6.6). No tolerance, however, was obtained to i.v. morphine. Tolerance to i.c.v. sufentanil in non-abstinent rats was not present when the Emax was considered but was when AUC was considered. During withdrawal animals showed tolerance as estimated with both the Emax and AUC. These results complement previous findings and show that the appearance of dissimilar degrees of cross-tolerance to different agonists depends not only on their intrinsic activities but also on their pharmacokinetic properties. These observations, along with the critical influence of withdrawal upon the manifestation of tolerance, support the need to distinguish between the development of the tolerance state and the degree of tolerance that can be expressed under specific conditions.

Animals↗
PubMed1989

Tolerance to respiratory actions of sufentanil: functional tolerance and route-dependent differential tolerance.

The work was aimed at 1) characterizing the development of chronic tolerance to the respiratory effects of sufentanil in anesthetized and awake rats and 2) analyzing the influence that routes of administration of opiates can exert on tolerance development and expression. Tolerance was developed by infusing sufentanil s.c. with osmotic minipumps for 7 days; it was evaluated by injecting acute sufentanil while the minipumps were still maintained. When maximal depression attained was considered, dose-response curves were displaced to the right, the tolerance indexes being 7.3 and 2.6 in awake and anesthetized rats, respectively. No displacement was observed when acute sufentanil was injected i.c.v. and i.v., indicating lack of tolerance. However, several signs of tolerance were detected when the areas under the time-course curve of the effects were considered: faster and more complete recovery of the depression and flattening of the slope of the dose-area under the curve responses, even after i.c.v. and i.v. administration. The results indicate the need for distinguishing between development and expression of tolerance. Differential tolerance can be explained by considering tolerance expression as a deferred phenomenon. In addition, functional compensation stands as a factor of tolerance and as a mechanism responsible for dose-response curve flattening in tolerant subjects.

Analgesics, Opioid↗
PubMed1987

Neonatal tolerance induction in the thymus to MHC-class II-associated antigens. III. Significance of hemopoietic stem cells for induction and maintenance of Mls tolerance by continuous supply of tolerance-inducing nonlymphocytes.

The role of hemopoietic stem cells and other cell types in the induction and maintenance of immunologic tolerance in the thymus was investigated by intravenous injection of Mls-semi-allogeneic cells into newborn mice less than 24 hr after birth. Mls-specific tolerance was induced by inoculation of peritoneal cells and thymus cells, and the tolerant state was compared with that induced by bone marrow cells which had hemopoietic stem cell activity and were able to create a stable chimera in both central and peripheral lymphoid organs. When peritoneal or thymus cells were injected, the level of tolerance attained was proportional to the number of cells injected, though peritoneal cells were 20 times as effective as thymus cells. In vivo functions of tolerance-inducing cells and their immediate precursors were radiosensitive and belonged to a Thy-1-, nylon-wool-nonadherent (probably non-B), weakly Sephadex G-10-adherent cell population. Tolerance induced by peritoneal cell injections was transient, starting to terminate within the first 2 weeks of life, while tolerance caused by bone marrow cell injections persisted through more than 6 weeks. Such transient tolerance induced by the former became long-lasting when followed by an additional injection of bone marrow cells, which did not cause thymic lymphocyte chimerism. All data indicated that bone marrow stem cells were engaged in tolerance induction and maintenance by continuously supplying tolerance-inducing nonlymphocytes.

Animals↗
PubMed1987

Studies on the recovery from tolerance to tumor antigens. I. Bone marrow cells from tolerant hosts are not rendered tolerant, but provide potential to reconstitute tumor-specific effector T cell clones.

The present study investigates the potential of bone marrow cells from mice tolerant to tumor antigens to repopulate tumor-specific effector T cells. C3H/He mice were inoculated i.v. with 10(6) 10,000 R X-irradiated syngeneic X5563 plasmacytoma tumor cells three times at 4-day intervals. This regimen abrogated the ability of spleen cells from these mice to develop anti-X5563 cytotoxic and in vivo protective (tumor-neutralizing) T cell-mediated immunity as induced by i.d. inoculation of viable X5563 cells followed by surgical resection of the tumor. Since such suppression was induced in a tumor-specific way, this represented a state of antitumor tolerance. When bone marrow cells from normal or X5563-tolerant mice were transferred i.v. into 950 R X-irradiated syngeneic C3H/He mice, both groups of recipient mice generated anti-X5563 tumor immunity over a similar time course and to almost the same degree. Anti-X5563 tumor immunity induced in (C3H/He X C57BL/6) F1 mice which had been transferred with bone marrow cells from normal or X5563-tolerant C3H/He mice were mediated by T cells expressing the Ly phenotype of C3H/He, but not of C57BL/6, excluding the possibility that the antitumor effector cells were derived from recipient mice. It was also demonstrated that C3H/He mice which had been reconstituted with normal marrow were rendered tolerant when the tolerance regimen was started 7 weeks, but not 1 week after the bone marrow reconstitution. These results indicate that bone marrow cells from antitumor tolerant mice are not rendered tolerant to the tumor but can provide the potential to repopulate antitumor CTL and in vivo protective effector T cells.

Animals↗
PubMed1987

Oral tolerance in protein-deprived mice. I. Profound antibody tolerance but impaired DTH tolerance after antigen feeding.

We have examined the effects of protein deprivation on the induction of oral tolerance for systemic antibody and DTH responses to the protein antigen ovalbumin (OVA). Mice were fed 4% or 24% protein diets from weaning and given a single feed of OVA 2 weeks later (short-term deprivation) or after 10 weeks (long-term deprivation). Tolerance for serum antibody responses was more profound in protein-deprived animals than in 24% protein-fed control groups. Conversely, tolerance for DTH responses was impaired in protein-deprived mice. This was demonstrated both for short-term deprivation, where nutritional rehabilitation after OVA feeding was necessary to demonstrate this effect on DTH, and for long-term deprivation. Furthermore, the effect of short-term deprivation on tolerance for DTH responses was similar to that observed after cyclophosphamide pretreatment of OVA-fed mice. Protein deprivation has disparate effects on the humoral and cell-mediated limbs of oral tolerance, and our results support the hypothesis that this regime selectively depletes a population of suppressor T cells responsible for the fine control of DTH tolerance.

Administration, Oral↗
PubMed1975

Studies on tolerance induction in vitro. I. Production of immunologically tolerant rabbit spleen cells and the transfer of tolerance to untreated cells.

Tolerance was induced in rabbit spleen cells by incubation with solubilized T2 phage (S-T2)2 at 37degrees C. Spleen cells thus treated maintained normal responsiveness to an unrelated antigen, S-SP82. Transfer of tolerance was demonstrated in in vitro in that the addition of washed tolerant cells caused suppression of the response of untreated cells to an immunogenic dose of S-T2. Evidence is presented that this suppression is not due to the transfer of tolerogenic quantities of antigen. Spleen cell populations depleted of adherent cells were still capable of being made tolerant and of transferring tolerance.

Animals↗
PubMed1977

Suppressor cells in tolerance to HGG: kinetics and cross-suppression in high dose tolerance--absence in low dose tolerance.

Spleen cells from mice made tolerant with high doses of human gamma-globulin (HGG) specifically suppress the immune response of normal, syngeneic, spleen cells. These suppressor cells were found to be cross-reactive in that they would suppress the immune response of normal spleen cells to bovine gamma-globulin (BGG) as well as to HGG. In contrast, suppressor cells could not be demonstrated in spleens of mice made tolerant with low doses of HGG (i.e., T-cell tolerance), nor could they be found in high dose tolerant mice following a second injection of DHGG at a time when the initial suppressor activity had waned. The role of suppressor cells in the induction, maintenance, and loss of tolerance is discussed.

Animals↗
PubMed1977

Is tolerance to delta-9-THC cellular or metabolic? The subcellular distribution of delta-9-tetrahydrocannabinol and its metabolites in brains of tolerant and non-tolerant rats.

Rats were injected intraperitoneally once every 12 h with 10 mg/kg delta-9-THC and the time course of the depressant effect was determined after one and nine injections. The motor activity of naive rats was maximally depressed between 1 and 4 h and returned to control levels 8 h after treatment. After nine injections, the maximum intensity of the depressant effect was not different from that after one injection but had completely disappeared at an earlier time point (4 h p.i.) indicating the development of tolerance to the duration of effect on motor activity. The subcellular distribution studies in brains of tolerant and non-tolerant rats indicated that an accelerated shift in the concentrations of delta-9-THC and 11-OH-delta-9-THC towards highly polar metabolites in the brains, rather than an increased elimination of these cannabinoids or decreased sensitivity of the brain may be responsible for the development of tolerance to delta-9-THC.

Animals↗
PubMed1992

Comparison of tolerance inducibility to class I or class II antigens between cyclophosphamide (CP)-induced tolerance and transfusion with donor cells: general effectiveness of CP-induced tolerance and difference of skin graft prolongation in each class I antigen-disparate combination.

Transfusion with allogeneic cells alone was reported to prolong skin allograft survival in the MHC class I antigen alone-disparate combination of B6.C-H-2bm1 (bm1; Kbm1, IAb, IE-, Db)-->C57BL/6 CrSlc (B6; H-2b). Using 6 class I antigen-disparate and 2 class II antigen-disparate combinations, we compared the effectiveness for skin graft prolongation between transfusion with donor cells (TDC) and our system of CP-induced tolerance, which comprises intravenous (i.v.) injection of allogeneic cells followed by cyclophosphamide (CP), i.e., TDC followed by CP. TDC was effective only in the combination of bm1-->B6, but not at all in the other combinations. On the other hand, CP-induced tolerance was effective in the 5 class I antigen-disparate and 2 class II antigen-disparate combinations except for bm1-->B6 combination. These results suggest that CP-induced tolerance may be more general for the induction of unresponsiveness than TDC.

Animals↗
PubMed1979

Tolerance induction during ontogeny. I. Presence of active suppression in mice rendered tolerant to human gamma-globulin in utero correlates with the breakdown of the tolerant state.

A specific state of T- and B-cell tolerance to human gamma-globulin (HGG) was induced in utero by intravenous administration of the deaggregated antigen to pregnant BALB/cCr mice. Tolerance persisted in the offspring until the 12th-wk of age and then began to gradually disappear. Suppressor cells could only be found when responsiveness to HGG ultimately appeared in the in utero-treated animals but not when they were completely unresponsives. In contrast, HGG-specific suppressors found in animals made unresponsive to HGG as adults appear to be associated with either the establishment and/or maintenance of the unresponsive state. To the extent that these experiments are consistent with natural self-tolerance to a serum protein, we conclude that active suppression is not a prerequisite from maintenance of unresponsiveness to self.

Animals↗
PubMed1965

Role of the thymus in tolerance. I. Tolerance to bovine gamma globulin in thymectomized, irradiated rats grafted with thymus from tolerant donors.

Rats thymectomized and irradiated as adults were restored to immunologic reactivity by grafts of normal adult rat thymus and bone marrow. Reactivity of the delayed (cellular) type and formation of mercaptoethanol-sensitive (MES) and mercaptoethanol-resistant (MER) antibody returned within 3 weeks, while Arthus reactivity remained subnormal till 9 weeks after irradiation and grafting. When the thymus donor was tolerant to BGG, the recipient showed specific non-reactivity to this antigen 3 weeks and, to a much lesser extent, 6 weeks after grafting. This non-reactivity affected delayed responses and MER antibody. No effect was noted on Arthus reactivity and a slight effect on MES antibody. Controls showed that the non-reactivity was not due to transfer of free antigen at the time of grafting. It was concluded that different source organs are responsible for different immune functions and that specific immunologic tolerance may be induced within such an organ as the thymus.

Animals↗
PubMed1986

Characteristics of tolerance, recovery from tolerance and cross-tolerance for cocaine used as a discriminative stimulus.

Rats were trained to discriminate an injection of cocaine (10 mg/kg) from saline using a two-lever choice procedure with food as a reinforcer. Subsequently, training was stopped, and cocaine was injected chronically. In one experiment, 10.0 or 20.0 mg/kg/8 hr 8 hr of cocaine for 7 days produced a 2-fold shift to the right of the discriminative stimulus dose-effect curve. A dose of 5.0 mg/kg/8 hr for up to 14 days did not shift the dose-effect curve. In a second experiment, 20 mg/kg/8 hr for 7 or 14 days produced comparable degrees of tolerance. In a third experiment, after termination of 12 days of chronic cocaine injection (20 mg/kg/8 hr), base-line sensitivity to the training stimulus recovered progressively across 18 days. Additional experiments tested the effects of chronic administration of drugs that were substituted (d-amphetamine) or were not substituted (morphine) for the training stimulus. d-Amphetamine (2.5 mg/kg/8 hr for 7 days) produced a 4-fold shift to the right of the dose-effect curve for the detection of both d-amphetamine and cocaine; in contrast, 7 days of escalating morphine doses produced signs of physical dependence but did not alter the sensitivity of rats to the cocaine training stimulus. These results provide evidence that tolerance for cocaine used as a discriminative stimulus occurs as a function of chronic dose, dosing regimen and class of drug administered.

Animals↗
PubMed1986

Bidirectional cross-tolerance between methadone (mu)- and ethylketocyclazocine (kappa)-tolerant rats.

Our laboratory previously reported on unidirectional cross-tolerance between morphine and methadone, both mu opioid agonists, and between morphine and ethylketocyclazocine (EKC), the latter being a relatively selective kappa opioid agonist. Morphine-tolerant rats were found to be non-cross-tolerant to methadone and EKC, but methadone- and EKC-tolerant rats were cross tolerant to morphine. In the present study, we characterized the cross-tolerance between methadone and EKC. A group of female adult Sprague-Dawley rats was made tolerant to methadone by a series of automatic i.v. injections ranging from 0.25 mg/kg per 2 h on the first day to 2.0 mg/kg per 1.5 h on the ninth day. Another group of rats was similarly made tolerant to EKC with doses ranging from 0.5 mg/kg per 2 h on the first day to 4 mg/kg per h on the ninth day. Relatively similar degrees of tolerance development to the EEG and behavioral effects of methadone and EKC were reflected by decreases in durations of action and decreases in opioid-induced EEG power spectral changes. Methadone-tolerant rats were found to be cross-tolerant to the EEG and behavioral effects of EKC, and, similarly, EKC-tolerant rats were found to be cross-tolerant to those of methadone. Thus, a bidirectional cross-tolerance between a mu and a kappa agonist was demonstrated. The present results together with those reported earlier indicate that cross-tolerance may not be directly related to the receptor selectivity of the opioids. It is possible that differential physicochemical properties of these opioids may play a more decisive role in the phenomenon of cross-tolerance.

Analgesics, Opioid↗
PubMed1991

Rapid tolerance as an index of chronic tolerance.

Hypothermia and motor impairment (tilt-plane test) were used to assess the phenomenon of rapid cross-tolerance between ethanol and pentobarbital in rats. The hypothermic and motor-impairment responses were significantly reduced on day 2 in animals receiving ethanol on day 1, compared to the control group pretreated with saline. Ethanol pretreatment, however, did not result in rapid cross-tolerance to pentobarbital on either test. Pentobarbital pretreatment on day 1 resulted in rapid tolerance to pentobarbital on day 2. However, in contrast to the lack of rapid cross-tolerance to pentobarbital after pretreatment with ethanol, pentobarbital pretreatment clearly conferred rapid cross-tolerance to ethanol. Determination of ethanol and pentobarbital blood levels suggested that pharmacokinetic alterations did not contribute significantly to the observed rapid tolerance and cross-tolerance. The asymmetry of rapid cross-tolerance seen in these studies mimics the results obtained by us in chronic tolerance and cross-tolerance studies reported recently. These results suggest that rapid tolerance and cross-tolerance can be used as predictors of chronic tolerance and cross-tolerance.

Animals↗
PubMed1972

Immune status of mice tolerant of living cells. II. Continuous presence and nature of facilitation-enhancing antibodies in tolerant animals.

CBA mice were rendered highly tolerant to A/Jax cells by neonatal intravenous injections of (CBA x A)F(1) spleen cells. The high degree of tolerance was ascertained by the absence of circulating antibodies detected in the sera by the usual tests and by the perfect state of A skin grafts during all the experiments. Tolerant sera (sera from tolerant animals) were studied at three periods of tolerance: before skin test grafting, from 2 to 11 wk after grafting, and at time of sacrifice at almost 6 months of age. The tolerant sera were shown to have specific facilitation-enhancing properties promoting the take and growth of A/Jax sarcoma (SaI and /Sa 15091a grafted on normal CBA mice. These properties were present throughout the duration of the experiments, showing that they were not the result of a beginning interruption of tolerance. The tolerant sera, although lacking the usual serological properties (hemagglutination, hemolysis, cytotoxicity, passive cutaneous anaphylaxis) had, however, specific synergistic hemagglutinating properties (increasing the hemagglutinating titer of a reference immune serum). Antibodies giving direct specific hemagglutination could be extracted from spleens of 20% of highly tolerant mice. The tolerant sera were also found to contain more IgG1 and more IgA than normal sera while they contained normal quantities of the complement-fixing immunoglobulins IgG2 and IgM. Fractionation of tolerant sera on DEAE chromatography column confirmed the data concerning immunoglobulin classes and demonstrated direct specific serological activities undetected in unfractionated sera: a weak hemolysis in the most cationic fractions and a weak hemagglutination in the middle fractions. Synergistic hemagglutination, detected in unfractionated serum, was localized in fast anionic fractions containing high IgA concentration, along with facilitation-enhancing activity, thus confirming a link suggested previously between these three properties. The relation between immunological tolerance and facilitating antibodies was discussed in the light of the fact that antibodies, possibly of a particular class continuously present at low dose in the sera of highly tolerant animals, are able to transfer (at least partly) this state of tolerance provided a sensitive test system is utilized.

Animals↗
PubMed1986

Functional tolerance to chlormethiazole and cross-tolerance to ethanol in the rat: importance of test and mode of drug administration.

Tolerance to the effects of chlormethiazole on circular maze performance, and cross-tolerance to ethanol, were investigated in rats. Tolerance to chlormethiazole in the moving belt test was also measured in the same rats. Treatment with a total daily dose of subcutaneous chlormethiazole, 200 mg/kg, for 20 days produced clear tolerance to chlormethiazole and cross-tolerance to ethanol in the circular maze test. This treatment, however, failed to produce tolerance to chlormethiazole in the moving belt test. No evidence of physical dependence was found. In other studies, continuous intravenous infusion of chlormethiazole, 30-50 mg/kg/h for 9 days, resulted in clear functional tolerance to chlormethiazole and cross-tolerance to ethanol in the moving belt test. Similarly, chronic ethanol treatment, 4-6 g/kg daily for 3 weeks, resulted in functional tolerance to ethanol and cross-tolerance to chlormethiazole in the same test. These results indicate that the demonstration of functional tolerance to chlormethiazole and cross-tolerance to ethanol is dependent both on the sensitivity of the behavioural measurement tests employed, and on the degree of continuity of exposure of the central nervous system to the drug. It is concluded that, for doses that are equipotent in acute log-dose studies, chlormethiazole produces less tolerance and physical dependence than ethanol, perhaps because of a shorter half-life.

Animals↗