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Results for “Tolerability”

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PubMed1988

Tolerance to oxotremorine's effects on schedule-controlled behavior in physostigmine-tolerant rats.

Tolerance to the effects of physostigmine and oxotremorine in rats was evaluated using a multiple fixed-ratio 10, extinction schedule of food presentation. Physostigmine was administered either once daily or three times daily for 18 consecutive days. Tolerance to physostigmine's response decreasing effects was observed under both administration regimens. Cumulative dose-effect functions for oxotremorine (0.0056-0.562 mg/kg) were determined before and after chronic physostigmine administration. Oxotremorine's potency to produce response rate suppression decreased in rats receiving physostigmine three times daily but did not substantially change in rats receiving single daily injections. These results demonstrate that the dose or duration of action of physostigmine can determine whether tolerance to physostigmine's effects is accompanied by cross-tolerance to oxotremorine's effects.

Animals↗

PubMed1988

Modulation of morphine-induced EEG and behavioral effects by dynorphin A-(1-13) in non-tolerant and morphine-tolerant rats.

The purpose of the present study was to assess effects of dynorphin A-(1-13) on morphine-induced changes in electroencephalographic (EEG) spectral power and morphine-induced suppression of slow-wave sleep in non-tolerant and morphine-tolerant rats. Adult female Sprague-Dawley rats were implanted with chronic cortical EEG electrodes, electromyographic electrodes in the temporalis muscle and with intracerebroventricular (i.c.v.) cannulae and, in some cases, additional intravenous (i.v.) cannulae. Injections of morphine (i.c.v., 20 micrograms/rat) produced a biphasic EEG and behavioral response, composed of 2-3 hr of slow-wave bursts and increased spectral power (0-4 Hz) in the EEG, associated with behavioral stupor, followed by 2-3 hr of EEG and behavioral arousal. Dynorphin (i.c.v., 20 micrograms/rat), administered 10 min before injections of morphine in non-tolerant rats, antagonized morphine-induced increases in spectral power of the EEG and morphine-induced suppression of slow-wave sleep. In addition, EEG power spectra obtained after intraventricular administration of morphine from rats, treated with dynorphin and morphine intraventricularly 24 hr earlier, were qualitatively similar to those previously found after acute administration of kappa opioid agonists. In morphine-tolerant rats, pretreatment with dynorphin given intraventricularly, 10 min prior to intraventricular administration of morphine, restored morphine-induced increases in EEG spectral power and suppression of slow-wave sleep. The results suggest that dynorphin may modulate the characteristics of opioid receptors.

Animals↗

PubMed1994

Absence of appreciable tolerance and morphine cross-tolerance in rats with adrenal medullary transplants in the spinal cord.

Adrenal medullary transplants in the spinal subarachnoid space may be a means of achieving sustained local delivery of pain-reducing neuroactive substances on a continually renewable basis. However, a potential limitation of this approach is tolerance development to agents released from the transplanted cells. In particular, since adrenal medullary chromaffin cells release opioid peptides, reduced antinociceptive efficacy of opioids is possible. To determine this, alterations in the dose-effectiveness of morphine were assessed in animals with adrenal medullary transplants. Results indicated that, not only was there no apparent tolerance, but that adrenal medullary transplants could potentiate the analgesic efficacy of morphine. An additional goal of these studies was to determine whether chronic or intermittent nicotine could produce increased antinociception, since stimulation of cell surface nicotinic receptors increases release of neuroactive substances from chromaffin cells. This was assessed using subcutaneously implanted nicotine pellets or repeated systemic administration of nicotine. Findings indicated that exposure to nicotine results in an acute tolerance, or tachyphylaxis, to nicotine which is rapidly reversed following cessation of nicotinic stimulation. Together, these results suggest that adrenal medullary transplants may provide a constant source of opioid peptides, augmentable by intermittent nicotinic stimulation, without the development of appreciable tolerance to these pain-reducing neuroactive substances.

Adrenal Medulla↗

PubMedDate not supplied

Tolerance and cross-tolerance to the effects of amphetamine, methamphetamine and fenfluramine on milk consumption in the rat.

It has been reported that rats develop tolerance to the milk intake suppressant effects of d-amphetamine, d-methamphetamine, and d, l-fenfluramine. However, it has been hypothesized that the mechanism of action of fenfluramine is different from that of the other two drugs. In the present experiment, rats were given one of these 3 phenylethylamine derivatives each day until tolerance developed to the suppression of milk intake. A second of these drug s was then substituted and milk intake measured. There was cross-tolerance to the drug-induced suppression between d-amphetamine and d-methamphetamine, but not between d-amphetamine and d,l-fenfluramine. The lack of cross tolerance suggests a different mechanism of action for these drugs.

Animals↗

PubMed1991

Tolerance to ethanol and cross-tolerance to pentobarbital and barbital in four rat strains.

Chronic ethanol treatment by gastric intubation conferred tolerance to ethanol-induced motor impairment and hypnosis in four different rat strains: Fischer 344, Long-Evans, Sprague-Dawley, and Wistar. Cross-tolerance to barbital was also observed in all strains after chronic treatment with ethanol. However, chronic ethanol treatment failed to produce cross-tolerance to pentobarbital-induced motor impairment and hypnosis in any of the four strains. The demonstration of cross-tolerance to barbital and the lack of it to pentobarbital after chronic ethanol treatment confirms and extends recent observations on the specificity of the site and/or mechanism of action of sedative-hypnotic drugs that differ in lipid solubility.

Animals↗

PubMed1981

Different states of transplantation tolerance, and the problem of inheritance of tolerance.

In agreement with previous results, we failed to observe hereditary transmission of transplantation tolerance in the progeny of tolerant male mice when tested by skin grafting. At the same time we showed that the detection of the tolerance state depended on the test of immunity used. The possibility has not excluded that positive results with hereditary transmission of tolerance via fathers [1-3] may be due to the appropriate detection systems.

Animals↗

PubMed1994

Differential patterns of T cell clonal deletion in neonatal H-2 tolerance and I-E/Mls induced self-tolerance.

The pattern of clonal deletion of putative I-E-reactive (V beta 11) and Mls-reactive (V beta 3) T cells was evaluated and compared by cytofluorographic and immunohistochemical methods in a model of neonatal H-2 tolerance and in I-E- or Mls-bearing strains of mice which normally delete these cell populations (self-tolerance). The ontogeny of deletion of V beta 11+ cells was studied by evaluating thymic changes from birth until maturity in B10.S (H-2s/I-E-), B10.A (H-2k/d/I-E+) and B10.S mice intravenously infused at birth with (B10.SxB10.A)F1 lymphohaematopoietic cells. The reduction in V beta 11+ cells was most prevalent in the medullary region of the naive B10.A and neonatally injected B10.S animals and was corroborated by flow cytometry which demonstrated a marked reduction in single CD4 and CD8 positive B beta 11 T cells when compared to naive B10.S mice. However, immunohistochemistry illustrated that 'deletion' was never complete since V beta 11+ cells remained in the thymic cortex and splenic lymphoid follicles. By comparison, DBA/2 mice (Mlsc+ and previously documented to have decreased levels of V beta 3+ cells) showed a different pattern of deletion of V beta 3+ T cells than what was found for T cells bearing V beta 11 in animals deleting this population. DBA/2 thymi contained fewer thymic V beta 3- cells and there was more complete elimination of these cells, particularly in the periphery, by flow cytometry and immunohistology. The mice which do not delete V beta 3 cells (Mlsc-) showed that the majority of V beta 3- cells were located in the medulla with a few cells distributed in the cortical region. This pattern was notably different than the distribution of V beta 11 cells in thymi. Despite their location by histology, the majority of remaining V beta 3+ cells were dual CD4/CD8 positive (CD4+CD8+) by flow cytometric analysis. Our data illustrate that V beta 11 and V beta 3 T cells appear to be eliminated (i.e. 'deleted') at similar stages of maturation (single positive) during self-tolerance as well as in a neonatal H-2 tolerance model. However, the degree of elimination and the location of the cells remaining in these mice is dramatically different, depending on which T cell population is being evaluated and which deleting ligand is presented intrathymically. Thus, the accepted tenet of dual CD4+CD8+ cells localizing to the thymic cortex appears to have exceptions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2004

Lack of cross-tolerance to the antinociceptive effects of systemic and topical cannabinoids in morphine-tolerant mice.

Opioids and cannabinoids produce antinociception through activity at spinal, supraspinal and peripheral sites. Tolerance to the antinociceptive effects of both the opioids and the cannabinoids develop when these agents are administered chronically. Although mutual potentiation of antinociceptive effects have been reported between opioids and cannabinoids, the development of antinociceptive cross-tolerance between these systems has not been demonstrated consistently. In the present investigation, we explored the possibility of antinociceptive cross-tolerance between systemic or topical morphine and systemic or topical cannabinoids in mice. Mice were made tolerant to morphine either by the subcutaneous (s.c.) implantation of a morphine pellet or repeated topical administration and then challenged with the mixed CB(1) and CB(2) receptor agonist WIN 55, 212-2 given s.c. or topically. Antinociception was indicated by increased tail-flick latencies to noxious radiant heat. Implantation with morphine pellets did not attenuate the antinociceptive potency of systemic or topical WIN 55,212-2. Moreover, twice-daily topical administration of morphine did not attenuate the antinociceptive potency of WIN 55,212-2 applied topically. These observations suggest that opioids and cannabinoids produce antinociception through mechanisms that are independent of each other at either the systemic or peripheral levels.

Analgesics↗

PubMed1997

Lack of cross-tolerance to short-term linsidomine in forearm resistance vessels and dorsal hand veins in subjects with nitroglycerin tolerance.

BACKGROUND: Therapy with nitroglycerin is widely used in the treatment of angina pectoris, but development of tolerance is a major problem. Nitrovasodilators other than nitroglycerin may be less prone to induce vascular tolerance. This investigation was designed to test whether the alternative nitric oxide donor linsidomine maintains its vasodilator effects in the presence of nitroglycerin tolerance. METHODS: We tested the vascular effects of nitroglycerin and linsidomine (SIN-1) in forearm resistance arteries (venous occlusion plethysmography) and hand veins (venous compliance technique) using a randomized, double-blind placebo-controlled regimen in 33 healthy subjects (age range, 22 to 38 years; mean age, 26 years) before and after 7 days of assignment to either 1 week of nitroglycerin administration (0.83 mg/hr) for induction of tolerance or placebo administration. RESULTS: Vascular responses of both vascular beds to nitroglycerin (in veins: mean difference, 42.3%; confidence interval [CI], 3% to 81.7%; p < 0.05; in arteries: mean difference, 65.0%; CI, 38.9% to 91.1%; p < 0.01) but not to linsidomine (in veins: mean difference, -13.8%; CI, -53.5 to 25.8%; not significant; in arteries: -19.7%; CI, -33.7% to -5.6%; not significant) were attenuated in the nitroglycerin patch group, whereas the placebo group showed no differences to either nitroglycerin (in arteries: mean difference, -7.5%; CI, -44.6% to 29.6%; in veins: -10.6%; CI, -58.2% to 36.9%) or linsidomine (in arteries: 4.5%; CI, -12.8% to 21.7%; in veins: -13.1%; CI, -4.5% to 29.8%). CONCLUSION: These results suggest that short-term administration of sydnonimines can overcome the loss of vascular relaxation associated with long-term nitroglycerin therapy.

Adult↗

PubMed2000

Novel S-nitrosothiols do not engender vascular tolerance and remain effective in glyceryl trinitrate-tolerant rat femoral arteries.

Organic nitrates, such as glyceryl trinitrate, are nitric oxide (NO) donor drugs that engender tolerance with long-term use. Here, we tested the hypothesis that our novel S-nitrosothiols, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6, tetra-O-acetyl-beta-D-glucopyranose (RIG200) and S-nitroso-N-valeryl-D-penicillamine (D-SNVP), do not induce vascular tolerance ex vivo. Femoral arteries from adult male Wistar rats were preconstricted with phenylephrine and perfused with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Perfusion pressure was measured during 20-h treatment with supramaximal concentrations of NO donor (10 microM). Perfusion with glyceryltrinitrate caused a vasodilatation, which recovered over 2-20 h. In contrast, the S-nitrosothiols caused vasodilatations that were maintained throughout the 20-h perfusion period. Responses to S-nitrosothiols were partially reversed by the NO scavenger ferrohaemoglobin and fully reversed by the soluble guanylate cyclase inhibitor [1H-[1,2,4] oxadiazole [4,3-a]quinoxaline-1-one (ODQ). Glyceryltrinitrate-tolerant vessels were fully responsive to bolus injections of S-nitrosothiols. Resistance to tolerance is an attractive property of our novel compounds, particularly in view of their sustained activity in arteries with damaged endothelium.

Animals↗

PubMed2000

Novel S-nitrosothiols do not engender vascular tolerance and remain effective in glyceryltrinitrate-tolerant rat femoral arteries.

Organic nitrates, such as glyceryltrinitrate, are nitric oxide (NO) donor drugs that engender tolerance with long-term use. Here, we tested the hypothesis that our novel S-nitrosothiols, N-(S-nitroso-N-acetylpenicillamine)-2-amino-2-deoxy-1,3,4,6, tetra-O-acetyl-beta-D-glucopyranose (RIG200) and S-nitroso-N-valeryl-D-penicillamine (D-SNVP), do not induce vascular tolerance ex vivo. Femoral arteries from adult male Wistar rats were preconstricted with phenylephrine and perfused with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Perfusion pressure was measured during 20 h treatment with supramaximal concentrations of NO donor (10 microM). Perfusion with glyceryltrinitrate caused a vasodilatation, which recovered over 2-20 h. In contrast, the S-nitrosothiols caused vasodilatations that were maintained throughout the 20 h perfusion period. Responses to S-nitrosothiols were partially reversed by the NO scavenger ferrohaemoglobin and fully reversed by the soluble guanylate cyclase inhibitor [1H-[1,2,4] oxadiazole [4,3-a]quinoxaline-1-one (ODQ). Glyceryltrinitrate-tolerant vessels were fully responsive to bolus injections of S-nitrosothiols. Resistance to tolerance is an attractive property of our novel compounds, particularly in view of their sustained activity in arteries with damaged endothelium.

Animals↗

PubMed1984

Tolerance and reverse tolerance to toluene inhalation: effects on open-field behavior.

Rats were exposed by inhalation to extremely high concentrations of toluene vapors twice daily for six weeks, as an animal model of organic solvent abuse. At preset intervals during repeated exposure, the rats were exposed to test concentrations of toluene and effects on behavior in an open field were measured. Concentration-effect curves were determined during Weeks 4 to 6 of repeated exposure. Tolerance to toluene was measured as a decreased response to the test exposure and a shift of the concentration-effect curve to the right. Reverse tolerance was measured as an increased response to the test exposure and a shift shift of the concentration-effect curve to the left. Results demonstrated that the effects of repeated exposure to toluene showed behavioral selectivity: tolerance developed to ataxia, hindlimb myoclonus, and inhibition of rearing, whereas reverse tolerance developed to headshakes and increased locomotor activity.

Animals↗

PubMed2000

Decrement in operant performance produced by NMDA receptor antagonists in the rat: tolerance and cross-tolerance.

Current perspectives on the clinical use of NMDA receptor antagonists infer repeated administration schedules for the management of different pathological states. The development of tolerance and cross-tolerance between different NMDA receptor antagonists may be an important factor contributing to the clinical efficacy of these drugs. The present study aimed to characterize the development of tolerance and cross-tolerance to the ability of various site-selective NMDA receptor antagonists to produce a decrement of operant responding (multiple extinction 9 s fixed-interval 1-s schedule of water reinforcement). Acute administration of D-CPPen (SDZ EAA 494; 1-5.6 mg/kg), dizocilpine (MK-801; 0.03-0.3 mg/kg), memantine (0.3-17 mg/kg), ACEA-1021 (10-56 mg/kg), and eliprodil (1-30 mg/kg) differentially affected operant responding. Both increases and decreases in response rates and accuracy of responding were observed. Repeated preexposure to D-CPPen (5.6 mg/kg, once a day for 7 days) attenuated a behavioral disruption produced by an acute challenge with D-CPPen or ACEA-1021, but potentiated the effects of dizocilpine, memantine, and eliprodil. Based on the present results, one can suggest that the repeated administration of a competitive NMDA receptor antagonist differentially affects the functional activity of various sites on NMDA receptor complex.

Animals↗

PubMed2000

The dopamine D2/D3 antagonist DS121 potentiates the effect of cocaine on locomotion and reduces tolerance in cocaine tolerant rats.

To explore the significance of dopamine (DA) autoreceptors in cocaine tolerance and cocaine induced locomotor activity rats were treated with saline and cocaine (40 mg/kg per day via osmotic minipump; normal and cocaine tolerant rats, respectively). Injections of DS121 (0-7 mg/kg, i.p.; S(-)-3-(3-(cyanophenyl)-N-n-propylpiperidine), a DA D2/3 and autoreceptor preferring antagonist, either alone (i.e. DS121 + saline injection) or in combination with cocaine (7.5 mg/kg, i.p.) were also given. DS121 (+ saline) increased locomotor activity in both saline and cocaine pump (CP) treated animals. DS121 also potentiated the effect of cocaine on locomotor activity; this effect was greatest in CP (tolerant) animals. It is concluded that DS121 can increase locomotor activity and that this effect is greatest when the DA tone is high, that is when cocaine is present, suggestive of a presynaptic mechanism. Furthermore, because DS121 potentiation of cocaine induced locomotor activity is greatest in tolerant animals it is concluded that supersensitive DA autoreceptors underlie this effect. These data further support our previous data, which show that DA autoreceptors are sensitized after continuous cocaine (minipump) treatment.

Animals↗

PubMed2001

Dilution of the 75-g oral glucose tolerance test improves overall tolerability but not reproducibility in subjects with different body compositions.

Poor reproducibility of the 75-g oral glucose tolerance test (75-g OGTT) is a major criticism. To test whether dilution might be a contributor, we studied the effect of administering it at 300, 600, and 900 ml on the coefficient of variation (CV) and overall tolerability. Each dilution was randomly repeated three times by 35 subjects: 11 lean (body fat [BF]: 11.5+/-1.5%, body mass index (BMI): 24.1+/-0.8 kg/m(2), age: 33+/-3 years), 12 normal (BF: 24.3+/-1.3%, BMI: 23.9+/-0.7 kg/m2, age: 33+/-3 years), and 12 obese (BF: 34.1+/-1.5%, BMI: 34.5+/-1.6 kg/m(2), age: 41+/-4 years). The protocol followed, the American Diabetes Association (ADA) guidelines with venous samples drawn at 0, 15, 30, 45, 60, 90, and 120 min. Scales assessing palatability, acceptability, satiety, nausea, and dizziness were also completed. No differences were detected in CV between the three dilutions at the 2 h-diagnostic-endpoint in any group. CV for glycemia, however, was lower for the 300-ml OGTT (10+/-2.1%) than either the 600 ml (17.9+/-2.1%) or 900-ml OGTT (19.9+/-4.4%) at 45 min in the lean group (P<0.05). CV for insulinemia was lower for the 300 ml (30.6+/-4.5%) and 600 ml (30.6+/-4.1%) OGTT than the 900-ml OGTT (53.7+/-7.9%) at 60 min in the obese group (P<0.05). When affective ratings were compared, the 600-ml OGTT scored highest on palatability and acceptability (P<0.05). We concluded that the dilution of the 75-g OGTT improves the overall tolerability but not reproducibility of results. Practitioners may choose to give it at the best-tolerated dilution.

Adult↗

PubMed1997

Progression of normal glucose tolerance to impaired glucose tolerance or diabetes in the elderly.

Factors predicting impared glucose tolerance (IGT) and diabetes (DM) were studied in a community-living population aged 70 years or over, with initial normal glucose tolerance (NGT). The baseline examinations from 1991 to 1992 included an oral glucose tolerance test (OGTT), physical examinations and questionnaires. The follow-up examinations in 1994 and 1995 comprised of an OGTT. One hundred and thirteen of the eligible 134 subjects, with baseline NGT, participated in the re-examinations. Thirty six percent of these subjects progressed to IGT and 3% to DM. Obesity was the best predictor of IGT or DM, and central obesity was also associated with them. In addition, abnormal progression of glucose tolerance was also associated with those aged greater than 80 years, with systolic blood pressure greater than 160 mmHg, diastolic blood pressure greater than 80 mmHg, fasting blood glucose value of greater than 5.3 mmol/l, and 2 h of blood glucose value greater than 6.8 mmol/l.

Aged↗

PubMed1985

Drug-induced tolerance to allografts in mice II. Tolerance to tumor allografts of large doses associated with rejection of skin allografts and tumor allografts of small doses.

Antigen-specific tolerance to tumor allografts in mice was obtained by stimulation with allogeneic spleen cell antigens and treatment with cyclophosphamide (CY) 2 days later in various strain combinations between donor mice of spleen cell antigens and recipients. In such tolerant mice, skin allografts were rejected in various combinations of the donor-recipient. Furthermore, some of the tolerant mice showed accelerated rejection of tumor allografts of small doses, even though they allowed progressive growth of the same tumor allografts of large doses. Our results suggest that the rejection of tumor allografts of large doses may depend upon a mechanism that is distinct, qualitatively or quantitatively, from that one responsible for the rejection of tumor allografts of small doses and skin allografts. One of the most important properties of lymphocytes to separate these two different mechanisms may be a capacity of clonal expansion, namely, sensitivity to CY-induced tolerance of the lymphocytes mediating allograft rejection.

Animals↗

PubMed2003

Acute antinociceptive tolerance and partial cross-tolerance to endomorphin-1 and endomorphin-2 given intrathecally in the mouse.

The effect of pretreatment with endomorphin-1 (EM-1) or endomorphin-2 (EM-2) given intrathecally (i.t.) on the tail-flick inhibition induced by subsequent i.t. injection of EM-1 or EM-2 was studied in CD-1 mice. Pretreatment with EM-1 (32.7 nM) for 1-3 h, but not 4 h, attenuated the tail-flick inhibition induced by i.t. EM-1 (16.3 nM), while pretreatment with EM-2 (70 nM) for 0.5-1.5 h, but not 2 h, attenuated tail-flick inhibition induced by i.t. EM-2 (35 nM). EM-1 (32.7 nM) pretreatment for 1.5 h produced 5.3- and only 2.4-folds shift to the right of the dose-response curves for EM-1- and EM-2-induced tail-flick inhibition, respectively, while EM-2 (70 nM) pretreatment for 1 h caused 4.3- and 4.5-folds shift to the right for EM-2- and EM-1-induced tail-flick inhibition, respectively. Thus, mice made antinociceptive tolerant to EM-1 were partially cross-tolerant to EM-2 and mice made antinociceptive tolerant to EM-2 were completely cross-tolerant to EM-1. It is proposed that EM-1- and EM-2-induced antinociception are mediated by the stimulation of two different subtypes of mu-opioid receptors in mouse spinal cord; one subtype is stimulated by both EM-1 and EM-2, and another subtype is stimulated by EM-2.

Analgesics↗