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PubMed1988

Assessment of opiate tolerance and dependence in vitro.

Experiments were performed to induce opiate tolerance and physical dependence in vitro and assess the applicability of the procedures for studying the basic mechanisms in tolerance and dependence development. It was established that tolerance and physical dependence could be demonstrated in the excised guinea pig ileum and mouse vas deferens by direct incubation with an opiate agonist. The selectivity of the response to opiates was determined by experiments demonstrating stereospecificity, naloxone reversibility and cross-tolerance. The magnitude of tolerance and physical dependence was found to be dose, time, and agonist type-dependent. A standardized degree of tolerance and dependence were induced by using a dose of agonist sufficient to inhibit electrically stimulated contractions by 50% (IC50). In the isolated guinea pig myenteric plexus of the longitudinal muscle, incubation of the IC50 of an agonist at 37 degrees C for one hour produced a 2 to 5-fold tolerance as evidenced by the increase in its IC50. The rank order of decreasing potency in developing tolerance was morphine, normorphine and methadone. Physical dependence on the opiate was established by a contractual response to naloxone or a supersensitive response to electrical stimulus after removal of the agonist by washing. The degree of dependence developed was found to be proportional to that of tolerance. Similar incubation experiments on the mouse vas deferens with opioids also resulted in the development of tolerance and dependence. Although naloxone failed to evoke a contractual response, it enhanced dose-dependently the sensitivity of the preparation to electrical stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Pharmacodynamic model of tolerance: application to nicotine.

The authors propose a model of pharmacodynamic response that, when integrated with a pharmacokinetic model, allows characterization of the development of functional tolerance. The model may be conceived of in several equivalent ways; one of these sees tolerance as a result of (noncompetitive) antagonism of agonist effect by a hypothetical substance (e.g., metabolite) produced by a first-order process, driven by agonist concentration. Tolerance thus lags behind, and is approximately proportional to, agonist concentrations. Two new parameters quantifying tolerance are introduced: kantO, which describes the elimination kinetics of the antagonist and determines the rate of development and disappearance of tolerance, and Cant50, which determines the magnitude of tolerance that can be achieved. The model was tested in eight volunteers on data produced after three sequences of paired i.v. administrations of nicotine separated by different intervals of time. Blood concentrations of nicotine and heart rate were measured. The proposed tolerance model was fitted to the nicotine data. The estimate of kantO suggests a half-life of development and regression of tolerance of 35 min, and the estimate of Cant50 suggests that tolerance, at its full development, causes an approximately 80% reduction of initial (nontolerant) effect. This model provides a quantitative pharmacokinetic-pharmacodynamic description of the development of acute tolerance that also carries physiologic meaning. The quantitative information provided by this model may improve understanding of the temporal patterns of drug abuse and complications thereof.

Adult↗
PubMed1978

Physical dependence to barbital compared to pentobarbital. II. Tolerance characteristics.

This study describes the tolerance characteristics of barbital compared to pentobarbital, the standard drug, during "chronically equivalent" treatment. Barbiturate tolerance was assessed as the increase in dose from the beginning to the end of treatment required to achieve equieffective peak effect. Dispositional tolerance was assessed as a reduction in the elimination half-life of barbiturate from blood. Functional tolerance was assessed as the increase in blood concentration of barbiturate at the time of peak effect. Overall, greater tolerance was developed to pentobarbital than to barbital. For pentobarbital, tolerance was both dispositional and functional; the dispositional tolerance developed rapidly and was almost complete at 1 week. For barbital, tolerance was exclusively functional. A most interesting finding was that functional tolerance to barbital and pentobarbital developed at the same slow rate for chronically equivalent treatment. This finding suggests that functional tolerance development is independent of the particular barbiturate reflecting the adaptability of the central nervous system to chronic depression.

Animals↗
PubMed1983

Functional clonal deletion and suppression as complementary mechanisms operative in adult hapten-induced cytotoxic T cell tolerance.

Immunologic tolerance to the hapten TNP was induced in adult mice through the i.v. injection of reactive TNBS. To probe the cellular basis of the tolerant state, splenic cytotoxic T lymphocyte precursors (CTL-P) were stimulated in vitro with haptenated, x-irradiated syngeneic spleen cells in the presence or absence of exogenously added growth factors derived from Concanavalin A-stimulated spleen cell conditioned medium (CAS). The cultures were either conventional bulk cultures or limit dilution cloning cultures. For the latter, cytotoxicity was assessed through a semi-automated, radioautographic 111In-release assay. Suppressive potential was assessed by mixing spleen cells from tolerant mice with normal spleen cells before culture. In the absence of CAS, bulk cultures showed profound tolerance, and suppressive capacity was clearly evident. Suppression was dependent on the presence of TNP-self during culture and affected the generation of CTL from CTL-P and not the effector function of CTL. Cyclophosphamide treatment did not prevent tolerance induction. In the presence of CAS, bulk cultures still showed marked tolerance, but mixing experiments now yielded no evidence of suppression. As documented previously, limit dilution cultures of tolerant spleen cells in the presence of CAS showed a functional clonal deletion of hapten-specific CTL-P. In the absence of CAS, limit dilution cultures became dependent on helper T cells as the limiting element. Tolerant populations showed a diminution of activatable helper T lymphocyte precursors (HTL-P), which may have been due to a functional clonal deletion of HTL-P and/or a concomitant activation of suppressor T cells. Adoptive transfer studies showed that cells from tolerant mice did not detectably influence the number of hapten-specific CTL-P in the spleens of host animals. Taken together, the results suggest that both functional clonal deletion of CTL-P and suppression of HTL-P contribute to the tolerant state induced.

Animals↗
PubMed1984

Neurohypophyseal peptides maintain tolerance to the incoordinating effects of ethanol.

Arginine vasopressin (AVP), lysine vasopressin (LVP) and [des-9-glycinamide]LVP (DGLVP), administered systemically, delayed the disappearance of functional tolerance to the motor-incoordinating effect of ethanol in mice. This result is consistent with previous findings that AVP and related neuropeptides maintain tolerance to the sedative-hypnotic and hypothermic effects of ethanol, and suggests that the peptides modulate the rate of disappearance of tolerance per se, rather than simply influencing the tests used to evaluate tolerance. However, both the duration of tolerance to the incoordinating effect of ethanol, and the duration of peptide maintenance of this tolerance, were less than those observed for tolerance to the hypnotic and hypothermic effects of ethanol. Tolerance to various effects of ethanol clearly can develop and dissipate at different rates, and our results suggest that the characteristics of the maintenance of ethanol tolerance by neurohypophyseal peptides are influenced, to some extent, by the neural systems which mediate the expression of the functional tolerance which is being investigated.

Animals↗
PubMed1982

Minor physiological relevance of oral glucose tolerance test.

The physiological relevance of the oral glucose tolerance test was evaluated in ten healthy nonobese subjects and nine subjects with slightly impaired glucose tolerance. In random order, all subjects received a 50 g oral glucose tolerance test or a standardized breakfast meal of equivalent carbohydrate content. Changes in plasma glucose, insulin, and pancreatic glucagon concentrations were measured. In both groups, plasma glucose increased significantly during the oral glucose tolerance test and the meal test but the incremental glucose area (0-60 min) of the oral glucose tolerance test was about 350% and 120% greater than that of the mean test (p less than 0.001) in the normals and the patients with impaired glucose tolerance, respectively. In both groups, insulin responded almost similarly to the oral glucose tolerance test and the meal test whereas plasma glucagon declined significantly during the oral glucose tolerance test only (p less than 0.001). Glucagon remained unchanged during the meal test in the normals and increased slightly (p less than 0.05) in the group with impaired glucose tolerance. These data show that the response of glucose, insulin and glucagon to an oral glucose tolerance test in various respects is different to that obtained by the more physiological stimulation with a breakfast meal.

Administration, Oral↗
PubMed1980

Nitrate tolerance and dependence. A critical assessment.

Tolerance and cross-tolerance to nitrates has been known since 1900 but the actual clinical importance of this phenomenon is unclear. Vasodilator treatment of congestive heart failure has provided an important new role for long-acting nitrates. The advent of high-dose nitrate regimens for both angina and heart failure raises the possibility that nitrate tolerance could be a potential detriment to therapy. A number of older studies have documented the development of tolerance and cross-tolerance to blood pressure and heart rate responses to nitrates as well as the rapid onset of tolerance to nitrate headaches in subjects given nitrates on a regular basis. Animal experiments also confirm the ready appearance of nitrate tachyphylaxis. Needleman has proposed a cellular mechanism for nitrate tolerance based on a chemical alteration of nitrate receptors in the vascular wall. In spite of these studies, there is considerable evidence that clinically relevant tolerance to nitrates is rare. Several recent investigations designed to look at this problem using high-dose isosorbide dinitrate (ISD) failed to demonstrate tachyphylaxis to the anti-anginal or hemodynamic effect of ISD. However, very recent work in patients with angina suggests that tolerance to high dose ISD does occur and may reduce the duration of action of long-acting nitrates. Overall, the bulk of current evidence does not support tolerance to be a major problem in nitrate treatment of cardiac diseases, although attenuated vasodilator responses may occur after several weeks of nitrate therapy.

Angina Pectoris↗
PubMed1981

Modification of environmentally cued tolerance to ethanol in mice.

Tolerance to the hypnotic and hypothermic effects of ethanol in mice develops with multiple injections. The tolerance to both of these effects of ethanol can be reduced by testing the animals in a novel environment, suggesting that the tolerance may be learned. Tolerance to the hypothermic effect of ethanol develops more rapidly than tolerance to the hypnotic effect. Disruption of the brain catecholamine systems, with either 6-hydroxydopamine or alpha-methyl-p-tyrosine slows the rate of development of tolerance to the hypnotic effect of ethanol. Intraventricular injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine, increases initial sensitivity to ethanol-induced narcosis and facilitates the development of tolerance to the hypnotic effects of ethanol. Tolerance to the hypothermic effect of ethanol in a familiar environment is unaffected by either of the neurotoxins or by alpha-methyl-p-tyrosine. However, initial sensitivity to the temperature-lowering effect of ethanol is increased by 6-hydroxydopamine and decreased by alpha-methyl-p-tyrosine administration. Learning may be an important factor in development of tolerance to ethanol under some conditions and tolerance produced under these conditions can be modified by disruption of central catecholamine systems.

5,7-Dihydroxytryptamine↗
PubMed1995

Anticonvulsant tolerance and withdrawal characteristics of benzodiazepine receptor ligands in different seizure models in mice. Comparison of diazepam, bretazenil and abecarnil.

The use of benzodiazepines (BDZs) in the long-term treatment of epilepsy is greatly restricted by their capacity to induce tolerance and dependence. Thus, the development of new BDZ-related therapeutic agents should be directed by strategies that minimize tolerance- and dependence-inducing properties. Experimental procedures used to determine the success of such strategies often rely on a single assay procedure (e.g., one seizure model), which might lead to false predictions. Furthermore, the different types of tolerance, i.e., "pharmacological" (metabolic or functional) and "behavioral" ("learned" or "contingent"), are often not dealt with in such studies. This prompted us to compare the chronic anticonvulsant efficacy and withdrawal characteristics of diazepam and two novel BDZ receptor ligands, i.e., the partial agonist bretazenil and the subtype-selective agonist abecarnil, in different seizure models in mice. Myoclonic, clonic and tonic seizures were induced by i.v. infusion of pentylenetetrazol and by transcorneal or transauricular application of electrical stimuli. Prolonged administration of diazepam (5 mg/kg twice daily for 6 days) resulted in marked anticonvulsant effects on myoclonic, clonic and tonic seizure thresholds at the onset of treatment, but pronounced tolerance developed rapidly during subsequent treatment. The time course and extent of tolerance was similar with most seizure models. Tolerance characteristics were not affected by study design, i.e., use of separate or the same animals for each seizure induction, indicating that learned or contingent tolerance was not significantly involved under these experimental conditions. After termination of treatment with diazepam, significant seizure threshold decreases were determined, indicating withdrawal hyperexcitability in response to physical dependence. During prolonged administration of abecarnil (10 mg/kg twice daily for 6 days), some anticonvulsant tolerance was seen with electroshock seizures, but not with pentylenetetrazol seizures; no withdrawal hyperexcitability was determined upon termination of treatment. Bretazenil (10 mg/kg twice daily for 6 days) produced no tolerance in any of the seizure models, but a significant decrease in electroshock seizure threshold was seen in the withdrawal period. The data indicate that tolerance and withdrawal characteristics of BDZ receptor partial and subtype-selective agonists in mice depend on the experimental model used, whereas the influence of the experimental protocol is less critical in the case of a full BDZ receptor agonist such as diazepam.

Animals↗
PubMed1994

Tolerance to lipopolysaccharide involves mobilization of nuclear factor kappa B with predominance of p50 homodimers.

Stimulation of the human monocytic cell line Mono Mac 6 with lipopolysaccharide (LPS) leads to rapid and transient expression of cytokines like tumor necrosis factor (TNF). When such cells are precultured for 2 days with a low dose of LPS (20 ng/ml) followed by stimulation with a high dose of LPS (1 microgram/ml), expression of the TNF gene is minimal, i.e. the cells are tolerant. In nuclear run-on analysis, such tolerant cells show only a low degree of transcription, indicating that tolerance operates at or upstream of the transcription level. The CD14 LPS receptor is, however, up-regulated (not down-regulated) in tolerant cells, and LPS can, in fact, still lead to activation of tolerant cells as evidenced by mobilization of the transcription factor nuclear factor kappa B (NF-kappa B). Resolution of the NF-kappa B complex in gel shift analysis shows that the binding protein, mobilized in naive Mono Mac 6 cells, consists mainly of p50-p65 heterodimers, while in tolerant cells, the p50 homodimer is predominant. This increase in p50 homodimers coincides with an increase in p105 mRNA, suggestive of a transcriptional up-regulation of p50. Reporter gene analysis reveals that the NF-kappa B complex mobilized in tolerant cells is functionally inactive in that NF-kappa B-dependent luciferase constructs containing the human immunodeficiency virus long terminal repeat or the TNF 5'-region show only minimal transactivation after LPS stimulation. Similar to Mono Mac 6 cells, primary blood monocytes, when precultured with a low dose of LPS, also become tolerant and produce little TNF after LPS stimulation. The tolerant blood monocytes also up-regulate CD14, and they mobilize NF-kappa B with a predominance of p50 homodimers. Taken together, these results demonstrate that tolerance to LPS is determined by post-receptor mechanisms that involve an altered composition of the NF-kappa B complex.

Antigens, CD↗
PubMed1995

Cross-tolerance between kappa and mu opioid agonists in the guinea pig ileum myenteric plexus.

The aim of the present investigation was to determine whether chronic activation of kappa opioid receptor induces development of tolerance of kappa (specific tolerance) and to mu (cross-tolerance) agonists in the guinea pig ileum myenteric plexus-longitudinal muscle strip. trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidynyl)ciclohexyl]-benzeneacetamide (U-50,488H) a selective kappa agonist, morphine (prototype of a mu agonist) and DAMGO (a selective mu agonist) were chosen. Tolerance to the kappa agonist was induced by chronic administration of the kappa agonist (15 mg/kg i.p. twice a day for 4 days). The guinea pigs were killed on day 5. Tolerance to U-50,488H was observed after its chronic administration and was revealed as a rightward shift of the concentration-response curve. In addition, we observed a decrease in the maximum response and in the slope. Preparations from chronically U-50,488H-treated guinea pigs were also tolerant to the inhibitory effects of both the mu-selective agonist DAMGO and morphine. That is, there was cross-tolerance to the mu agonists. The development of tolerance to DAMGO and morphine was characterized by a rightward shift of the concentration-response curve, a decrease in maximum response and a decrease in the slope, although the degree of tolerance appeared to be less than that observed to U-50,488H. These data suggest that tolerance at the myenteric plexus level may be associated with a functional change in the myenteric neurons that is unrelated to the individual receptor system.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

[Alcohol tolerance and the clinical course of alcoholism].

The authors investigated in 250 hospitalized men in different clinical stages of alcoholism the alcohol tolerance and described the phenomenon of primary extension and secondary reduction in the variety of abused alcoholic beverages. While an increased tolerance was found in all patients, a markedly increased tolerance was recorded in 22% and the actual tolerance dominates unequivocally in toxicomanic drug dependence. In reduced tolerance (36%) associated findings such as hepatopathies, craniocerebral injury, epilepsy, ulceration etc. were present in 10%. The variety of alcoholic beverages comprised in 66.8% drinking of liquor with beer or wine--described by the author as the obligatory variety. In 20.4% preference of liquors was recorded, in 4.8% preference of wine, in 3.6% preference of beer. During secondary reduction of the variety (14%) in the majority the patients abandoned liquor in favour of wine, beer etc. Changes in the alcohol tolerance along with changes of the variety of consumed drinks are more marked within the framework of clinical pictures described by the author in the monograph "Klinika alkoholismu" (Clinical aspects of alcoholism) (1988). In systematic alcohol abuse (developing dependence) the increase of tolerance takes place along with profilization of the variety (obligatory variety, preference of liquors etc.). In alcoholic toxicomania dominates secondary and in particular actual tolerance with a markedly increased tolerance and preference of liquors. In habitual ethylism despite the increase the tolerance is not extreme, the obligatory variety dominates.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1994

Evidence that ultraviolet B radiation induces tolerance and impairs induction of contact hypersensitivity by different mechanisms.

Tumour necrosis factor-alpha (TNF-alpha) and cis-urocanic acid (UCA) have recently been implicated in the process by which ultraviolet B radiation (UVB) impairs the induction of contact hypersensitivity when dinitrofluorobenzene (DNFB) is painted on UVB-exposed skin. The evidence supports the hypothesis that UVB radiation converts trans- to cis-UCA in the epidermis which in turn causes the epidermis of UVB-susceptible mice to produce/contain excessive local amounts of TNF-alpha. When hapten is painted on TNF-alpha- or UVB-treated skin, contact hypersensitivity fails to develop. As UVB radiation also induces hapten-specific tolerance and suppressor T cells when hapten is applied to UVB-exposed skin of UVB-susceptible strains of mice, we examined whether TNF-alpha and/or UVB-irradiated UCA (UV-UCA) might be similarly involved in the mechanism by which UVB induces tolerance. We report that intracutaneously-injected TNF-alpha and UV-UCA altered the cutaneous environment such that when DNFB was painted on the injected site, hapten-specific tolerance was induced and suppressor cells were generated. However, the tolerance induced by UVB radiation and the tolerance that followed intracutaneous injection of UV-UCA were not reversed by neutralizing anti-TNF-alpha antibodies. Moreover, UV-UCA and TNF-alpha-induced tolerance and suppressor cells in both UVB-susceptible (UVB-S) and UVB-resistant mice, whereas UVB radiation induced tolerance only in UVB-S mice. We conclude that the mechanism by which UVB radiation induces tolerance in mice is separate and distinct from the mechanism by which UVB radiation impairs contact hypersensitivity induction. Moreover, our data support the view that the generation of suppressor cells and the development of hapten-specific tolerance may be mechanistically distinct. The possible molecular and cellular mediators of UVB-induced tolerance are discussed.

Animals↗
PubMed1995

Pharmacodynamic model for acute tolerance development to the electroencephalographic effects of alfentanil in the rat.

This investigation was carried out to characterize the rate and extent of acute tolerance development to the pharmacodynamics of alfentanil in the rat with the electroencephalogram (EEG) as a measure of alfentanil's effects on the central nervous system. Alfentanil was administered by use of three different drug infusion strategies in order to develop a pharmacokinetic-pharmacodynamic model for acute tolerance: I) intravenous infusion of 0.5 mg/kg in 10 min, achieving peak alfentanil concentrations of 750 ng/ml; II) computer-controlled infusion to rapidly achieve and maintain a constant drug level of 750 ng/ml, followed by washout; III) computer-controlled infusion to step through multiple constant drug levels (up to 1500 ng/ml), followed by washout. Frequent arterial plasma samples were taken and assayed for alfentanil. EEG signals were continuously recorded until effects returned to base-line values. The amplitudes in the 0.5- to 3.5-Hz (delta) frequency band were calculated by aperiodic analysis and used as an EEG effect measure. The pharmacokinetic data were characterized by a three-compartment model with nonlinear clearance. Nonlinear kinetics was apparent from the multiple steady-state protocol III. Clearance values ranged from (S.E.) 49.7 (2.8) ml/min/kg at low alfentanil concentrations to a minimum value of 29.3 (0.8) ml/min/kg at high concentrations. The pharmacodynamic data showed profound acute tolerance development reflected as proteresis in the concentration-effect pairs after protocol I and a rapidly declining effect in the presence of stable alfentanil concentrations after protocols II and III. The effect stabilized within 15 min after a change in target concentration. A physiological tolerance model was developed to characterize the rate and extent of tolerance development to the effects of alfentanil. The models are generally applicable and consider the physiological homeostatic mechanisms responsible for the tolerance development to be an integral part of the pharmacodynamic system. Tolerance was modeled as a negative feedback control of the drug-induced effect with a first-order transfer function. The model required only two tolerance parameters to quantify the rate and extent of tolerance development and allowed for a rebound effect. Maximum tolerance diminished alfentanil's effect by 46% and was achieved with a half-life of 7.0 min.

Alfentanil↗
PubMed1997

Type 2 helper T cell-type cytokines and the development of "infectious" tolerance in rat cardiac allograft recipients.

CD4-targeted therapy with a nondepleting RIB-5/2 mAb abrogates accelerated (< 36 h) rejection in presensitized LEW rats and results in permanent acceptance of LBNF1 cardiac allografts in conjunction with the features of infectious tolerance. This study examined the role and functional significance of the Th1 and Th2 cytokine network and systemic host allospecific Ab (allo-Ab) responses in the development of the infectious tolerance pathway in this model. Long term survival of cardiac transplants in rats treated with the tolerizing RIB-5/2 mAb regimen was accompanied by profound depression of Th1 (IL-2 and IFN-gamma) and Th2 (IL-4, IL-10) cytokines at the graft site, as shown by competitive template reverse transcription-PCR and immunohistochemistry. In contrast, the expression of Th2-type cytokines was selectively up-regulated after transfer of infectious tolerance by spleen cells into new generations of primary and secondary test recipients. Donor-specific circulating IgM allo-Ab responses were diminished throughout, and the switch from IgM to IgG allo-Ab was completely prevented in tolerant hosts, as shown by flow cytometry. The demonstration that treatment with cytolytic anti-CD4, but not anti-CD8, mAb recreated rejection of test cardiac allografts with simultaneous down-regulation of IL-4 mRNA/protein expression underlines the importance of this cytokine in the development of infectious tolerance. Hence, this report documents distinct cytokine elaboration patterns in animals tolerized by CD4-targeted therapy compared with those rendered tolerant by putative regulatory Th2-like cells. The mechanism of tolerance in anti-CD4 mAb-treated hosts appears distinct from that operating in the absence of mAb, when the tolerant state is being transferred in an infectious manner to new cohorts of test recipients.

Adoptive Transfer↗
PubMed1997

A rodent model of in utero chimeric tolerance induction.

BACKGROUND: In utero tolerance induction has potential application in pediatric heart transplantation. Immunotolerance appears to be more easily induced in the fetus before full immunocompetence is established; however, the mechanisms behind this phenomenon are still undefined. METHODS: One hundred thirty Lewis (RT1l) rat fetuses from 10 litters were inoculated intraperitoneally at 18 days gestation with 1 x 10(7) ACI (RT1a) rat fetal liver cells. Fifty of the 100 viable neonates successfully brought to term were grafted with neonatal ACI skin within 24 hours of birth and heterotopic ACI hearts at 8 to 10 weeks of age (group 1A); the remaining 50 neonates only received heterotopic ACI heart grafts at 8 to 10 weeks (group 1B). Control groups consisted of 50 Lewis fetuses (five litters) inoculated in utero with phosphate-buffered saline solution (group 2) and 50 Lewis fetuses (five litters) that received no inoculum (group 3); all of these surviving progeny received both neonatal ACI skin and adult ACI cardiac allografts. Skin and cardiac grafts were monitored by daily visual inspection and palpation, respectively. Limiting dilution analysis was performed among all groups to assess precursor cytotoxic lymphocyte frequencies. Likewise, peripheral blood lymphocyte and splenocyte populations were analyzed with flow cytometry to detect allogeneic chimerism. RESULTS: Abortion rates among groups 1, 2, and 3 were 23% (30/130 abortions), 10% (5/50 abortions), and 6% (3/50 abortions), respectively. Tolerance to both ACI skin and cardiac allografts was induced in 14 of the 50 group 1A Lewis recipients (28%). Tolerance was not achieved in any of the recipients in groups 1B, 2, or 3. Limiting dilution analysis among all groups revealed a marked reduction of precursor cytotoxic T-lymphocytes in tolerant allograft recipients compared with recipients in the other groups. Flow cytometry detected significant splenocyte chimerism among tolerant rats; significant peripheral blood chimerism was not noted. CONCLUSIONS: We describe allogeneic tolerance induction in utero to both rat skin and heart tissue by use of donor-strain fetal liver cells. Compared with previous studies with adult splenocytes as the tolerogen, we achieved a higher frequency of tolerance with a markedly lower cell inoculum and lower abortion rate. Allogeneic chimerism was noted in the tolerant recipients, suggesting hematopoietic stem cell engraftment. Cytotoxic T-lymphocyte precursor frequencies were markedly depressed in tolerant animals. Interestingly, both donor-strain fetal liver cells and neonatal skin grafts were required to induce tolerance. These data suggest a period of hematopoietic "education" during and shortly after hematopoietic stem cell engraftment.

Animals↗
PubMed1998

The nitric oxide/cyclic GMP system at the supraspinal site is involved in the development of acute morphine antinociceptive tolerance.

The role of the supraspinal nitric oxide (NO)/cyclic GMP system in the development of acute morphine antinociceptive tolerance was investigated by use of the mouse 55 degrees C warm-water tail-flick test. A single intracerebroventricular (i.c.v.) pretreatment of mice with morphine (3 nmol, 140 min before testing) produced an acute antinociceptive tolerance to subsequent i.c.v. doses of morphine, as demonstrated by a 120-fold rightward shift of the morphine dose-response curve. When co-administered with morphine (140 min before testing), the NO synthase inhibitors: N-nitro-L-arginine methyl ester (L-NAME), 3-bromo-7-nitroindazole, 7-nitroindazole and NG-monomethyl-L-arginine, attenuated the development of morphine tolerance. All four NO synthase inhibitors completely blocked the rightward shift of the morphine dose-response curve caused by i.c.v. morphine pretreatment (3 nmol, 140 min before testing). This effect was partially antagonized by L-arginine, but not D-arginine, in a dose-dependent manner. Also, D-NAME did not block the development of tolerance. Like the NO synthase inhibitors, LY-83,583, a guanylyl cyclase inhibitor, blocked the development of tolerance, which suggests that NO acting through the cyclic GMP pathway is involved in the development of acute antinociceptive tolerance. The effects of increased NO production on acute morphine antinociceptive tolerance were also studied. When co-administered with morphine (140 min before testing), neither L-arginine (100 nmol) nor the NO donors, sodium nitroprusside (5 nmol) and isosorbide dinitrate (10 nmol), had any effect on the magnitude of morphine antinociceptive tolerance. These results suggest that NO, acting through the cyclic GMP pathway, mediates the development of acute antinociceptive tolerance, but that NO production does not alter the magnitude of antinociceptive tolerance.

Analgesics, Opioid↗
PubMed1998

Endotoxin tolerance alters macrophage membrane regulatory G proteins.

Administration of sublethal doses of endotoxin (LPS) or tumor necrosis factor-alpha (TNF alpha) renders rats tolerant to supralethal doses of LPS. Peritoneal macrophages from tolerant rats are refractory to LPS induced arachidonic acid (AA) metabolism and cytokine production in vivo, and exhibit reduced membrane GTPase activity and GTP gamma S binding. Since LPS stimulated AA metabolism is mediated by Gi alpha proteins, we sought to determine whether Gi alpha and/or other G proteins are reduced in LPS tolerance. Rats were rendered tolerant by two daily sublethal doses of Salmonella enteritidis LPS, 100 micrograms/kg and 500 micrograms/kg administered intraperitoneally. Animals were allowed to rest for 72 hours. Alternatively, tolerance to LPS was induced by sublethal administration of human recombinant TNF alpha (10 micrograms/kg) intraperitoneally 24 hrs before the experiments. Macrophage membrane G protein content was determined by immunoblot analysis with specific antisera to Gi1,2 alpha, Gi3 alpha, Gs alpha and the G protein beta subunits (G beta). Membrane G proteins were differentially decreased in tolerant macrophages. In macrophages from rats rendered tolerant by sublethal doses of LPS, Gi3 alpha was reduced the most to 48 +/- 8% of control (n = 3, P < 0.05) and this reduction was significant compared to those of other G proteins. Gi1,2 alpha and G beta were reduced to 73 +/- 5% (n = 3, P < 0.05) and 65 +/- 4% (n = 3, P < 0.05) of control respectively. Gs alpha(L) and Gs alpha(H) were also reduced to 61 +/- 5% (n = 3, P < 0.05) and 68 +/- 3% (n = 3, P < 0.05) of control, respectively. In contrast, only Gi3 alpha was reduced in macrophage membranes from rats pretreated with TNF alpha. Gi3 alpha was reduced to 57 +/- 11% of control (n = 4, P < 0.05) whereas Gi1,2 alpha and G beta were not significantly affected. These results demonstrate selective changes in tolerant macrophage membrane G proteins and suggest a potential role for Gi3 alpha in mediating LPS tolerance. The molecular mechanisms underlying these changes and their significance in LPS tolerance merit further investigation.

Animals↗