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PubMed2005

Attenuation of morphine tolerance by intrathecal gabapentin is associated with suppression of morphine-evoked excitatory amino acid release in the rat spinal cord.

This study was designed to investigate the effect of acute and chronic intrathecal (i.t.) injection of gabapentin (GBP) on the antinociceptive effect of morphine and tolerance development using a tail-flick latency test. Levels of excitatory amino acids (EAA) in i.t. CSF dialysates were also measured by high performance liquid chromatography. Male Wistar rats were implanted with either one or two i.t. catheters for drug injection or pump infusion and with a microdialysis probe for CSF dialysate collection. The effect of acute GBP (10 microg i.t.) injection on the morphine dose response was examined in both naïve rats and rats made tolerant by continuous infusion of morphine (15 microg/h i.t.) for 5 days. At such a low dose (10 microg i.t.), GBP did not enhance morphine's antinociception in naïve rats. In morphine-tolerant rats, however, acute GBP (10 microg i.t.) injection potentiated morphine's antinociception and yielded a 14.6-fold shift in morphine's dose-response curve. When GBP (10 microg/h i.t.) was co-infused with morphine (15 microg/h i.t.) to examine its effect on the development of morphine tolerance, GBP attenuated the development of morphine tolerance. The effect of GBP and morphine on CSF glutamate and aspartate levels was examined in naïve rats, and the effect of morphine challenge on CSF glutamate and aspartate levels was examined in rats previously infused for 5 days with morphine alone or morphine plus GBP. Acute injection of GBP (10 microg i.t.), morphine (50 microg i.t.), or GBP (10 microg i.t.) followed by morphine (50 microg i.t.) 30 min later had no significant effect on CSF EAA concentration in naïve rats; however, in tolerant rats, morphine challenge (50 microg i.t.) increased aspartate and glutamate levels to 221 +/- 22% and 296 +/- 43%, respectively, of those before morphine challenge, and this phenomenon was inhibited by GBP co-infusion. Our results show that GBP, at a dose without enhanced effect on morphine's antinociception in naïve rats, not only potentiates morphine's antinociceptive effect in morphine-tolerant rats but also attenuates the development of morphine tolerance. The mechanism of the effect of GBP on morphine tolerance might be via suppression of the EAA concentration in spinal CSF dialysate.

Amines↗
PubMed2005

Intermittent dosing prolongs tolerance to the antinociceptive effect of morphine microinjection into the periaqueductal gray.

Tolerance to the antinociceptive effect of microinjecting morphine into the ventrolateral periaqueductal gray (vPAG) develops with repeated administration. The objective of the present experiment was to determine whether the magnitude and duration of tolerance differ depending on the interval between injections. Rats were injected with morphine or saline into the vPAG either once daily for 4 days or twice daily for 2 days. All rats were injected with morphine into the vPAG for the fifth injection to determine whether tolerance had developed. Morphine microinjection produced tolerance in both morphine-pretreated groups regardless of inter-dose interval. One and two weeks later, microinjection of morphine produced an increase in hot plate latency in all groups except rats pretreated with daily morphine microinjections. That is, tolerance was evident 2 weeks following the induction of tolerance produced by daily, but not twice daily injections of morphine. Although a long inter-dose interval has been shown to prolong the duration of tolerance after systemic morphine administration, this is the first report showing a similar effect with direct administration of morphine into the brain. Given that associative learning underlies prolonged tolerance with systemic morphine administration, the present data suggest that associative mechanisms of tolerance are also engaged when morphine administration is restricted to the PAG.

Analgesics, Opioid↗
PubMed2005

Transposon mutagenesis identifies genes which control antimicrobial drug tolerance in stationary-phase Escherichia coli.

Tolerance to antimicrobial agents is a universal phenomenon in bacteria which are no longer multiplying or whose growth rate slows. Since slowly multiplying bacteria occur in clinical infections, extended periods of antimicrobial chemotherapy are needed to eradicate these organisms and to achieve cure. In this study, the molecular basis of antibiotic tolerance was investigated using transposon mutagenesis. We screened 5000 Escherichia coli Tn10Cam mutants for reduction of kanamycin tolerance in late stationary phase and found that 4935 mutants were able to grow to late stationary phase. Reduced tolerance was observed in nine mutants which became sensitive to killing by kanamycin. The mutant KS639 was the most sensitive one to kanamycin, and its genome was disrupted in an intergenic region which lies between aldB and yiaW open reading frames. This mutant showed increased sensitivity not only to kanamycin but also to gentamicin, ciprofloxacin and rifampicin. Reduced tolerance of KS639 to kanamycin was also observed in a murine thigh infection model. P1 transduction to the wild type strains confirmed that the intergenic region was responsible for the tolerance of the bacterium to antibiotics. Using PCR-directed one-step gene replacement, we inactivated the genes aldB, yiaW and yiaV. We also deleted the intergenic region. There was no difference in kanamycin tolerance between each mutant (DeltaaldB, DeltayiaW and DeltayiaV) and the parental strain. But the mutant lacking the intergenic region showed reduced tolerance to kanamycin. These data suggest that the intergenic region between aldB and yiaW genes may be involved in tolerance to antimicrobial agents in E. coli. Furthermore, they show that it is important in murine infection during antibiotic treatment and lead to a faster kill of the mutant bacteria.

Animals↗
PubMed2004

Determination of food specific IgE levels over time can predict the development of tolerance in cow's milk and hen's egg allergy.

BACKGROUND: The majority of children with cow's milk and hen's egg allergy develop clinical tolerance with time. However, there are no good indices to predict when and in whom this occurs. OBJECTIVE: The aim of this study was to determine if monitoring food specific IgE levels over time could be used as a predictor for determining when patients develop clinical tolerance. METHODS: Eighty-eight patients with hen's egg and 49 patients with cow's milk allergy who underwent repeated double-blind, placebo-controlled food challenges were included in the study. Using the Pharmacia CAP-System FEIA, specific IgE (sIgE) levels to cow's milk and hen's egg were retrospectively determined from stored serum samples obtained at the time of the food challenges. Logistic regression was used to evaluate the relationship between tolerance development and the decrease in sIgE levels over a specific time period between the two challenges. RESULTS: Twenty-eight of the 66 egg-allergic and 16 of the 33 milk-allergic patients lost their allergy over time. For egg, the decrease in sIgE levels (P=.0014) was significantly related to the probability of developing clinical tolerance, with the duration between challenges having an influence (P=.06). For milk there also was a significant relationship between the decrease in sIgE levels (P=.0175) and the probability of developing tolerance to milk but no significant contribution with regard to time. Stratification into 2 age groups, those below 4 years of age and those above 4 years of age at time of first challenge, had an effect, with the younger age group being more likely to develop clinical tolerance in relation to the rate of decrease in sIgE. The median food sIgE level at diagnosis was significantly less for the group developing "tolerance" to egg (P <.001), and a similar trend was seen for milk allergy (P=.06). Using these results, we developed a model for predicting the likelihood of developing tolerance in milk and egg allergy based on the decrease in food sIgE over time. CONCLUSION: We found that the rate of decrease in food sIgE levels over time was predictive for the likelihood of developing tolerance in milk and egg allergy. Using the likelihood estimates from this study could aid clinicians in providing prognostic information and in timing subsequent food challenges, thereby decreasing the number of premature and unnecessary double-blind, placebo-controlled food challenges.

Age Factors↗
PubMed2006

Low zone tolerance induced by systemic application of allergens inhibits Tc1-mediated skin inflammation.

BACKGROUND: The induction of tolerance may be a promising target of strategies aimed at preventing harmful allergic diseases. Low zone tolerance (LZT), induced by epicutaneous application of low doses of contact allergens, inhibits the development of T(C)1-mediated contact hypersensitivity (CHS). OBJECTIVE: We evaluated the effect of systemic (oral, intravenous) administration of low amounts of haptens on specific immune reactions and tolerance induction. METHODS: By using the mouse model of LZT, we analyzed immune reactions in vivo (skin inflammation) and T-cell responses in vitro after oral, intravenous, or epicutaneous application of low amounts of the contact allergen 2,4,6-trinitro-1-chlorobenzene (TNCB). RESULTS: Subimmunogenic doses of TNCB applied orally and intravenously induced a significant tolerance reaction in vivo comparable to epicutaneously tolerized mice, indicating that LZT is a systemically mediated tolerance reaction. In vitro analysis in all models of LZT revealed the generation of IL-10 secreting, regulatory CD4+ T cells that were absolutely required for the development of hapten-specific CD8+ T(C)2 cells. Adoptive transfer experiments identified CD8+ T(C)2 cells as effector T cells of LZT inhibiting the development of CHS-promoting T(C)1 cells and consequently the manifestation of CHS. These suppressor CD8+ T(C)2 cells were found as well in skin-draining as in mesenteric lymph nodes and in the spleen of tolerized animals independent of the route of tolerization. CONCLUSION: These data indicate that systemic uptake and presentation of small amounts of haptens (eg, contact allergens, drugs, metals) induce the development of LZT and thus prevent inappropriate activation of the immune system and protect from allergic diseases. CLINICAL IMPLICATIONS: These findings will be of particular importance because tolerance induction by protocols applying subimmunogenic, low amounts of haptens may be used as tools for immunotherapy in allergic and autoimmune diseases.

Administration, Cutaneous↗
PubMed2004

A theory of drug tolerance and dependence I: a conceptual analysis.

A mathematical model of drug tolerance and its underlying theory is presented. The model extends a first approach, published previously. The model is essentially more complex than the generally used model of homeostasis, which is demonstrated to fail in describing tolerance development to repeated drug administrations. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary only in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behavior to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes. In addition, it establishes a relation between the drug dose at any moment, and the resulting drug effect and relates the magnitude of the reactions following withdrawal to the rate of tolerance and other parameters involved in the tolerance process. The present paper analyses the concept behind the model. The next paper discusses the mathematical model.

Adaptation, Physiological↗
PubMed2005

Role of lipids and lipid signaling in the development of cannabinoid tolerance.

Cannabinoid agonists such as Delta9-tetrahydrocannabinol (THC) produce a wide range of pharmacological effects both in the central nervous system and in the periphery. One of the most striking features of cannabinoids such as THC is the magnitude to tolerance that can be produced upon repetitive administration of this substance to animals. Relatively modest dosing regimens are capable of producing significant tolerance, whereas greater than 100-fold tolerance can be obtained with aggressive treatments. While cannabinoid tolerance has been studied quite extensively to establish its relevance to the health consequences of marijuana use, it has also proven to be a valuable strategy in understanding the mechanism of action of cannabinoids. The discovery of the endocannabinoid system that contains two receptor subtypes, CB1 and CB2, associated signaling pathways, endocannabinoids (anandamide and 2-arachidonoylglycerol) and their synthetic and degradative pathways has provided a means of systematically evaluating the mechanism of cannabinoid tolerance. It is well known that the CB1 cannabinoid receptor is down-regulated in states of cannabinoid tolerance along with uncoupling from its second messenger systems. Endocannabinoid levels are also altered in selected brain regions during the development of tolerance. While it is reasonable to speculate that a likely relationship exists between receptor and endocannabinoid levels, at present, little is known regarding the biological signal that leads to alterations in endocannabinoid levels. It is also unknown to what degree synthetic and degradative pathways for the endocannabinoids are altered in states of tolerance. The discovery that the brain is abundant in fatty acid amides and glycerols raises the question as to what roles these lipids contribute to the endocannabinoid system. Some of these lipids also utilize the endocannabinoid metabolic pathways, produce similar pharmacological effects, and are capable of modulating the actions of anandamide and 2-arachidonoylglycerol. In addition, there are dopamine, glycine, and serotonin conjugates of arachidonic acid that may also contribute to the actions of endocannabinoids. A systematic examination of these lipids in cannabinoid tolerance might shed light on their physiological relevance to the endocannabinoid system.

Cannabinoid Receptor Modulators↗
PubMed2005

Evidence for an intrinsic mechanism of antinociceptive tolerance within the ventrolateral periaqueductal gray of rats.

Repeated microinjections of morphine into the ventrolateral periaqueductal gray produce antinociceptive tolerance. This tolerance may be a direct effect of morphine on cells within the ventrolateral periaqueductal gray or may require activation of downstream structures such as the rostral ventromedial medulla or spinal cord. Experiment 1 examined whether tolerance develops when opioid receptors in the ventrolateral periaqueductal gray are blocked prior to repeated systemic morphine administration. Microinjections of naltrexone hydrochloride (1microg/0.4microl) into the ventrolateral periaqueductal gray blocked antinociception and significantly attenuated the development of antinociceptive tolerance produced from systemic morphine administration. Experiment 2 examined whether tolerance develops when the effects of morphine are isolated to the ventrolateral periaqueductal gray. This was accomplished by microinjecting morphine (5microg/0.4microl) into the ventrolateral periaqueductal gray while simultaneously blocking the descending output through the rostral ventromedial medulla. Inhibition of neurons within the rostral ventromedial medulla by microinjecting the GABA(A) agonist muscimol (10ng/0.5microl) blocked the antinociception produced by microinjection of morphine into the ventrolateral periaqueductal gray but did not block the development of tolerance. These data demonstrate that the ventrolateral periaqueductal gray is both necessary and sufficient to produce tolerance to the antinociceptive effect of morphine. The ventrolateral periaqueductal gray is necessary in that tolerance does not develop if opiate action within the ventrolateral periaqueductal gray is blocked (experiment 1). The ventrolateral periaqueductal gray is sufficient in that tolerance occurs even when morphine's effects are restricted to the ventrolateral periaqueductal gray (experiment 2).

Analgesics↗
PubMed2005

The spinal nitric oxide involved in the inhibitory effect of midazolam on morphine-induced analgesia tolerance.

Previous studies had shown that pretreatment with midazolam inhibited morphine-induced tolerance and dependence. The present study was to investigate the role of spinal nitric oxide (NO) in the inhibitory effect of midazolam on the development of morphine-induced analgesia tolerance. Subcutaneous injection of 100 mg/kg morphine to mice caused an acute morphine-induced analgesia tolerance model. To develop chronic morphine tolerance in mice, morphine was injected for three consecutive days (10, 20, 50 mg/kg sc on Day 1, 2, 3, respectively). In order to develop chronic tolerance model in rats, 10 mg/kg of morphine was given twice daily at 12 h intervals for 10 days. Midazolam was intraperitoneally injected 30 min prior to administration of morphine. Tail-flick test, hot-plate and formalin test were conducted to assess the nociceptive response. Immunocytochemistry, histochemistry and western blot were performed to determine the effect of midazolam on formalin-induced expression of Fos protein, nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) and nitric oxide synthase (NOS) in chronic morphine-tolerant rats, respectively. The results showed that pretreatment with midazolam significantly inhibited the development of acute and chronic morphine tolerance in mice, which could be partially reversed by intrathecal injection of NO precursor L-arginine (L-Arg). In chronic morphine-tolerant rats, pretreatment with midazolam significantly decreased the formalin-induced expression of Fos and Fos/NADPH-d double-labeled neurons in the contralateral spinal cord and NADPH-d positive neurons in the bilateral spinal cord. Both inducible NOS (iNOS) and neuronal NOS (nNOS) protein levels in the spinal cord were significantly increased after injection of formalin, which could be inhibited by pretreatment with midazolam. The above results suggested that the decrease of the activity and expression of NOS contributed to the inhibitory effect of midazolam on the development of morphine tolerance.

Analgesia↗
PubMed1998

The relationship between abnormal glucose tolerance and hypertensive disorders of pregnancy in healthy nulliparous women. Calcium for Preeclampsia Prevention (CPEP) Study Group.

OBJECTIVE: The study's aim was to determine whether healthy nulliparous women with abnormal glucose tolerance during pregnancy are at increased risk for development of pregnancy-associated hypertension or preeclampsia. STUDY DESIGN: A series of 4589 healthy nulliparous women from 5 university centers were evaluated prospectively to determine whether calcium supplementation would prevent preeclampsia. Pregnancy-associated hypertension was a diastolic blood pressure > or = 90 mm Hg on 2 occasions 4 hours to 1 week apart. Pregnancy-associated proteinuria was proteinuria > or = 1+ by dipstick testing on 2 occasions 4 hours to 1 week apart, proteinuria > or = 300 mg/24 h, a protein to creatinine ratio of > or = 0.35, or a single dipstick measurement of > or = 2+. Preeclampsia was defined as pregnancy-associated hypertension and pregnancy-associated proteinuria documented within 7 days of each other. Normal glucose tolerance was a plasma glucose level < 140 mg/dL 1 hour after a 50-g oral glucose challenge. Abnormal glucose tolerance was a plasma glucose level > or = 140 mg/dL 1 hour after a 50-g oral glucose challenge followed by a 3-hour 100-g oral glucose tolerance test yielding < 2 abnormal values. Gestational diabetes mellitus was a plasma glucose level > or = 200 mg/dL 1 hour after a 50-g oral glucose challenge in the absence of an oral glucose tolerance test or > or = 2 abnormal plasma glucose values in a 3-hour 100-g oral glucose tolerance test (> or = 105 mg/dL fasting, > or = 190 mg/dL at 1 hour, > or = 165 mg/dL at 2 hours, or > or = 145 mg/dL at 3 hours). For purposes of this study women with preeclampsia were excluded from the category of pregnancy-associated hypertension. RESULTS: Calcium supplementation did not prevent pregnancy-associated hypertension or preeclampsia. Of 3689 women with complete glucose testing data, 227 (6%) had abnormal glucose tolerance and 81 (2%) had gestational diabetes mellitus. Compared with women with normal glucose tolerance, women with abnormal glucose tolerance were significantly older, had greater body mass index, and were more likely to be white non-Hispanic, to smoke, and to have private medical insurance. Among women with gestational diabetes mellitus, after adjustment for clinical center the relative risks of preeclampsia and of all hypertensive disorders were increased (relative risk 1.67, 95% confidence interval 0.92-3.05, and relative risk 1.54, 95% confidence interval 1.28-2.11, respectively). Risk ratios were not substantially reduced after further adjustment for race and body mass index (odds ratios 1.41 and 1.48, respectively). Even within the normal range, multivariate analysis demonstrated that the level of plasma glucose 1 hour after a 50-g oral glucose challenge was an important predictor of preeclampsia. CONCLUSION: Even within the normal range, the level of plasma glucose 1 hour after a 50-g oral glucose challenge was positively correlated with the likelihood of preeclampsia. Women with gestational diabetes mellitus were at increased risk for hypertensive disorders during pregnancy after adjustment for clinical center, race, and body mass index, although the increase was not statistically significant. These findings suggest that insulin resistance may play a role in the pathogenesis of the hypertensive disorders of pregnancy.

Adult↗
PubMed2000

Differential effects of a dihydropyridine calcium channel antagonist on the components of ethanol tolerance.

The dihydropyridine calcium channel antagonist, nimodipine, was found to decrease the extent of tolerance that developed to the ataxic action of ethanol in experimental designs in which the tolerance was not context-specific, when ethanol was given by liquid diet. When ethanol was given by injection, so that cues were present for the effects of ethanol during the chronic treatment, tolerance to the ataxic actions of ethanol was unaffected. Nimodipine, however, decreased the tolerance to the hypothermic actions of ethanol, when the ethanol was given by injection. When the rats were given practice sessions on the motor task while under the influence of the ethanol, during the chronic treatment, nimodipine did not affect tolerance to the ataxic actions of ethanol. When nimodipine was given before the motor task learning and ethanol after the practice sessions, the tolerance to the ataxic effect of ethanol was increased. A similar schedule of drug treatment with the NMDA antagonist CGP37849 given before the practice sessions, and ethanol afterwards, resulted in decreased tolerance to ethanol. It is suggested that these changes in ethanol tolerance may be explained by dual actions of nimodipine in, firstly, decreasing the form of tolerance to ethanol that is not dependent on contextual cues and, secondarily, in increasing the learning of a motor task.

2-Amino-5-phosphonovalerate↗
PubMed1997

Effects of noribogaine on the development of tolerance to antinociceptive action of morphine in mice.

The effects of noribogaine, a metabolite of ibogaine, on the development of tolerance to the antinociception action of morphine was determined in male Swiss-Webster mice. Ibogaine is an alkaloid isolated from the bark of the African shrub, Tabernanthe iboga. Morphine tolerance in mice was developed by two different methods. Mice were rendered tolerant to morphine either by subcutaneous implantation of a pellet containing 25 mg morphine free base for 4 days or by injecting morphine (20 mg/kg, s.c.) twice a day for 4 days. Placebo pellet implanted mice or vehicle injected mice served as controls. To determine the effect of intraperitoneally administered noribogaine on tolerance development, the drug was injected in the appropriate dose twice a day. In pellet implanted mice, a dose of 20 mg/kg of noribogaine attenuated the tolerance to morphine whereas lower doses had no effect. Similarly, in mice given multiple injections of morphine, noribogaine attenuated tolerance development at 20 and 40 mg/kg doses. Previous studies from this laboratory had shown that ibogaine at 40 and 80 mg/kg doses inhibited tolerance to morphine. Because noribogaine could attenuate morphine tolerance at lower doses than ibogaine, it is concluded that the attenuating effect of ibogaine on morphine tolerance may be mediated by its conversion to noribogaine, a more active metabolite.

Analgesics, Opioid↗
PubMed2000

Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in the Kashmir Valley of the Indian subcontinent.

This cross-sectional population survey was undertaken to determine the prevalence of type 2 diabetes and impaired glucose tolerance in subjects aged 40 years or more in Kashmir Valley, India. The study was carried out in two phases. In phase one, 6091 randomly selected subjects, 40 years or older, from all six districts of the valley were surveyed for prevalence of known diabetes mellitus. In phase two, 5083 subjects, 40 years or older, were screened with oral glucose tolerance test for prevalence of undiagnosed (asymptomatic) diabetes mellitus and impaired glucose tolerance. Abnormalities of carbohydrate intolerance were determined as recommended by WHO. Of 6091 subjects interviewed, 115 were known cases of diabetes mellitus with an overall prevalence of 1.89% (1.98% in males and 1.77% in females). Results of glucose tolerance test revealed that mean fasting as well as mean 2 h blood glucose was significantly more in females as compared to males (4.68+/-0.91 and 6.40+/-2.12 vs. 4.49+/-0.96 and 5.94+/-2.03 mmol/l, respectively, P < 0.0001). Of 5083 subjects who were subjected to glucose tolerance test (GTT), 627 (12.34%) had an abnormal test; with 411 (8.09%) having impaired glucose tolerance (IGT) and 216 (4.25%) having diabetes mellitus. The prevalence of IGT as well as of diabetes was significantly more in females as compared to males (P < 0.001). Subjects who had family history of diabetes had a significantly higher prevalence of abnormal GTT. Prevalence of known diabetes as well as that of abnormal GTT steadily increased with age, with a highest prevalence in the age group of > or = 70 years (P < 0.001). Obese subjects had a significantly higher basal as well as 2 h blood glucose in males as well as in females. Subjects with diabetes on GTT had a higher waist/hip ratio. Overall the prevalence of diabetes as well as IGT was significantly higher in the urban population. We conclude that 1.89% of the general population have known diabetes, 4.25% have undiagnosed diabetes and 8.09% have impaired glucose tolerance test; making the total load of abnormal glucose tolerance 14.23% in Kashmir Valley. In subjects greater than 40 years of age having a family history of diabetes, obesity, higher age (50 years or above), female sex, and urban origin have more chance (odds ratio: 4.65, 2.30, 1.87, 1.49 and 1.16, respectively) of developing abnormal glucose tolerance.

Adult↗
PubMed1989

Establishment of a novel method to induce tolerance in adult mice across fully allogeneic (entire H-2 plus multiminor histocompatibility) antigen barriers, using supralethal irradiation followed by injection of syngeneic bone marrow cells plus (donor X recipient) F1 spleen cells.

A novel method was established which can regularly induce profound tolerance in mice across entire H-2 plus multiminor histocompatibility (H) antigen (fully allogeneic) barriers. When recipient AKR/J Sea (AKR; H-2k) or C3H/He Slc (C3H; H-2k) mice were irradiated with 900 rad followed 1 day later by injection of 1 X 10(7) T cell-depleted syngeneic bone marrow cells plus 5 X 10(7) viable, but not mitomycin C-treated, [C57BL/6 Slc(B6) X AKR (or C3H)] F1 spleen cells via intravenous (i.v.) route, a specific tolerant state was induced against B6 (H-2b) antigens. In the tolerant C3H mice, the EL-4 tumor, which originates from B6, was accepted in a tolerogen-specific manner. Moreover, B6 skin grafts were permanently accepted in most of the tolerized AKR and C3H mice. Immunological parameters, including cytotoxic T lymphocyte (CTL) activity and the mixed lymphocyte reaction (MLR), were almost completely suppressed in the tolerant mice. An assay for chimerism using a direct immunofluorescence method revealed that the tolerant AKR mice were chimeric for the first 5 weeks after tolerance induction but not definitely chimeric thereafter. In the tolerant AKR mice, strong suppressor cells were not detected. This method could be used in order to investigate mechanisms of tolerance to allogeneic antigens in future experiments.

Animals↗
PubMed2002

Spontaneous tolerance: experience with the rat liver transplant model.

Soluble major histocompatibility complex (MHC) class I antigens released from hepatocytes and the passenger leukocyte population of the liver allograft have both been considered as important contributors for spontaneous liver tolerance upon allogeneic transplantation into fully MHC-mismatched hosts. This study was conducted to delineate the role of "passenger leukocytes" (PL) as well as local intra-graft defence mechanisms of long-term accepted liver allografts in more detail. Orthotopic liver transplantation was performed in male inbred rats as follows (n = 4-6): (i) Lewis (LEW; RT1.(l)) --> LEW; (ii) DA (RT1.(av1)) --> DA; (iii) DA --> LEW; (iv) LEW --> DA; (v) LEW (10-Gy whole body irradiation [WBI], d-7) --> DA; (vi) LEW (10-Gy WBI, d-7) --> LEW; (vii) LEW (10-Gy WBI, d-7) --> LEW (parked for 36 hours) --> DA; and (viii) LEW (10-Gy WBI, d-7) --> DA (parked for 36 hours) --> DA. The model specifically investigated the role of PLs as potential contributors to liver tolerance as WBI destroys this nonresident liver population. Characterization of Fas/FasL expression and the frequency of apoptotic cell death was performed by immunohistochemistry and TUNEL staining. Reverse transcriptase-polymerase chain reaction, by the use of Fas and FasL-specific cDNA probes, was performed on isolated hepatocytes of tolerized and rejected livers at various time points after transplantation. Animal survival in the various experimental groups was calculated using Kaplan-Meier survival statistics and related log-rank statistics as follows: (i) < 100 days; (ii) > or = 100 days; (iii) > 100 days; (iv) 11.3 +/- 1.0 day; (v) 9.0 +/- 0.5 days; (vi) > 100 days; (vii) 5/6 > 100 days; and (viii) 8.0 +/- 1.5 days. Immunohistochemistry revealed high numbers of proliferating cells in tolerized liver allografts. Apoptotic cell death of hepatocytes could be detected in both rejecting and to a lower extent in tolerized animals. Conversely, only tolerized but not rejected liver allografts revealed upregulation of FasL-expression on hepatic parenchymal cells from day 3 onwards. Irradiated LEW livers, in turn, lose their ability to survive in allogeneic DA hosts (group v) whereas they survive in syngeneic hosts (group vi), indicating that irradiation itself does not destroy the liver parenchyma. Reconstitution of irradiated LEW livers with syngeneic (group vii) but not with allogeneic (group viii) PLs restored tolerance induction. The underlying mechanisms of immune-privilege observed with liver allografts appear to share characteristics of clonal exhaustion suggesting that alloreactive lymphocytes are depleted by AICD via the FasL/Fas signal transduction pathway. The high frequency of apoptotic lymphocytes found in the portal tract of tolerized (but not rejected) LEW grafts supposes that functional FasL expression on graft hepatocytes mediates specific elimination of graft-directed effector lymphocytes. This mechanism constitutes peripheral deletion as one of the possible tolerogenic mechanisms involved. Chimerical liver grafts consisting of donor (LEW) parenchyma and host (DA) passenger leukocytes lose their tolerogenic capacity. In contrast, syngeneic reconstitution with LEW-PLs, restores liver graft acceptance upon transplantation into allogeneic DA hosts. This phenomenon is not relying on the induction of micro- or macrochimeric hosts, as no LEW PLs were found in spleen, thymus or the blood compartment from long-term surviving DA rats. Thus, non-resident liver cells contribute significantly to liver graft acceptance. Subsequently, liver tolerance appears to be mainly induced in the graft itself.

Animals↗
PubMed1997

Tolerance to the hypothermic and hyperthermic effects of chlorpyrifos.

Hypothermia is a commonly reported thermoregulatory response in rodents acutely exposed to organophosphates (OP); however, our laboratory has recently found a delayed hyperthermic response following the initial hypothermia when exposed to the OP, chlorpyrifos. It is well known that rodents display tolerance to OP-induced hypothermia but little is known about tolerance to OP-induced hyperthermia. Twenty female rats of the Long-Evans strain were made tolerant to chlorpyrifos by administering 0 or 10 mg/g chlorpyrifos by gavage daily for four days. Core temperature (T[c]) and motor activity (MA) were monitored continuously by telemetry. Twenty-four hours after the fourth 10 mg/kg injection, the animals were administered a challenge dose of 25 mg/kg chlorpyrifos or corn oil while the telemetry data were monitored for the next 72 h. Non-tolerant rats displayed an initial hypothermic response with reduced MA followed by a delayed increase in T(c) 24 h after exposure. The tolerant animals displayed a blunted hypothermic response with virtually no change in MA, but a delayed increase in T(c) similar to that of non-tolerant animals. The hyperthermic response of the non-tolerant animals persisted for two days, whereas the tolerant animals recovered by the second day. The data indicate that tolerance to the hypothermic and hyperthermic effects of chlorpyrifos involve separate neurochemical pathways.

Administration, Oral↗
PubMed2002

Cross-tolerance between the different mu-opioid receptor agonists endomorphin-1, endomorphin-2 and morphine at the spinal level in the rat.

In the present study we investigated the development of tolerance to an antinociceptive effect after intrathecal administration of endomorphin-1, endomorphin-2 and morphine in tail-flick and paw pressure tests. We also assessed cross-tolerance between the antinociceptive effects of the two endogenous mu-opioid receptor agonists - endomorphins and morphine. The tolerance developed on day 3 after i.th. injection of both endomorphins, endomorphin-2 (18, 36 nmol), endomorphin-1 (16 nmol). After morphine (30 nmol) the tolerance developed on day 6. Our study described the cross-tolerance between morphine and endomorphin-1, but not endomorphin-2. In comparison with naive rats, morphine had a weaker antinociceptive effect in rats tolerant to endomorphin-1. In contrast, no cross-tolerance was observed after administration of endomorphin-2 in rats tolerant to endomorphin-1. In rats tolerant to endomorphin-2, the antinociceptive effect of morphine and endomorphin-1 was attenuated in both the tests used. Our results suggest that the three ligands of mu-opioid receptors probably act via different subtypes of the mu-opioid receptor.

Analgesics, Opioid↗
PubMed1996

Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective mu or delta opioid agonists in mice.

N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to block the development of antinociceptive tolerance to morphine. Assessment of the effects of NMDA antagonists on development of antinociceptive tolerance to selective opioid mu (mu) and delta (delta) agonists, however, has not been reported. In these experiments, selective mu and delta receptor agonists, and morphine, were repeatedly administered to mice either supraspinally (i.c.v.) or systemically (s.c.), alone or after pretreatment with systemic NMDA antagonists. Antinociception was evaluated using a warm-water tail-flick test. Repeated i.c.v. injections of mu agonists including morphine, fentanyl, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) or [D-Ala2, Glu4]deltorphin, a delta agonist, or s.c. injections of morphine or fentanyl, produced antinociceptive tolerance as shown by a significant rightward displacement of the agonist dose-response curves compared to controls. Single injections or repeated administration of MK801 (a non-competitive NMDA antagonist) or LY235959 (a competitive NMDA antagonist) at the doses employed in this study did not produce behavioral toxicity, antinociception or alter the acute antinociceptive effects of the tested opioid agonists. Consistent with previous reports, pretreatment with MK801 or LY235959 (30 min prior to agonist administration throughout the tolerance regimen) prevented the development of antinociceptive tolerance to i.c.v. or s.c. morphine. Neither NMDA antagonist, however, affected the development of antinociceptive tolerance to i.c.v. fentanyl, DAMGO, or [D-Ala2, Glu4]deltorphin. Additionally, MK801 pretreatment did not affect the development of antinociceptive tolerance to i.c.v. PL017 or to s.c. fentanyl. Further, MK801 pretreatment also did not affect the development of tolerance to the antinociception resulting from a cold-water swim-stress episode, previously shown to be a delta-opioid mediated effect. These data lead to the suggestion that the mechanisms of tolerance to receptor selective mu and delta opioids may be regulated differently from those associated with morphine. Additionally, these findings emphasize that conclusions reached with studies employing morphine cannot always be extended to 'opiates' in general.

Analgesics, Opioid↗