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PubMed1988

Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians.

Impaired glucose tolerance often presages the development of non-insulin-dependent diabetes mellitus. We have studied insulin action and secretion in 24 Pima Indians before and after the development of impaired glucose tolerance and in 254 other subjects representing the whole spectrum of glucose tolerance, including subjects with overt non-insulin-dependent diabetes. The transition from normal to impaired glucose tolerance was associated with a decrease in glucose uptake during hyperinsulinemia, from 0.018 to 0.016 mmol per minute (from 3.3 to 2.8 mg per kilogram of fat-free body mass per minute) (P less than 0.0003). Mean plasma insulin concentrations increased during an oral glucose-tolerance test, from 1200 to 1770 pmol per liter (from 167 to 247 microU per milliliter). In 151 subjects with normal glucose tolerance, the insulin concentration measured during an oral glucose-tolerance test correlated with the plasma glucose concentration (r = 0.48, P less than or equal to 0.0001). This relation was used to predict an insulin concentration of 1550 pmol per liter (216 microU per milliliter) in subjects with impaired glucose tolerance (actual value, 1590 pmol per liter [222 microU per milliliter]; P not significant), suggesting that these subjects had normal secretion of insulin. In contrast, plasma insulin concentrations in the diabetics decreased as glucose concentrations increased (r = -0.75, P less than or equal to 0.0001), suggesting deficient secretion of insulin. This relative insulin deficiency first appears at the lower end of the second (diabetic) mode seen in population frequency distributions of plasma glucose concentrations. Our data show that impaired glucose tolerance in our study population is primarily due to impaired insulin action. In patients with non-insulin-dependent diabetes mellitus, by contrast, impaired insulin action and insulin secretory failure are both present.

Adult↗

PubMed2002

Does insulin secretion in patients with one abnormal glucose tolerance test value mimic gestational diabetes mellitus?

OBJECTIVE: The purpose of this study was to investigate the insulin response to a 3-hour oral glucose tolerance test and to compare the insulin levels in the gestational diabetes mellitus and single abnormal test value groups with a nondiabetic control group. STUDY DESIGN: One hundred ten Turkish women with uncomplicated pregnancy participated in this prospective controlled study between 24 to 28 weeks of gestation. A 100-g 3-hour oral glucose tolerance test was given, and glucose and insulin plasma levels were assayed. The subjects were classified according to established criteria. Early-phase insulin secretion was assessed by the insulinogenic index. Total insulin secretion was assessed by mean insulin level during the oral glucose tolerance test; insulin resistance was assessed by fasting insulin concentration and by the use of the homeostasis model. Data were analyzed by the Student t test and 1-way analysis of variance, with posthoc Bonferroni correction. RESULTS: The fasting insulin levels of patients with normal oral glucose tolerance test results were significantly lower than those of patients with gestational diabetes mellitus and a single value abnormality (P <.001 and P <.005, respectively). The insulinogenic index as a marker of early-phase insulin secretion was significantly lower in gestational diabetes mellitus, compared with that of patients with normal oral glucose tolerance test results (P <.05). The worsening of glycemic profile from normal oral glucose tolerance test results to gestational diabetes mellitus was associated with an increase in the homeostasis model; no significant difference was found between gestational diabetes mellitus and a single value abnormality group in terms of both the homeostasis model and the insulinogenic index. Values for total insulin secretion were highest in gestational diabetes mellitus, followed by the single value abnormality group, both significantly differing from the values of patients with normal oral glucose tolerance test results (P <.001 and P <.005, respectively). CONCLUSION: In this prospective study of Turkish subjects, we found a striking similarity in terms of patient characteristics between the gestational diabetes mellitus group and the single value abnormality group. Additionally, when we used fasting insulin level and insulin resistance as 2 separate criteria of analysis, patients with single value abnormality were indistinguishable from patients with gestational diabetes mellitus; both groups were significantly different from the normal oral glucose tolerance test group. Our findings suggest that a single abnormal test value on an oral glucose tolerance test should be regarded as a pathologic finding and that the patient with a single abnormal test value may be treated similarly to the patient with gestational diabetes mellitus.

Adult↗

PubMed1999

Ontogeny of T cell tolerance to peripherally expressed antigens.

Transgenic expression of the influenza virus hemagglutinin (HA) in the pancreatic islet beta cells of InsHA mice leads to peripheral tolerance of HA-specific T cells. To examine the onset of tolerance, InsHA mice were immunized with influenza virus A/PR/8 at different ages, and the presence of nontolerant T cells was determined by the induction of autoimmune diabetes. The data revealed a neonatal period wherein T cells were not tolerant and influenza virus infection led to HA-specific beta cell destruction and autoimmune diabetes. The ability to induce autoimmunity gradually waned, such that adult mice were profoundly tolerant to viral HA and were protected from diabetes. Because cross-presentation of islet antigens by professional antigen-presenting cells had been reported to induce peripheral tolerance, the temporal relationship between tolerance induction and activation of HA-specific T cells in the lymph nodes draining the pancreas was examined. In tolerant adult mice, but not in 1-week-old neonates, activation and proliferation of HA-specific CD8(+) T cells occurred in the pancreatic lymph nodes. Thus, lack of tolerance in the perinatal period correlated with lack of activation of antigen-specific CD8(+) T cells. This work provides evidence for the developmental regulation of peripheral tolerance induction.

Aging↗

PubMed2003

Bcl-3 and NFkappaB p50-p50 homodimers act as transcriptional repressors in tolerant CD4+ T cells.

The transcriptional events that control T cell tolerance are still poorly understood. To investigate why tolerant T cells fail to produce interleukin (IL)-2, we analyzed the regulation of NFkappaB-mediated transcription in CD4(+) T cells after tolerance induction in vivo. We demonstrate that a predominance of p50-p50 homodimers binding to the IL-2 promoter kappaB site in tolerant T cells correlated with repression of NFkappaB-driven transcription. Impaired translocation of the p65 subunit in tolerant T cells was a result from reduced activation of IkappaB kinase and poor phosphorylation and degradation of cytosolic IkappaBs. Moreover, tolerant T cells expressed high amounts of the p50 protein. However, the increased expression of p50 could not be explained by activation-induced de novo synthesis of the precursor p105, which was constitutively expressed in tolerant T cells. We also demonstrate the exclusive induction of the IkappaB protein B cell lymphoma 3 (Bcl-3) in tolerant T cells as well as its specific binding to the NFkappaB site. These results suggest that the cellular ratio of NFkappaB dimers, and thus the repression of NFkappaB activity and IL-2 production, are regulated at several levels in tolerant CD4(+) T cells in vivo.

Animals↗

PubMed2003

Possible mechanisms of action in quercetin reversal of morphine tolerance and dependence.

In an earlier study, we reported the ability of quercetin to reverse the development of morphine tolerance and dependence in mice. In the present study we have attempted to explore the possible involvement of nitric oxide (NO) system in quercetin reversal of morphine tolerance and dependence in mice. Co-administration of L-N(G)-nitro arginine methyl ester (L-NAME) or quercetin with morphine during the induction phase (days 1-9) delayed the development of tolerance to the antinociceptive action of morphine and also reversed naloxone precipitated withdrawal jumps. L-Arginine administration during the induction phase enhanced the development of tolerance to the antinociceptive effect of morphine but had no effect on the naloxone-precipitated withdrawal jumps. During the expression phase (day 10) acute administration of quercetin or L-NAME reversed, whereas L-arginine facilitated naloxone- precipitated withdrawal jumps in morphine-tolerant mice, but none of these drugs affected the nociceptive threshold in morphine-tolerant mice. Further, co-administration of quercetin or L-NAME with L-arginine during the induction phase antagonized the latter effects on the development of morphine tolerance. Also, prior administration of quercetin or L-NAME reversed the L-arginine potentiation of nalaxone-precipitated withdrawal jumps in morphine-tolerant mice. The results of the present study suggest that quercetin reversal of morphine tolerance and dependence may involve its ability to suppress nitric oxide synthase (NOS) activity.

Analgesics↗

PubMedDate not supplied

Oral tolerance: therapeutic implications for autoimmune diseases.

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-beta) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy.

Administration, Oral↗

PubMed1960

Passive transfer of tolerance to pyrogenicity of bacterial endotoxin.

The typical febrile response of normal rabbits given bacterial endotoxin intravenously may be modified by prior administration of plasma or, less effectively, serum of endotoxin-tolerant donors. This altered response is characterized by disappearance of the second rise in fever and by a striking reduction in fever index. It thus resembles the course of fever shown by rabbits made tolerant to endotoxin by one or more previous daily doses. This transfer of tolerance by plasma or serum depends critically upon the manner in which tolerance is induced in the donors. The plasma of donor rabbits made tolerant, then given an RES-blocking dose of carbon, still confers tolerance upon normal recipient rabbits. Such donors have lost their tolerance and are highly sensitive to endotoxin at the time their blood is taken. The implications of these findings for endotoxin tolerance and for transfer of this phenomenon are discussed. The evidence is consistent with the hypothesis that both tolerance and its transfer are based upon RES function and are independent of antibody.

Animals↗

PubMed1972

Rapid breaking of tolerance against Escherichia coli lipopolysaccharide in vivo and in vitro.

The breaking of tolerance against the lipopolysaccharide from E. coli 055:B5 was studied. It was found that immune responsiveness recovered very slowly in vivo, tolerance still existing 3 wk after the last tolerizing injection. However, if spleen cells from tolerant mice were transferred into irradiated syngeneic recipients, the tolerant state was readily broken. Spleen cells transferred 3 days after the last tolerance-maintaining dose did not respond, whereas cells transferred on day 5 or 7 responded equally well as normal spleen cells. It was also possible to break tolerance by incubating tolerant spleen cells, which did not respond after transfer, for 20 hr in vitro before transfer into irradiated recipients. The results suggest that there exist reversibly inactivated cells in tolerant animals and that these cells can be reactivated upon removal of the cells to a neutral environment.

Animals↗

PubMed1975

Demonstration of an antibody-mediated tolerance state and its effect on antibody affinity.

We have described a model of immunological tolerance induced, in adult mice, by a single injection of a moderate dose of a hapten-protein conjugate. The data suggest that the mechanism of this tolerance state is the production of small amounts of high affinity antibody in response to the tolerance-inducing antigen injection. This antibody acts to inhibit the response to a subsequent challenge with antigen in complete Freund's adjuvant by a mechanism comparable to that of passive antibody-medicated immune suppression. It was shown that a small but high affinity. Tolerance was not terminated by transfer of normal syngeneic spleen or peritoneal cells into tolerant animals. Spleen cells from tolerant mice, when transferred into lethally irradiated, syngeneic animals, produced a PFC response which is greater in magnitude and tolerance state had a significant degree of carrier specificity which was shown to be comparable to the carrier specificity of antibody-mediated immune suppression. hus, evidence was presented to show that one mechanism of tolerance in adult animals in the suppressive effect of small amounts of high affinity antibody formed in response to the tolerizing injection of antigen.

Animals↗

PubMed1975

The in vitro induction of immunological tolerance in the B lymphocyte by oligovalent thymus-dependent antigens.

B-cell tolerance has been induced by oligovalent thymus-dependent antigens in an entirely in vitro system. Dissociated spleen cells from congenitally athymic (nu/nu) mice were preincubated for 24 h with 0.1 -- 1 mg/ml of either fowl gamma globulin (FGG) of DNP-human gamma globulin (DNP-HGG). After washing, the cells were tested for the ability to mount in vitro, thymus-independent responses against FGG and DNP. A state of specific responsiveness to either FGG or DNP was thus demonstrated. Features of this wholly in vitro system that paralleled previous findings on the in vivo induction of B-cell tolerance in nu/nu mice were the kinetics, 24 h being required for tolerance induction in either case, the abrogation of tolerance induction by the presence of POL both in vivo and in vitro, and finally the observation that in neither case was there a requirement for the antigens to be deaggregated. It was shown that DNP-(Fab) 2 fragments prepared from HGG induced DNP-specific tolerance indicating that the Fc piece was not required for tolerance induction in this in vitro system. DNP-bovine serum albumin was less effective than DNP-HGG or DNP-(Fab)2. Preincubation with subtoxic concentrations of DNP-lysine of DNP-epsilon-capric acid had only a marginal effect on DNP responsiveness. Since nu/nu mice, lacking in detectable T-cell function, were used as spleen cell donors, this work provides further evidence that B-cell tolerance to thymus-dependent antigens can be induced without the participation of T cells. It is suggested that B-cell tolerance to thymus-dependent antigens occurs when the antigen in a sufficient concentration and over a sufficient period of time has direct access to the B cell. This contact with antigen must be in the absence of an additional influence provided either by adjuvants like endotoxin or POL, or by activated macrophages, which may be stimulated by activated T cells; otherwise not tolerance but B-cell activation will occur.

Animals↗

PubMed1983

IgE class-restricted tolerance induced by neonatal administration of soluble or cell-bound IgE.

Induction of IgE class-restricted tolerance was studied in high IgE-responder (BALB/c X SJL)F1 mice, of which the parental BALB/c and SJL mice are high and low IgE-responder mice, respectively. 2,4-Dinitrophenyl (DNP)-specific monoclonal IgE was administered to (BALB/c X SJL)F1 mice neonatally in two forms: soluble IgE at 250 micrograms per injection, or 10-100 ng of IgE coupled to 25-50 X 10(6) syngeneic splenocytes by binding to the chemically reactive hapten trinitrobenzene sulfonate (TNBS) or directly conjugated via a heterobifunctional reagent, N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). Polyclonal induction of IgE class-restricted tolerance was observed in (BALB/c X SJL)F1 mice, neonatally treated with soluble IgE or IgE-conjugated syngeneic splenocytes. Thus these mice failed to mount IgE antibody responses to either keyhole limpet hemocyanin or ovalbumin challenge, assessed by the passive cutaneous anaphylaxis reaction. The IgG antibody responses to these same antigens, however, were not affected by this treatment. The IgE class-restricted tolerance induced by both forms of IgE persisted up to at least 6 mo with repeated antigenic challenges. IgE coupled to syngeneic cells by TNBS or the SPDP method induced prolonged tolerance up to 9 mo. The induction of polyclonal IgE class-restricted tolerance was achieved only by monoclonal IgE, whereas DNP-specific monoclonal IgG1 plus IgG2b coupled to syngeneic splenocytes by the SPDP method failed to modulate either IgE or IgG antibody responses. In contrast, (BALB/c X A/J)F1 mice, of which both parental strains are high IgE responders, developed IgE class-restricted tolerance upon repeated neonatal injection of soluble IgE, but not IgE-conjugated syngeneic splenocytes, indicating that gene products of the low IgE-responder mice contributed to the effective presentation and/or recognition of epsilon heavy chain of the IgE molecules. Taken collectively, these results demonstrated that non-antigen-specific, isotype-restricted tolerance can be induced in the IgE antibody system. The differential induction of IgE class-restricted tolerance by different forms of tolerogen in the strains studied perhaps distinguishes two underlying cellular mechanisms for IgE class-restricted tolerance.

Animals↗

PubMed2001

CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade.

Immune regulatory CD4(+)CD25(+) cells play a vital role in the induction and maintenance of self-tolerance and are essential for T cell homeostasis and the prevention of autoimmunity. Induction of tolerance to allogeneic donor grafts is a clinically desirable goal in bone marrow and solid organ transplantation. To determine whether CD4(+)CD25(+) cells regulate T cell responses to alloantigen and are critical for tolerance induction, murine CD4(+) T cells were tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte-associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to alloantigen in vivo. CD4(+)CD25(+) T cells were found to be potent regulators of alloresponses. Depletion of CD4(+)CD25(+) T cells from the CD4(+) responder population completely abrogated ex vivo tolerance induction to alloantigen as measured by intact responses to alloantigen restimulation in vitro and in vivo. Addback of CD4(+)CD25(+) T cells to CD4(+)CD25(-) cultures restored tolerance induction. These data are the first to indicate that CD4(+)CD25(+) cells are essential for the induction of tolerance to alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.

Abatacept↗

PubMed2004

Compartmentalization of tolerance to endotoxin.

BACKGROUND: Tolerance to endotoxin has been defined and analyzed either entirely in vivo or entirely in vitro. In contrast, the hyporeactivity of circulating leukocytes reported in patients with sepsis, and often referred to as the phenomenon of tolerance to endotoxin, is an ex vivo observation. Therefore, our objective was to set up an ex vivo model of tolerance to endotoxin. METHODS: Mice were injected intravenously with lipopolysaccharide (LPS), and their leukocytes, derived from different compartments, were challenged in vitro with LPS or heat-killed Staphylococcus aureus Cowan I (SAC), for production of tumor necrosis factor (TNF). RESULTS: Production of TNF was observed in in vitro cultures of bronchoalveolar cells, peritoneal cells, splenocytes, and whole-blood samples harvested from mice 1-3 h after injection of LPS. Bone marrow cells, in contrast, did not release TNF. In parallel, cells acquired tolerance to LPS within 1-3 h after in vivo injection of LPS. A dramatic decrease in the production of TNF, in response to LPS, was observed by use of circulating leukocytes, splenocytes, peritoneal cells, and bone marrow cells 24 h after injection of LPS. In contrast, LPS-induced production of TNF by bronchoalveolar cells was far less reduced. The kinetics of acquisition of tolerance and recovery were different for different compartments. Cross-tolerance with SAC did not parallel the phenomenon of tolerance to endotoxin that was observed by use of LPS. CONCLUSION: These data show that tolerance to endotoxin, as monitored by ex vivo analysis, is compartmentalized and that bronchoalveolar cells are less likely than splenocytes, peritoneal cells, and bone marrow cells to develop tolerance to endotoxin.

Animals↗

PubMed2002

Effect of diesel exhaust particle extracts on induction of oral tolerance in mice.

We examined the effect of diesel exhaust particle (DEP) extracts on oral tolerance in mice. For this examination, a single DEP sample was consecutively extracted with hexane (HEX-DEP), benzene (BEN-DEP), dichloromethane (DIC-DEP), methanol (MET-DEP), and 1 M ammonia (AMM-DEP). Residues unextracted (UNE-DEP) with the last extraction solvent 1 M ammonia were also used to test their ability to induce oral tolerance. To immunize mice, hen egg lysozyme (HEL) emulsified with an equal volume of CFA was injected sc (day 0). Oral tolerance was induced by feeding 10 mg HEL on days -5, -4, -3, -2, and -1. DEP, each DEP extract, and UNE-DEP were intranasally administered immediately after each feeding of HEL. The results showed that oral administration of HEL markedly suppressed production of anti-HEL IgG antibodies as well as proliferative responses of spleen cells to HEL. The suppression of anti-HEL IgG antibody production and the cell proliferation by the oral antigen was significantly blocked by DEP, DIC-, AMM-, and UNE-DEP. Neither HEX-, BEN-, nor MET-DEP modulated the orally induced suppression of these immune responses. When the levels of anti-HEL IgG2a antibodies and IFN-gamma (Th1 responses) and anti-HEL IgG1 antibodies and IL-4 (Th2 responses) were determined, DEP and DIC-DEP diminished the suppression of both Th1 and Th2 responses observed following oral administration of HEL. In contrast, UNE- and AMM-DEP prevented the reduction of Th1 but not Th2, and Th2 but not Th1 oral tolerance, respectively. Thus, UNE-DEP appears to contain compounds that block induction of Th1 but not Th2 oral tolerance, whereas AMM-DEP have compounds that abrogate induction of Th2 but not Th1 oral tolerance. DIC-DEP, as well as DEP, appear to contain components that block induction of both Th1 and Th2 oral tolerance. As oral tolerance is thought to play a critical role in preventing Th1 as well as Th2 food allergy, the blockade of oral tolerance by these DEP extracts suggests that DEP may contain compounds different in hydrophobicity associated with the cause of such adverse immunologic responses to food proteins.

Animals↗

PubMed1995

The effect of intrinsic efficacy on opioid tolerance.

BACKGROUND: The intrinsic efficacy of opioid analgesics has been suggested to play a role in the development of tolerance to these agents. However, the effect of differences in dosing protocol on tolerance to opioid analgesics of high or low efficacy has not been addressed. Therefore, the effect of opioid intrinsic efficacy on tolerance in mice was determined in protocols of continuous and intermittent administration of equieffective doses of opioid agonists. METHODS: Initial antinociceptive median effective doses (ED50s) for five opioid agonists that vary in intrinsic efficacy were estimated in untreated mice. Groups of mice received continuous infusions of morphine, fentanyl, or etorphine for 72 h or 7 days from osmotic minipumps implanted subcutaneously. The infusion doses were calculated as multiples of the initial antinociceptive ED50. An inert placebo was implanted subcutaneously in controls. At the end of treatment, the pumps and placebos were removed, and 4-24 h later, mice were tested in dose-response studies (tail flick) using the same drug that had been chronically administered. In another study using intermittent dosing, mice received subcutaneous injections every 24 h for 3 days of saline or morphine, etorphine, fentanyl, oxycodone, or meperidine, or received subcutaneous injections every 24 h for 7 days of saline or morphine, etorphine, or fentanyl. Daily doses were calculated as multiples of the initial antinociceptive ED50. Twenty-four hours after the last injection, mice were tested in dose-response studies. RESULTS: High-intrinsic-efficacy compounds (e.g., etorphine and fentanyl) produced less tolerance than a lower-intrinsic-efficacy drug (morphine) in 72-h and 7-day infusion studies. Tolerance for all compounds after intermittent treatment with equieffective doses was similar, and intrinsic efficacy had no effect on the magnitude of tolerance after intermittent dosing. CONCLUSIONS: These results indicate that the intrinsic efficacy of opioid analgesics is inversely related to the degree of tolerance after continuous infusion, but that intrinsic efficacy does not significantly affect tolerance after once-daily intermittent administration of these agents. These findings may be of clinical utility in understanding the development of tolerance to the antinociceptive effects of opioids.

Animals↗

PubMed1996

Ketamine attenuates and reverses morphine tolerance in rodents.

BACKGROUND: The development of tolerance complicates the use of morphine to manage persistent pain. N-methyl-D-aspartate receptor antagonists can attenuate or reverse morphine tolerance. The authors studied ketamine's ability to modulate morphine tolerance. METHOD: Tolerance was produced in mice given morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after morphine to attenuate the development of tolerance was assessed. The ability of 10 mg/kg ketamine to reverse tolerance produced by the subcutaneous implantation of morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal morphine and the effects of the coadministration of 12 micrograms intraspinal ketamine were assessed. RESULTS: Morphine given subcutaneously produced a fivefold increase in the median effective (ED50) dose of morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED50 produced by morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED50, which was almost completely attenuated by the coadministration of intraspinal ketamine. CONCLUSIONS: Systemically administered ketamine attenuates and reverses systemically induced morphine tolerance in mice, and intraspinal ketamine attenuates tolerance produced by intraspinal morphine in rats.

Analgesia↗

PubMed2000

Effect of antioxidant treatments on nitrate tolerance development in normotensive and hypertensive rats.

OBJECTIVES: To investigate the effect of chronic antioxidant treatments on the development of nitrate tolerance in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats by evaluating (i) coronary vascular reactivity, (ii) lipid peroxidation (malondialdehyde), and (iii) peroxynitrite formation (3-nitrotyrosine). METHODS: Tolerance was induced in 16-week-old male SHR and WKY, by 4 days of continuous treatment with nitroglycerin patches. Two groups were orally pre-treated (2-weeks) with antioxidants: N-acetyl-L-cysteine (NAC) or melatonin. Effects of serotonin (5-HT) and sodium nitroprusside (SNP) perfusion were tested in isolated Langendorff-perfused hearts. 3-Nitrotyrosine levels were measured in coronary sinus effluent and malondialdehyde in plasma. RESULTS: Nitrate tolerance reduced SNP-induced dilation in both strains. This alteration was differently improved by antioxidants: melatonin was effective in SHR, whereas NAC was effective in WKY. Tolerance also reduced 5-HT-mediated vasodilation in WKY, which was reversed by both antioxidants. By contrast, nitrate tolerance enhanced the vasoconstriction to 5-HT in SHR and both antioxidants prevented this response. Furthermore, tolerance was associated with higher malondialdehyde levels in both strains and with higher 3-nitrotyrosine levels in SHR. These changes were reversed by both antioxidants. CONCLUSIONS: A participation of oxidative stress was suggested during nitrate tolerance development, since antioxidants prevented the increase in lipid peroxidation and improved vascular responses to SNP and 5HT. Differential effects of antioxidants on SNP-induced vasodilation in SHR and WKY may suggest distinct mechanisms of tolerance development in hearts from hypertensive and normotensive rats. An increased peroxynitrite generation, expressed by higher 3-nitrotyrosine levels, could contribute to nitrate tolerance in the coronary circulation of SHR.

Acetylcysteine↗

PubMed1991

Endotoxin tolerance differentially alters hemodynamic responses to a thromboxane A2 mimetic and phenylephrine.

Repeated sublethal doses of endotoxin render rats tolerant to lethal doses of endotoxin and reduce thromboxane (Tx) A2 synthesis. Endotoxin-tolerant rats are also more resistant to lethal doses of U46619, a stable TxA2 mimetic. These observations raised the possibility that tolerance may alter hemodynamic responses to TxA2 via one or more mechanisms. Mean arterial pressure (MAP) responses to i.v. injections of the stable TxA2 mimetic U46619 at doses ranging from 0.17 to 8.4 micrograms/kg were determined. Despite an initial lower systemic vascular resistance in tolerant rats compared to control rats (2.4 +/- 0.3 vs 3.1 +/- 0.2 mm Hg/ml/min/100 g of body weight, respectively, p less than 0.05), the maximum pressor response to U46619 was significantly greater (p less than 0.05) at the higher doses of U46619 in tolerant rats compared to control rats. Tolerant and control rats also exhibited qualitatively different changes in MAP in response to U46619. Control rats manifested an initial hypotensive response (15 s) not observed in tolerant rats. In contrast, tolerant rats exhibited no depressor response, but a higher peak pressor response to U46619 than that seen in controls. Since prostaglandins may modulate vascular responses to U46619, subsequent studies were conducted in indomethacin-pretreated or essential fatty acid (EFA) deficient rats that were depleted of arachidonic acid substrate. Either indomethacin or EFA deficiency significantly prevented the initial hypotensive response in control rats, suggesting that prostaglandins may mediate this response to U46619. In additional studies, the MAP response in tolerant and control rats to the alpha 1-adrenergic agonist phenylephrine was determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗