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PubMed2005

Pretransplant donor peripheral blood mononuclear cells infusion induces transplantation tolerance by generating regulatory T cells.

BACKGROUND: It was suggested that maintenance of tolerance to organ transplantation may depend on the formation of T regulatory cells. METHODS: Lewis (LW) rats were made tolerant to a Brown Norway kidney by pretransplant donor peripheral blood mononuclear cells (PBMC) infusion. At greater than 90 days after transplantation, lymph node cells (LN) and graft-infiltrating leukocytes (GIL) alloreactivity was tested in mixed lymphocyte reaction (MLR), coculture, and transwell experiments. GIL phenotype was analyzed by FACS. mRNA expression of cytokines and other markers was analyzed on CD4+ T cells from LN. The tolerogenic potential of tolerant cells in vivo was evaluated by adoptive transfer. RESULTS: Tolerant LN cells showed a reduced proliferation against donor stimulators but a normal anti-third-party alloreactivity. In coculture, these cells inhibited antidonor but not antithird-party reactivity of naïve LN cells. Interleukin (IL)-10 and FasL mRNA expression was up-regulated in tolerant CD4+ T cells, but an anti-IL-10 monoclonal antibody (mAb) only partially reversed their inhibitory effect. Immunoregulatory activity was concentrated in the CD4+ CD25+ T-cell subset. In a transwell system, tolerant T cells inhibited a naïve MLR to a lesser extent than in a standard coculture. Regulatory cells transferred tolerance after infusion into naïve LW recipients. CD4+ T cells isolated from tolerized grafts were hyporesponsive to donor stimulators and suppressed a naïve MLR against donor antigens. CONCLUSIONS: Donor-specific regulatory T cells play a role in tolerance induction by donor PBMC infusion. Regulatory activity is concentrated in the CD4+ CD25+ subset and requires cell-to-cell contact. Regulatory CD4+ T cells accumulate in tolerized kidney grafts where they could exert a protective function against host immune response.

Animals↗
PubMed2001

The thymus and central tolerance.

T-cell differentiation in the thymus generates a peripheral repertoire of mature T cells that mounts strong responses to foreign antigens but is largely unresponsive to self-antigens. This state of specific immunological tolerance to self-components involves both central and peripheral mechanisms. Here we review the process whereby many T cells with potential reactivity for self-antigens are eliminated in the thymus during early T-cell differentiation. This process of central tolerance (negative selection) reflects apoptosis and is a consequence of immature T cells receiving strong intracellular signalling through T-cell receptor (TCR) recognition of peptides bound to major histocompatibility complex (MHC) molecules. Central tolerance occurs mainly in the medullary region of the thymus and depends upon contact with peptide-MHC complexes expressed on bone-marrow-derived antigen-presenting cells (APCs); whether tolerance also occurs in the cortex is still controversial. Tolerance induction requires a combination of TCR ligation and co-stimulatory signals. Co-stimulation reflects interaction between complementary molecules on T cells and APCs and probably involves multiple molecules acting in consort, which may account for why deletion of individual molecules with known or potential co-stimulatory function has little or no effect on central tolerance. The range of self-antigens that induce central tolerance is considerable and, via low-level expression in the thymus, may also include tissue-specific antigens; central tolerance to these latter antigens, however, is likely to be limited to high-affinity T cells, leaving low-affinity cells to escape. Tolerance to alloantigens and the possibility of using central tolerance to promote acceptance of allografts are discussed.

Animals↗
PubMed2004

Induction of systemic tolerance in normal but not in transgenic mice through continuous feeding of ovalbumin.

The ingestion of most dietary protein can cause systemic tolerance, and such tolerance is easier to induce in younger than in older mice. In this study, we examined whether oral tolerance to ovalbumin (OVA) could be induced in OVA-T-cell receptor (OVA-TCR)-specific transgenic mice. Continuous feeding or gavage with OVA induced tolerance, measured as reduced antibody production, in young and aged BALB/c mice, in a dose-dependent manner, but this effect was not observed in transgenic mice. Once BALB/c mice became tolerant, this state was maintained for over 44 weeks, although the tolerant state could be reversed by adoptive cell transfer. DO11.10 mice did not become tolerant upon continuous feeding with OVA, and the adoptive transfer of naïve cells increased the levels of specific antibodies in their sera after antigenic challenge. The immunization schedule used here leads to a Th2-dependent antibody response in normal BALB/c mice. However, the same schedule induced both Th1- and Th2-antibody responses in transgenic mice. Dendritic cells (DC) from tolerant BALB/c mice were less efficient in the induction of the proliferation of cocultured T cells from both BALB/c and DO11.10 mice, as well as Th1 [interleukin (IL)-2 and interferon (IFN)-gamma] and Th2 (IL-4 and IL-10) cytokine production. The DC from DO11.10 transgenic mice were equally efficient in the induction of T-cell proliferation in both normal and transgenic mice, as well as in the induction of Th1 and Th2 cytokines, whether or not the mice consumed OVA. Transforming growth factor (TGF)-beta secretion was significantly lower in the supernatants of T cells from both normal and transgenic mice cocultured with DC from DO11.10 mice that had consumed OVA, while it was significantly higher in the presence of DC from normal tolerant mice, thus implicating TGF-beta as a regulatory cytokine in oral tolerance in the murine model.

Adjuvants, Immunologic↗
PubMed2005

A comparison of urinary albumin excretion rate and microalbuminuria in various glucose tolerance subjects.

AIMS: To investigate the difference of urinary albumin excretion rate (UAER) and microalbuminuria (MAU) in various glucose tolerance subjects, especially between isolated-impaired glucose tolerance subjects and isolated-impaired fasting glycaemia subjects. METHODS: A total of 2934 subjects were divided into five groups with various glucose tolerances, based on a 75-g oral glucose tolerance test. Microalbuminuria was defined when urinary albumin excretion rate was between 20 and 200 microg/min. RESULTS: (i) The UAER in the newly diagnosed Type 2 diabetes mellitus group, impaired glucose tolerance/impaired fasting glycaemia group and isolated-impaired glucose tolerance group were all higher than that in the isolated-impaired fasting glycaemia group and normal glucose tolerance group, but it was comparable between isolated-impaired fasting glycemia group and normal glucose tolerance group. The prevalence of MAU and the odds ratio for MAU with adjustment for age and sex in various glucose tolerance groups showed the same trend as the UAER. (ii) After adjusting for age and sex, there is a significant association between logUAER and independent risk factors (partial correlation coefficients: r = 0.26 for 2-h post-challenge blood glucose, r = 0.26 for systolic blood pressure, r = 0.27 for diastolic blood pressure, r = 0.27 for body mass index and r = -0.13 for high density lipoprotein-cholesterol, all P < 0.001). The risks for MAU were 2-h post-challenge blood glucose, body mass index and diastolic blood pressure, while high density lipoprotein-cholesterol was protective. CONCLUSIONS: The urinary albumin excretion rate and prevalence of microalbuminuria were higher in isolated-impaired glucose tolerance subjects than those in isolated-impaired fasting glycaemia subjects. At early abnormal glucose tolerance stage, the increasing post-challenge glycaemia might be a more important risk factor for urinary albumin excretion rate and microalbuminuria than increasing fasting glycaemia.

Adult↗
PubMed1996

Long-term ethanol and nicotine treatment elicit tolerance to ethanol.

Several previous studies have shown that 1 to 2 weeks of treatment with ethanol elicits tolerance to several effects produced by ethanol and cross-tolerance to nicotine-induced hypothermia. Similarly, short-term, high-dose nicotine treatment produces tolerance to nicotine and cross-tolerance to ethanol-induced hypothermia. In the studies reported here, C57BL/6 mice were force-fed ethanol, nicotine, or an ethanol/nicotine combination in the drinking water for 6 months. All of the chronic drug-treated mice developed tolerance to ethanol as measured by open-field activity, body temperature, and sleep-time tests. Ethanol tolerance is due, in part, to enhanced metabolism and reduced CNS sensitivity in the two ethanol-treated groups but only to reduced CNS sensitivity in the nicotine-treated group. Similar levels of tolerance to nicotine developed in those two groups that were nicotine-treated, but no tolerance to nicotine was seen in those animals treated with ethanol alone. The tolerance to nicotine may be related to an upregulation of brain (cortex, hippocampus, and hypothalamus) [3H]-nicotine binding, but ethanol tolerance is not readily explained by changes in the number of the brain high affinity nicotine binding sites.

Animals↗
PubMed2000

Treatment of experimental colitis by oral tolerance induction: a central role for suppressor lymphocytes.

OBJECTIVE: Inflammatory bowel diseases (IBD) are immune-mediated disorders wherein an imbalance between proinflammatory (Th1) and antiinflammatory (Th2) cytokines is thought to play a role in the pathogenesis. The aim of this study was to test whether induction of oral tolerance to proteins extracted from inflammatory colon alleviates experimental colitis, and whether oral tolerization mediated by suppressor cells can induce immune tolerance. METHODS: Colitis was induced in rats by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Rats received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall. Splenocytes harvested from tolerized and control rats were transplanted into irradiated naive rats. RESULTS: Feeding of colitis-extracted proteins ameliorated colonic inflammation, as shown by reduction of colonic ulcerations, as well as decreased diarrhea, intestine and peritoneal adhesions, wall thickness, and edema. A marked reduction of the fraction of injured colonic area and colon weight, and decrease in colon weight, were observed in tolerized rats versus controls. Histological parameters for colitis were markedly improved in tolerized animals that showed significant reduction in inflammatory response and mucosal ulcerations. Tolerized rats developed an increase in TGFbeta1 and a decrease in IFNgamma serum levels. TNBS-induced colitis was significantly attenuated in naive recipients of splenocytes from tolerized rats, compared with rats that received splenocytes from control donors. CONCLUSIONS: Induction of oral tolerance to colitis-extracted proteins downregulates the anticolon immune response, thereby ameliorating experimental colitis. Suppressor lymphocytes mediate the tolerance by induction of a shift from a proinflammatory to an antiinflammatory immune response.

Administration, Oral↗
PubMed1979

Studies on acute tolerance to ethanol in the abstinence period after long-term barbital treatment in the rat.

Male rats were treated with sodium barbital in the drinking water for 18 weeks. The average weekly dosage was around 215 mg/kg in groups 1, 3 and 5. Groups 2, 4 and 6 were controls. Every week in the abstinence period after the barbital treatment the sensitivity to hexobarbital was tested with a threshold method after three different pretreatments. These pretreatments consisted of saline (groups 1 and 2) and ethanol (2.0 g/kg intraperitoneally) given either 0.25 hr (groups 3 and 4) or 2.5--3 hrs (group 5 and 6) prior to the hexobarbital test. Tolerance seen as a difference in the sensitivity to hexobarbital between groups 1 and 2 (saline pretreatment) were found on day 1, 8, 22 and 36 in the abstinence period. In groups 3 and 4 (tested 0.25 hr after ethanol) a tolerance was found on day 1 and 15. In groups 5 and 6 (tested 2.5--3 hrs after ethanol) a tolerance was only found on day 1. An acute tolerance to ethanol in the controls (seen as a difference between groups 4 and 6) was always recorded. Since tolerance in group 1 was not always accompanied by a tolerance in group 3, an acute tolerance to ethanol is unlikely as an unitary explanation to the tolerance induced by the barbital treatment, which instead seem to be part of much more complex changes. The acute tolerance to ethanol was influenced by the weekly administrations of ethanol used in the tests of the controls (groups 4 and 6) which means that acute tolerance could be one participant in these more complex changes.

Animals↗
PubMed1986

Tolerance to organic nitroesters in experimental animals. An assessment of in vitro and in vivo investigations.

This paper will present a short survey of the literature dealing with nitrate tolerance in experimental animals. Tolerance towards organic nitroesters has been experimentally established in animal models both in vivo and in vitro. However the dose of drug used to provoke tolerance has invariably been very high, which makes it difficult to apply experiences from animal experiments to the clinical setting. Several different hypothesis has been put forward in order to explain the mechanism of tolerance. Today, most evidence seem to point towards an altered metabolism of cGMP as a possible cause of tolerance. Cyclic GMP is the second messenger suggested to mediate the vasodilatory effect of organic nitroesters. The proposed role of critical tissue sulfhydryl groups in mediating the smooth muscle relaxant effect of nitroglycerin (NTG) have made experiments concerning reversal and prevention of tolerance to center on the use of various sulfhydryl reactive compounds. The results of these experiments are as yet ambiguous. Several studies show the existence of cross tolerance between NTG and various other vasodilatory organic nitroesters. In contrast no cross tolerance between NTG and chemically unrelated vasodilator drugs has been observed. The endogenous vasodilators acetylcholine and atrial natriuretic factor are known to induce cGMP increases. In view of this, their effect on NTG-tolerant bovine mesenteric arteries was investigated. However no cross-tolerance appears to exist under in vitro conditions.

Animals↗
PubMed1999

Cholecystokinin receptor mechanism(s) and morphine tolerance in mice.

In a previous work, the effects of cholecystokinin receptor agonists on tolerance to morphine antinociception were evaluated. In the present study, the influence of cholecystokinin antagonists on the inhibition of tolerance to morphine antinociception by cholecystokinin agonists has been investigated. Maximum tolerance to morphine antinociception was obtained by morphine administration (50 mg/kg) to mice once daily for 4 days. The cholecystokinin receptor agonists caerulein (0.005 mg/kg) or cholecystokinin-8 (0.01 mg/kg) but not unsulfated cholecystokinin-8 (0.01 mg/kg) decreased the development of tolerance to morphine (9 mg/kg). The cholecystokininA receptor antagonist MK-329 (1 mg/kg) or the cholecystokininB receptor antagonist L-365,260 (0.25, 0.5 and 1 mg/kg) also diminished the tolerance to morphine antinociception. When animals were challenged with different doses of MK-329 (0.25, 0.5 and 1 mg/kg) against cholecystokinin-8 (0.01 mg/kg), caerulein (0.005 mg/kg) or unsulfated cholecystokinin-8 (0.01 mg/kg) on day 4 in tolerant mice, different response were obtained. Higher doses of MK-329 (1 mg/kg) caused a small decrease in attenuation of the morphine tolerance induced by cholecystokinin-8 and caerulein. Low doses of L-365, 260 diminished the effect of cholecystokinin-8 on morphine tolerance. Conversely high doses of the drug potentiated the response of caerulein (0.005 mg/kg). When animals were treated with MK-329 or L-365,260 before unsulfated cholecystokinin-8, reduction of the tolerance to morphine antinociception was obtained. These data indicate that both cholecystokinin receptors may modulate morphine tolerance.

Animals↗
PubMed1982

The induction of tolerance to allergenic chemicals.

The first recognition of tolerance and partial tolerance to attempted sensitization with simple allergenic chemicals is described. A proper designation would be the Frei-Sulzbeger-Chase phenomenon. Coupling with self occurs in these experiments; there is not only resistance to developing contactant-type sensitivity but also to synthesis of immunoglobulins toward hapten-self complexes. The onset of tolerance is initiated by small doses of haptens. Various facets of these investigations speak strongly against a concept of clonal deletion as an explanation. The concept of the relative numbers of suppressor and effector cells also argues against clonal deletion. Evidence exists that tolerance can be transferred to syngeneic animals by cells during parabiosis (Polak, this volume). Contact sensitivity can be imposed on a tolerized guinea pig through a transfer of cells from outbred sensitized donors, but the tolerance remains after the transferred cells have been rejected. Tolerance could not be overcome in inbred guinea pigs by infusing normal or functionally "labeled" cell populations from close relatives before attempting sensitization, a fact that supports the existence of overwhelmingly large numbers of suppressor cells. Various routes of application have been explored to find a way to establish the tolerant state. The most successful are (1) feeding of small doses and (2) two intravenous injections of massive doses of DNP- or TNP-benzene sulfonates. Several other methods will effect tolerance in about half the animals, but experimental sensitization is the only method that will locate the tolerized animals.

Allergens↗
PubMed1963

ENDOTOXIN-INDUCED TOLERANCE TO TOXIC MANIFESTATIONS OF CANDIDA ALBICANS.

Hasenclever, H. F. (National Institutes of Health, Bethesda, Md.) and William O. Mitchell. Endotoxin-induced tolerance to toxic manifestations of Candida albicans. J. Bacteriol. 85:1088-1093. 1963.-Mice exposed to 425 r total body irradiation failed to become tolerant to Candida albicans toxicity after injection with lipopolysaccharide. Mice injected with lipopolysaccharide and then X-rayed did not demonstrate the tolerant state. An injection of thorium dioxide in mice that had previously received tolerance-inducing amounts of lipopolysaccharide rendered them as susceptible to acute C. albicans toxicity as control mice. A bimodal manifestation of tolerance was noted. Groups of mice given single injections of lipopolysaccharide at 6 or 1 days before challenge demonstrated high levels of tolerance, whereas the tolerance in mice given a single dose at 3 days was negligible. The bimodal effect was not observed in tolerant mice challenged with lipopolysaccharide. Injections of viable or nonviable pathogenic fungi known to produce tolerance to the toxicity of C. albicans in recipient mice did not produce tolerance to lipopolysaccharide. Serum from mice injected with lipopolysaccharide showed in vitro inhibitory activity for C. albicans.

Animals↗
PubMed2004

CD40/CD154 interactions at the interface of tolerance and immunity.

Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that alpha CD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of alpha CD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.

Animals↗
PubMed2005

Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance?

Opiates are the primary treatment for pain management in cancer patients reporting moderate to severe pain, and are being increasingly used for non-cancer chronic pain. However, prolonged administration of opiates is associated with significant problems including the development of antinociceptive tolerance, wherein higher doses of the drug are required over time to elicit the same amount of analgesia. High doses of opiates result in serious side effects such as constipation, nausea, vomiting, dizziness, somnolence, and impairment of mental alertness. In addition, sustained exposure to morphine has been shown to result in paradoxical pain in regions unaffected by the initial pain complaint, and which may also result in dose escalation, i.e. 'analgesic tolerance'. A concept that has been gaining considerable experimental validation is that prolonged use of opioids elicits paradoxical, abnormal pain. This enhanced pain state requires additional opioids to maintain a constant level of antinociception, and consequently may be interpreted as antinociceptive tolerance. Many substances have been shown to block or reverse antinociceptive tolerance. A non-inclusive list of examples of substances reported to block or reverse opioid antinociceptive tolerance include: substance P receptor (NK-1) antagonists, calcitonin gene-related peptide (CGRP) receptor antagonists, nitric oxide (NO) synthase inhibitors, calcium channel blockers, cyclooxygenase (COX) inhibitors, protein kinase C inhibitors, competitive and non-competitive antagonists of the NMDA (N-methyl-D-aspartate) receptor, AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) antagonists, anti-dynorphin antiserum, and cholecystokinin (CCK) receptor antagonists. Without exception, these substances are also antagonists of pain-enhancing agents. Prolonged opiate administration indeed induces upregulation of substance P (SP) and calcitonin gene-related peptide (CGRP) within sensory fibers in vivo, and this is accompanied by an enhanced release of excitatory neurotransmitters and neuropeptides from primary afferent fibers upon stimulation. The enhanced evoked release of neuropeptides is correlated with the onset of abnormal pain states and opioid antinociceptive tolerance. Importantly, the descending pain modulatory pathway from the brainstem rostral ventromedial medulla (RVM) via the dorsolateral funiculus (DLF) is critical for maintaining the changes observed in the spinal cord, abnormal pain states and antinociceptive tolerance, because animals with lesion of the DLF did not show enhanced evoked neuropeptide release, or develop abnormal pain or antinociceptive tolerance upon sustained exposure to opiates. Microinjection of either lidocaine or a CCK antagonist into the RVM blocked both thermal and touch hypersensitivity as well as antinociceptive tolerance. Thus, prolonged opioid exposure enhances a descending pain facilitatory pathway from the RVM that is mediated at least in part by CCK activity and is essential for the maintenance of antinociceptive tolerance.

Animals↗
PubMed2006

Additive effect of dextromethorphan on the inhibitory effect of anti-NT4 on morphine tolerance.

It has been proposed that opioid tolerance is a model of neuronal plasticity similar to learning and memory. Recent evidence suggests that neurotrophins may be involved in synaptic development and plasticity. Observations indicate that neurotrophin 4 (NT4) is required for the synaptic plasticity mediating both tolerance and memory. Also there are lines of evidence to indicate that NMDA receptors are involved in the neural plasticity underlying the development of opiate tolerance. Neurotrophins affect central transmission postsynaptically by enhancing NMDA receptor responsiveness. So we used the clinically available NMDA receptor antagonist, dextromethorphan, and the neurotrophin 4 antibody, anti-NT4, concomitantly and alone to investigate their effects on morphine tolerance. Tolerance was induced by injecting morphine (7 and 10 mg/kg i.p.) once per day for 4 days. Anti-NT4 (1 microg/rat i.c.v.) was administered 15 min before morphine. Results showed that chronic concomitant treatment of anti-NT4 with morphine in both doses inhibited the development of morphine tolerance. Also acute treatment of anti-NT4 significantly reversed the tolerance that was induced by morphine 7 mg/kg but failed to reverse the tolerance of morphine 10 mg/kg. Dextromethorphan in both doses (10 or 30 mg/kg) has an additive effect on the inhibitory effect of anti-NT4 on the reversal of morphine tolerance (7 mg/kg). These findings provide additional support for the hypothesis that NMDA receptor and NT4 may be involved in neural plasticity underlying opiate tolerance.

Analgesics, Opioid↗
PubMed2004

Molecular mechanisms of endotoxin tolerance.

The phenomenon of endotoxin tolerance has been widely investigated, but to date, the molecular mechanisms of endotoxin tolerance remain to be resolved clearly. The discovery of the Toll-like receptor (TLR) family as the major receptors for lipopolysaccharide (LPS) and other bacterial products has prompted a resurgence of interest in endotoxin tolerance mechanisms. Changes of cell surface molecules, signaling proteins, pro-inflammatory and anti-inflammatory cytokines and other mediators have been examined. During tolerance expression of LPS-binding protein (LBP), CD14, myeloid differentiation protein-2 (MD-2) and TLR2 are unchanged or up-regulated, whereas TLR4 is transiently suppressed or unchanged. Proximal post-receptor signaling proteins that are altered in tolerance include augmented degradation of interleukin-1 receptor-associated kinase (IRAK), and decreased TLR4-myeloid differentiation factor 88 (MyD88) and IRAK-MyD88 association. Tolerance has also been shown to be associated with decreased Gi protein content and activity, decreased protein kinase C (PKC) activity, reduction in mitogen-activated protein kinase (MAP kinase) activity, and reduced activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB) induced gene transactivation. However, not all signaling proteins and pathways are suppressed in tolerance and induction of specific anti-inflammatory proteins and signaling pathways may serve important counter inflammatory functions. The latter include induction of IRAK-M and suppressor of cytokine-signaling-1 (SOCS-1), phosphoinositide-3-kinase (PI3K) signaling, and increased or maintained expression of inhibitor-kappaB (IkappaB) isoforms. Also at the nuclear level, increase in the NF-kappaB subunit p50 homodimer expression and increased activation of peroxisome-proliferator-activated receptors-gamma (PPARgamma) have been linked to tolerance phenotype. Although there are species and cellular variations in manifestation of the LPS tolerant phenotype, it is clear that the tolerance phenomena have evolved as a complex orchestrated counter regulatory response to inflammation.

Animals↗
PubMed2006

Mitochondrial oxidative stress and nitrate tolerance--comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/- mice.

BACKGROUND: Chronic therapy with nitroglycerin (GTN) results in a rapid development of nitrate tolerance which is associated with an increased production of reactive oxygen species (ROS). According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) play an important role for the development of nitrate and cross-tolerance. METHODS: Tolerance was induced by infusion of wild type (WT) and heterozygous manganese superoxide dismutase mice (Mn-SOD+/-) with ethanolic solution of GTN (12.5 mug/min/kg for 4 d). For comparison, the tolerance-free pentaerithrityl tetranitrate (PETN, 17.5 mug/min/kg for 4 d) was infused in DMSO. Vascular reactivity was measured by isometric tension studies of isolated aortic rings. ROS formation and aldehyde dehydrogenase (ALDH-2) activity was measured in isolated heart mitochondria. RESULTS: Chronic GTN infusion lead to impaired vascular responses to GTN and acetylcholine (ACh), increased the ROS formation in mitochondria and decreased ALDH-2 activity in Mn-SOD+/- mice. In contrast, PETN infusion did not increase mitochondrial ROS formation, did not decrease ALDH-2 activity and accordingly did not lead to tolerance and cross-tolerance in Mn-SOD+/- mice. PETN but not GTN increased heme oxygenase-1 mRNA in EA.hy 926 cells and bilirubin efficiently scavenged GTN-derived ROS. CONCLUSION: Chronic GTN infusion stimulates mitochondrial ROS production which is an important mechanism leading to tolerance and cross-tolerance. The tetranitrate PETN is devoid of mitochondrial oxidative stress induction and according to the present animal study as well as numerous previous clinical studies can be used without limitations due to tolerance and cross-tolerance.

Acetylcholine↗
PubMed1986

[Pharmacological action of eptazocine (l-1,4-dimethyl-10-hydroxy-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benz azonine). (V). A comparison of eptazocine, pentazocine and morphine with regard to ability of tolerance development after successive administration].

It was investigated whether tolerance to the pharmacological actions and cross-tolerance between eptazocine and pentazocine/morphine were developed by successive administration of eptazocine. In the experiments of mice, successive administration of eptazocine failed to decrease the pharmacological actions of eptazocine on the acetic acid-induced writhing, the pressure and the wheel cage methods. Cross-tolerance between eptazocine and pentazocine/morphine was not observed. Tolerance to the actions of pentazocine and morphine was developed on the wheel cage and the acetic acid-induced writhing/pressure methods, respectively. Cross-tolerance between pentazocine and morphine was also developed on the pressure method. On the tail flick method of rats, tolerance to the action of eptazocine was observed, similar to morphine, but not cross-tolerance between eptazocine and morphine. These results suggest that there is species difference between mice and rats with regard to the ability of tolerance development and that the mechanisms of tolerance development between eptazocine and pentazocine/morphine may be different since eptazocine failed to show cross tolerance to these analgesics.

Analgesics↗
PubMed2003

Fluoxetine suppresses morphine tolerance and dependence: modulation of NO-cGMP/DA/serotoninergic pathways.

Although the phenomenon of opioid tolerance and dependence has been widely investigated, neither opioid nor non-opioid mechanisms are completely understood. In view of the modulation of 5-HT transport into presynaptic terminals in the brain by nitric oxide (NO) via cGMP, and the existence of a tonic 5-HTergic inhibition of dopamine release, the present study investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor, and NO modulators L-N(G)-nitroarginine methyl ester (L-NAME; NO synthase inhibitor) and L-Arginine (substrate for nitric oxide synthase) alone or in combination against morphine tolerance and dependence. Animals developed tolerance to the antinociceptive effect of morphine (10 mg/kg s.c. twice daily) on day 3 and the degree of tolerance was further enhanced on days 9 and 10. The development of tolerance to the antinociceptive effect of morphine was delayed by prior administration of fluoxetine (10 mg/kg i.p, twice daily for 9 days) and L-NAME (10 mg/kg i.p. twice daily for 9 days) alone or in combination. It was accentuated by L-Arginine (50 mg/kg i.p. twice daily for 9 days) alone or in combination with fluoxetine (10 mg/kg i.p. twice daily for 9 days). Similarly, fluoxetine (10 mg/kg i.p.) or L-NAME (10 mg/kg i.p.), when administered acutely on day 10, reversed morphine-induced tolerance. L-Arginine (50 mg/kg i.p.) however, when administered acutely on day 10, accentuated morphine tolerance. Fluoxetine (10 mg/kg i.p. twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg i.p.)-precipitated withdrawal jumps. This suppression of dependence was potentiated by L-NAME (10 mg/kg i.p. twice daily for 9 days) and reversed by L-Arginine (50 mg/kg i.p. twice daily for 9 days), respectively. Acute administration of the respective drugs on day 10 modulated morphine dependence in a similar fashion. L-Arginine also reversed fluoxetine-induced weight loss in morphine-dependent animals. The present study demonstrated that fluoxetine suppressed the dependence and development of tolerance to the antinociceptive effect of morphine. Fluoxetine-induced suppression was potentiated by L-NAME and accentuated by L-Arginine. The results therefore suggest that a complex phenomenon such as morphine tolerance and dependence might involve close interplay of the NO-c GMP/5-HT/DA receptor system. To the best of the authors' knowledge, this is the first report to suggest targeting this cascade for amelioration of opioid tolerance and withdrawal syndrome.

Animals↗