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PubMed1994

Differential expression of activation markers during tolerance induction by superantigens in T-cell receptor (beta-chain) transgenic mice.

To investigate the process of tolerance induction we have developed an in vivo model using TCR beta-chain transgenic mice tolerized with the superantigen staphylococcal enterotoxin B. We have previously demonstrated that tolerized peripheral T cells were anergic when stimulated in vitro with immunogenic peptides, superantigens, mitogens, and immobilized anti-TCR mAb. However, the development of anergy is preceded by an induction phase which produces expansion followed by contraction of the peripheral T cell population presumably due to proliferation and programmed cell death, respectively. The current experiments focus on the induction phase of tolerance. A kinetic functional analysis showed that the inhibition of proliferation was apparent 2-3 days post-tolerization. Interestingly, the inhibition of proliferation correlated with the loss of IL-2R alpha expression, which occurred 2 days post-tolerization following an initial increase in IL-2R alpha expression. In addition, the expression of multiple activation markers including CD44, Ly-6A/E, and very early activation marker H1.2F3 is induced, whereas the expression of CD45RB is decreased during tolerance induction. Elevated expression of Ly-6A/E persists up to 28 days post-tolerization; however, altered expression of the other markers does not persist and near baseline levels of the other markers are noted 7 to 28 days post-tolerization. These results show that tolerance induction is an active process which has functional and phenotypic similarities to antigen-specific immunity. However, tolerance induction in our system differs from immunity in terms of the early loss of IL-2R alpha expression, the persistent increased expression of Ly-6A/E, and the lack of development of CD45RBlo memory-type T cells.

Animals↗
PubMed1996

Modulation of kappa-opioid receptor mediated tolerance in the guinea-pig ileum by chronic co-administration of dihydropyridines.

The influence of the L-type Ca2+ channel modulators nimodipine (a Ca2+ blocker) and BAY K 8644 (a Ca2+ activator) on the expression of tolerance to the inhibitory effects of kappa- and mu-opioid agonists in the guinea-pig ileum from guinea-pigs rendered tolerant to the kappa-opioid receptor agonist U-50,488H was investigated. Tolerance to U-50,488H was induced by its administration (15 mg/kg twice a day) for 4 days. Control groups received saline at the same time schedule. Chronic infusion of guinea-pigs with nimodipine (2 micrograms/microliters/h for 7 days) or BAY K 8644 (0.5 microgram/microliters/h for 7 days), did not cause any modification of the height of contractions induced by electrical stimulation of the myenteric plexus-longitudinal muscle (MPLM) preparation from naïve guinea-pigs. The Ca2+ antagonist nimodipine increases the potency of U-50,488H (selective kappa agonist) to reduce the amplitude of neurogenic contractions of the MPLM strip in naïve animals, whereas the Ca2+ activator BAY K 8644 induced the opposite effect. However, the effect of DAMGO (selective mu agonist) was not modified in guinea-pigs infused with nimodipine or BAY K 8644. Tolerance to the inhibitory effects of both U-50,488H and DAMGO was observed following administration of U-50,488H for 4 days and was revealed as a rightward shift of the concentration-response curves for the two agonists. Chronic infusion of guinea-pigs with nimodipine concurrently with chronic U-50,488H, markedly attenuated the expression of selective tolerance to U-50,488H as well as the cross-tolerance between U-50,488H and DAMGO. By the contrary, the magnitude of tolerance to U-50,488H and to DAMGO was enhanced by concomitant infusion of BAY K 8644. The results suggest that, in the GPI, kappa-opioid receptor may be functionally linked to the dihydropyridine sensitive Ca2+ channel: The blockade of the channel increased whereas its activation reduced the potency of U-50,488H. In chronic experiments, nimodipine prevented the expression of tolerance to U-50,488H and the cross-tolerance between U-50,488H and DAMGO, whereas BAY K 8644 produced the opposite effect. These results suggest that, in the GPI, selective tolerance to kappa-agonist as well as cross-tolerance between kappa- and mu-opioid agonists would involve activation of L-type Ca2+ channels, which could indicate that intracellular Ca2+ may be the final common pathway through which myenteric neurons adapt to the chronic opioid exposure.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

Analysis of the role of drug-predictive environmental stimuli in tolerance to the hypothermic effects of the benzodiazepine midazolam.

The role of classical conditioning processes in the development of tolerance to the hypothermic effects of the short-acting benzodiazepine midazolam was studied in three experiments in rats. The experiments were all designed so that one set of environmental stimuli reliably predicted drug treatments whilst another set of stimuli predicted control (vehicle) treatment. According to the classical conditioning account of tolerance, the degree of tolerance observed should be greater in the presence of drug-predictive stimuli than in their absence, i.e. tolerance should show environmental (context) specificity. A preliminary study was conducted to determine the dose- and time-effect curves for midazolam-induced hypothermia. The results of this study provided essential background data for the design of all the subsequent tolerance studies. In the first tolerance study, it was found that virtually complete tolerance developed to the hypothermic effects of 4 mg/kg (IP) midazolam given on alternate days. However, the observed tolerance was clearly not environmentally specific. Since there is evidence that conditioned tolerance to some drug effects develops most readily if drugs are given at low doses with long inter-injection intervals, a second study was conducted with a lower (1.6 mg/kg IP) dose of midazolam, which was given every 5th day. Despite these procedural changes, the second study indicated that the observed tolerance again did not show context specificity, even though tolerance developed rapidly with the lower dose of a short acting drug which was given infrequently.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Initial sensitivity, acute tolerance and alcohol consumption in Fischer 344 and Long Evans rats.

In separate groups of Fischer 344 and Long Evans rats, initial sensitivity and acute tolerance to ethanol were determined in a jumping test. Sensitivity measurements in each strain were carried out in separate subgroups at ethanol doses of 1.5, 2.0, and 2.5 g/kg IP. Similarly, acute tolerance was measured in different subgroups of each strain using the method of two successive doses of ethanol (2 + 0.4 g/kg; 2 + 0.7 g/kg and 2 + 1.0 g/kg, respectively). After completion of sensitivity and acute tolerance measurement, acute tolerance was then tested in all rats. Based on their acute tolerance values, they were divided into three groups: high, medium, and low. Two weeks after the last acute tolerance test, six rats from each group (i.e., the six highest and six lowest from the high and low acute tolerance groups, respectively, and six from the mid-range of the medium tolerance group) were tested for voluntary ethanol drinking in the limited access model. Long Evans rats had lower initial CNS sensitivity to ethanol-induced impairment of jumping performance than Fischer 344 rats. Long Evans rats also drank significantly more alcohol than the Fischer 344 but there was no significant difference in acute tolerance development between these two strains. Moreover, within each strain the rats differing in acute tolerance development (i.e., high, medium, and low) showed no difference in alcohol consumption. These results suggest that acute tolerance development is not the main determinant of differences in ethanol drinking.

Alcohol Drinking↗
PubMed1998

Effects of NMDA receptor channel blockers, dizocilpine and memantine, on the development of opiate analgesic tolerance induced by repeated morphine exposures or social defeats in mice.

Development of tolerance to opiates involves various neurochemically and pharmacologically distinct processes. For instance, the diversity of opiate tolerance has been suggested by experiments comparing the establishment of diminished response to different effects of opiate agonists. Antagonists acting at N-methyl-D-aspartate (NMDA) receptors has become a very useful tool for studying opiate tolerance mechanisms since these drugs have been shown to retard the development of tolerance to analgesic properties of opiates. The present study compared the ability of two NMDA receptor channel blockers, dizocilpine and memantine, to affect the development of tolerance to morphine analgesia induced by repeated social defeat or by repeated morphine administrations. Male BALB/c mice were assessed for the tail-flick response before and after the defeat in five social confrontations, or before and after repeated morphine injections (20 mg/kg, s.c., once daily for 8 days). Repeated morphine injections were explicitly paired with environmental cues. Socially-defeated as well as morphine-treated mice developed significant tolerance to morphine analgesia. Separate groups of mice were exposed to repeated social confrontations or injections of morphine with each defeat or morphine injection followed by administration of either dizocilpine (0.03-0.3 mg/kg, i.p.) or low-affinity channel blocker memantine (3-30 mg/kg, i.p.). Both dizocilpine and memantine were effective in preventing the development of repeated morphine-induced tolerance to acute morphine analgesia. Treatments with NMDA receptor antagonists that retarded development of non-associative tolerance also suppressed the establishment of associative tolerance significantly. Social defeat-induced tolerance was prevented by dizocilpine but not by memantine. Our results suggest some degree of similarity in the mechanisms of morphine analgesic tolerance induced by pharmacological, contextual and social stimuli.

Analgesics, Opioid↗
PubMed2000

Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice.

The tail-flick test was used to investigate the effects of chronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan, memantine and MRZ 2/579, on the development and reversal of morphine tolerance in mice in three separate experiments. Experiment 1 investigated the effects of NMDA receptor antagonists on the development of tolerance. Morphine (10 mg/kg for 6 days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose-response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance. In experiment 2, in which the effects on the reversal were investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days (between tests 2 and 3) with vehicle+vehicle, NMDA receptor antagonist+vehicle, vehicle+morphine or NMDA receptor antagonist+morphine. Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.

Analgesics, Opioid↗
PubMed2005

Associative and behavioral tolerance to the analgesic effects of nicotine in rats: tail-flick and paw-lick assays.

RATIONALE: Theories of drug tolerance differentiate between associative and behavioral (instrumental) drug tolerance. However, there is little research comparing these two forms of drug tolerance beyond alcohol and morphine. OBJECTIVE: We examined the time course development of associative and behavioral tolerance to the analgesic effects of nicotine. METHODS AND RESULTS: Associative tolerance was investigated by giving independent groups of rats one, five, 15, ten or 20 administrations of nicotine either explicitly paired or unpaired with a distinctive context. Associative tolerance, assessed in the tail flick, developed more rapidly and reached greater magnitude when nicotine and distinctive context were explicitly paired than when they were unpaired. This effect was evidenced after the fifth conditioning session and was maintained through the tenth, 15th, and 20th sessions. Contextual tolerance, assessed in the hot plate, was first evident after ten sessions. However, this effect disappeared safter 15 and 20 sessions. A second study examined the acquisition of behavioral tolerance to the disruptive effects of nicotine on the hot-plate response. Animals that practiced the test response while drugged developed greater tolerance than animals receiving as much nicotine and hot-plate practice but with these two conditions explicitly unpaired. This effect was evident in two different environments but did not generalize to the tail-flick test. CONCLUSIONS: The findings suggest that contextual tolerance to drug effects is test specific, with tail-flick responses depending on cue-associative tolerance processes and hot-plate responses requiring procedures that allow the animal to practice the test response while drugged.

Analgesics↗
PubMed1984

Differential analgesic cross-tolerance to morphine between lipophilic and hydrophilic narcotic agonists.

Mice were rendered tolerant to morphine by the subcutaneous implantation of one 75 mg morphine pellet. Seventy-two hours post-pellet implantation, the animals were evaluated in the tail-flick assay for analgesic tolerance and cross-tolerance to subcutaneously administered morphine, normorphine, methadone, etorphine and intracerebroventricularly administered morphine. With the pellet remaining in situ during testing, there was the expected analgesic tolerance to peripherally administered morphine and analgesic cross-tolerance to normorphine. However, with the pellet in situ during testing, there was a surprising lack of analgesic tolerance to intracerebroventricular administered morphine and no analgesic cross tolerance to peripherally administered etorphine or methadone. In contrast, removal of the morphine pellet 3 hours prior to the analgesic evaluation apparently unmasked the expression of tolerance and cross-tolerance as evidenced by a three fold, parallel shift to the right of the analgesic dose-response curve for subcutaneously administered etorphine and methadone and a seven fold shift to intracerebroventricularly administered morphine. These data emphasize that a more rigorous evaluation of tolerance development methodologies need be explored and support the suggestion that removal of the morphine-inducing pellet prior to analgesic determinations results in a distinct state of "tolerance" quite different from that observed with the pellet remaining in situ during testing.

Analgesics, Opioid↗
PubMed1985

Tolerance to the anticonvulsant action of benzodiazepines. Relationship to decreased receptor density.

Tolerance to the anticonvulsant action of benzodiazepines was studied in rats that had been treated for 4 weeks with 100-150 mg/kg per day of flurazepam. Previous studies had shown that this treatment produced tolerance to motor impairment induced by benzodiazepines and also down-regulation of benzodiazepine receptors in brain, which was seen as a reduced number of binding sites with no change in binding affinity. In the present study, seizures were produced using pentylenetetrazol (PTZ). In rats that had been chronically treated with flurazepam, pretreatment with diazepam was significantly less effective in blocking pentylenetetrazol-induced seizures, thus indicating tolerance. This tolerance could not be explained by a change in sensitivity to pentylenetetrazol resulting from chronic treatment, nor by any differences in levels of active drug in the brain following doses of diazepam. Residual amounts of flurazepam and its active metabolites may have artifactually reduced the apparent degree of tolerance measured 12 hr after the end of chronic treatment, but not at later times. Tolerance to the antipentylenetetrazol action of diazepam was evident up to the fourth day following chronic treatment with flurazepam, but tolerance had largely disappeared a week after chronic treatment. The duration of tolerance was much longer than that reported for tolerance to motor impairment induced by benzodiazepines, and for down-regulation of receptors. These results suggest that different mechanisms or different neural systems must mediate tolerance to these different actions of benzodiazepines. Furthermore, an adaptive reduction in the number of benzodiazepine receptors does not seem to be a likely mechanism for tolerance to the anticonvulsant action of these drugs.

Animals↗
PubMed1987

Cross-tolerance between muscarinic agonists: role of muscarinic receptors.

In order to explore the relationship between response to muscarinic agonists and brain muscarinic receptors, two mouse strains that differ in acute sensitivity (DBA and C3H) were injected chronically with DFP or infused with oxotremorine. Chronic DFP-treated DBA mice were not tolerant to DFP's effects on any measure, but they were cross-tolerant to the effects of oxotremorine on heart rate and body temperature. DFP-treated C3H mice were not tolerant to DFP or cross-tolerant to oxotremorine on any measure. Oxotremorine infusion resulted in tolerance to oxotremorine in both mouse strains, and chronically infused DBA mice were cross-tolerant to DFP on five of the six measures. Oxotremorine-infused C3H mice were cross-tolerant to DFP on two of the measures. These results suggest that genetic factors influence the development of tolerance or cross-tolerance. These genetic factors do not seem to be related to changes in brain QNB binding. Both mouse strains showed comparable changes in QNB binding following chronic DFP and oxotremorine with DFP eliciting reductions in QNB binding in striatum and hippocampus and oxotremorine eliciting reductions in nearly every brain region. However, tolerance and cross-tolerance did not seem to correlate with changes in binding which suggests that the relationship between receptor changes and responses to muscarinic agonists must be examined further.

Animals↗
PubMed1988

Tolerance to minor histocompatibility antigens.

A neonatal tolerance model employing fully allogeneic lymphoid cells as tolerogen was used in an investigation of tolerance to self and donor minor histocompatibility antigens (miHA). Tolerance was assessed by skin grafting and subsequently by the generation of cytotoxic T lymphocytes. Two strain combinations were investigated. In the first, BALB/c-B10, none of the mice became tolerant to H-2d: all gave responses to BALB/c and B10.D2 antigens comparable to uninjected controls. However, tolerance was secured to BALB miHA in the face of reactivity to the original donor cells (i.e., BALB/c), showing that multiple miHA can induce tolerance independently of major histocompatibility complex (MHC) antigens. In the reverse strain combination, in which tolerance to B10 antigens was successfully established in BALB/c recipients, MHC restriction of tolerance to self miHA could not be demonstrated, as mice tolerant to B10 were unresponsive to BALB.B antigens, too. Again, the induction of tolerance to multiple donor miHA proved to be independent of tolerance to donor MHC antigens, and a great deal easier.

Animals↗
PubMedDate not supplied

Comparative effects of Pro-Leu-Gly-NH2 and cyclo(Leu-Gly) administered orally on the development of tolerance to the analgesic effect of morphine in the rat.

Comparative effects of Pro-Leu-Gly-NH2 (MIF) and cyclo(Leu-Gly) (CLG) administered orally at different stages of chronic morphine treatment on the development of tolerance to the analgesic effect of morphine in the rat were determined. Male Sprague-Dawley rats were implanted with either 6 placebo or morphine pellets during a 7-day period. Implantation of morphine pellets resulted in the development of a high degree of tolerance as evidenced by a decrease in the analgesic response to morphine. Administration of CLG (8 and 16 mg/kg/day) on day 5, 6 and 7 of implantation inhibited the development of tolerance to morphine but 4 and 32 mg/kg doses had no effect. Further, CLG (2 mg/kg/day for 7 days) inhibited the development of tolerance but higher doses (4 and 8 mg/kg) had no effect. MIF (26 and 52 mg/kg) administered orally on the last three days of the implantation schedule inhibited the development of tolerance to morphine. MIF (6.5 mg/kg/day for 7 days) inhibited the development of tolerance but the higher doses had no effect. Concurrent administration of MIF (6.5 mg/kg) and CLG (2 mg/kg) for seven days failed to inhibit the development of tolerance. A single dose of MIF or CLG administered a day before the assessment of tolerance did not affect the morphine tolerance. Thus, even after a significant degree of tolerance to morphine had developed, neuropeptides like MIF and CLG given orally, in appropriate doses, can inhibit development of tolerance to morphine and restore the analgesic effect of morphine.

Administration, Oral↗
PubMed2004

Effect of repeated administration of TRK-820, a kappa-opioid receptor agonist, on tolerance to its antinociceptive and sedative actions.

Repeated administration of micro-opioid receptor agonist, morphine induces tolerance not only to the antinociceptive effect but also to other pharmacological effects, resulting in shortened working duration and decreased efficacy. But less is known about kappa-opioid agonist-induced tolerance. The tolerance-development potency of kappa-opioid receptor agonists with a focus on TRK-820 was characterized. After five administrations of kappa-opioid receptor agonists, TRK-820 (0.1-0.8 mg/kg), U-50,488H (10-80 mg/kg) and ICI-199,441 (0.025-0.2 mg/kg) subcutaneously over 3 days, tolerance to the antinociceptive effects, assessed by an acetic acid-induced abdominal constriction test, developed in a repeated dose-dependent manner. The tolerance-development potency of TRK-820 was the least among these kappa-opioid receptor agonists. Similarly, TRK-820 and U-50,488H induced tolerance to their sedative effects as judged by a wheel-running test in mice. Greater tolerance was developed to the sedative effect than to the antinociceptive effect in both compounds. After repeated administration, the number of kappa-opioid receptors in the mouse brain was reduced by U-50,488H (80 mg/kg) but not by TRK-820 (0.4 mg/kg). There was no change of the affinity by the treatment with both compounds. These results demonstrated that the kappa-opioid receptor agonists developed tolerance both to the antinociceptive and the sedative effects, though the tolerance to the sedative effect developed more readily than tolerance to the antinociceptive effect. The difference in the potency for down-regulating the kappa-opioid receptors in the brain may account for the tolerance-development potency of the compounds.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2005

Morphine tolerance does not develop in mice treated with endothelin-A receptor antagonists.

Long-term use of morphine leads to development of antinociceptive tolerance. We provide evidence that central endothelin (ET) mechanisms are involved in development of morphine tolerance. In the present study, we investigated the effect of ET(A) receptor antagonists, BQ123 and BMS182874, on morphine antinociception and tolerance in mice. Mechanism of interaction of ET(A) receptor antagonists with morphine was investigated. BQ123 (3 microg, i.c.v.) and BMS182874 (50 microg, i.c.v.) significantly enhanced antinociceptive effect of morphine (P < 0.05), through an opioid-mediated effect. Treatment with a single dose of BQ123 (3 microg, i.c.v.) reversed tolerance to morphine antinociception in morphine-tolerant mice. BQ123 or BMS182874 did not affect naloxone binding in the brain. Therefore, ET(A) receptor antagonists did not bind directly to opioid receptors. [35S]GTPgammaS binding was stimulated by morphine and ET-1 in non-tolerant mice. Morphine- and ET-1-induced GTP stimulation was significantly lower (P < 0.05) in morphine-tolerant group (33% and 42%, respectively) compared to control group. BQ123 and BMS182874 did not activate binding in non-tolerant mice. BQ123 and BMS182874 significantly increased G protein activation in morphine-tolerant mice (96% and 86%, respectively; P < 0.05). These results provide evidence that uncoupling of G protein occurs in morphine-tolerant mice, and ET(A) antagonists promote coupling of G protein to its receptors, thereby restoring antinociceptive effect. These findings indicate that ET(A) receptor antagonists potentiate morphine antinociception and reverse antinociceptive tolerance in mice, through their ability to couple G proteins to opioid receptors.

Analgesics, Opioid↗
PubMed2004

Aldehyde dehydrogenase, nitric oxide synthase and superoxide in ex vivo nitrate tolerance in rat aorta.

The role of aldehyde dehydrogenase (ALDH) in ex vivo tolerance to transdermal glyceryl trinitrate was explored in rat aorta. ALDH activity, measured by aldehyde-induced NADH formation, was strongly depressed in the tolerant arteries. ALDH inhibitors, chloral hydrate (0.3 mM) and cyanamide (0.1-1 mM) inhibited relaxation to glyceryl trinitrate in non-tolerant and tolerant arteries. The inhibition differed from tolerance in that (a) the glyceryl trinitrate concentration-response curve was sigmoidal cf. biphasic in tolerance, (b) the potentiating effect of nitric oxide synthase (eNOS) inhibition was unchanged cf. increased in tolerance and (c) superoxide inhibited the response cf. no significant effect in tolerant or non-tolerant arteries. Hence, reduced ALDH activity does not account fully for ex vivo tolerance. The discrepancies are consistent with evidence that (a) organic nitrates, unlike chloral and cyanamide, irreversibly inactivate ALDH (hence reduced enzyme saturability can explain the biphasic curve) and (b) eNOS contributes to tolerance by a mechanism independent of glyceryl trinitrate metabolism.

Aldehyde Dehydrogenase↗
PubMed2006

Effects of memantine on estrogen-dependent acute tolerance to the morphine analgesia in female rats.

Both human and animal studies suggest that there are sex differences in responding to noxious stimulation as well as in effects of opiate analgesic drugs. Development and/or expression of tolerance to opiate analgesia are also affected by the hormonal status of the experimental subjects. The present study aimed to compare acute tolerance to morphine in cycling and ovariectomized female rats and to evaluate the effects of N-methyl-D-aspartate (NMDA) receptor channel blocker memantine as well as 17-beta-estradiol on tolerance development using the tail-flick test. Acute tolerance to morphine analgesia was observed as a substantial reduction in the response to a test dose of morphine (10 mg/kg) given 6 h after the tolerance-inducing dose (10 mg/kg). Significant acute tolerance was observed in proestrous female rats and was prevented by memantine (3 or 10 mg/kg) treatment. Ovariectomized rats did not demonstrate tolerance to morphine analgesic effects but chronic estradiol administration (5 microg/day, 5 days) reinstated induction of tolerance. Both estrogen receptor modulator tamoxifen (5 mg/kg/day, 5 days) and memantine (3 mg/kg/day, 5 days) prevented estradiol-induced tolerance in ovariectomized rats. Thus, estrogens were found to play a key role in induction of acute tolerance to morphine antinociception. Estradiol-induced acute morphine tolerance may have NMDA receptor-dependent mechanisms.

Analgesics, Opioid↗
PubMed2003

Endothelial modulation and tolerance development in the vasorelaxant responses to nitrate of rabbit aorta.

We investigated the endothelial modulations in nitrate tolerance in isolated rabbit aorta. Nitrate tolerance was induced by a 72-h treatment with transdermal nitroglycerin (NTG, 0.4 mg/h) in conscious rabbits, which was verified by a 20-fold increase in the EC50 values [NTG tolerance (6.1 +/- 0.8) x 10(-7) M vs control (3.0 +/- 0.6) x 10(-8) M]. The relaxations to NTG in tolerant and nontolerant aortic strips were enhanced when their endothelia were denuded [E(-)]. In the presence of endothelium [E(+)], NTG-tolerant vessels were not tolerant to acetylcholine (ACh), which can release endothelial nitric oxide (NO), exogenous NO or 8-bromo (Br)-cGMP. In NTG-tolerant and nontolerant vessels with endothelium, concentration-response curves for NO were the same as those in endothelium-absent tolerant vessels. In both NTG-tolerant and nontolerant vessels, treatment with superoxide dismutase (SOD, 20 units/ml), an O2-. scavenger, unaffected the responses to NTG reduced in the presence of endothelium, but treatment with NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), an NO synthase (NOS) inhibitor, reversed these reductions. Thus, our data did not indicate that an increased endothelial superoxide O2-. production contributes to nitrate tolerance. Our study suggested that (i) an impaired biotransformation process from NTG to NO is responsible for the occurrence of nitrate tolerance and (ii) vascular response to NTG enhanced by endothelial removal is related to blocked endothelial NO release.

Acetylcholine↗
PubMed2003

Induction of cytokine tolerance requires internalization of Chylomicron-Bound LPS into hepatocytes.

BACKGROUND: Chylomicron-bound LPS (CM-LPS) renders hepatocytes unresponsive to stimulation by proinflammatory cytokines, a process termed cytokine tolerance. We have shown that cytokine tolerance is a time- and dose-dependent process requiring functional low-density lipoprotein receptors (LDLR). Thus, we hypothesized that cytokine tolerance directly correlates with the internalization of CM-LPS complexes, and inhibition of lipoprotein binding and/or internalization inhibits the induction of cytokine tolerance in hepatocytes. MATERIALS AND METHODS: We correlated the rate of internalization of radioiodinated CM-LPS complexes with hepatocellular NO production as a measure of cytokine responsiveness. In additional studies, we used four different strategies to inhibit binding/internalization of CM-LPS via LDLR and then determined the effect of each strategy on the induction of cytokine tolerance. RESULTS: There was a strong inverse correlation between the internalization of CM-LPS and the responsiveness of hepatocytes to proinflammatory cytokines (r(2) = -0.997). Furthermore, the greater the degree of LDLR inhibition, the less susceptible hepatocytes were to the induction of cytokine tolerance by CM-bound LPS. Accordingly, cytokine tolerance induction was inhibited in hepatocytes with decreased membrane expression of LDLR as compared to control cells (69 versus 12% control; P = 0.005). Competitive inhibition of CM-LPS binding prevented internalization of CM-LPS and resulted in loss of the cytokine-tolerant phenotype. Whereas CM-LPS successfully induced cytokine tolerance in ldlr(-/-) hepatocytes, it only occurred after a prolonged pretreatment period of 8 h. CM-LPS complexes containing apolipoprotein (apo) E(2) also required a prolonged pretreatment period to induce a level of cytokine tolerance comparable to that induced by CM-LPS complexes containing either apo E(3) or E(4). CONCLUSION: Lipoprotein-bound LPS inhibits the responsiveness of hepatocytes to proinflammatory cytokines in a manner directly correlated with the internalization of LPS. Furthermore, inhibition of lipoprotein binding/internalization prevents this LPS-mediated induction of cytokine tolerance in rodent hepatocytes.

Animals↗