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PubMed2001

GABA(B) receptors play a role in the development of tolerance to ethanol in mice.

RATIONALE: There is evidence that drugs that improve or impair learning can facilitate or block ethanol tolerance, respectively. Since GABA(B) receptors have been shown to be involved in processes related to learning, it is possible that this system could play a role in the development of rapid tolerance to ethanol. OBJECTIVES: The aim of this study was to verify the influence of one GABA(B) agonist and two GABA(B) antagonists on tolerance to the effect of ethanol on motor coordination. METHODS: Male Swiss mice were trained on a continuously accelerating rota-rod device. Animals were pretreated with the GABA(B) agonist (-)-baclofen (3, 5, or 7 mg kg(-1)) or saline, 30 min before ethanol (1.75 g kg(-1)), and were tested 5, 10, and 15 min later on the rota-rod. In another set of experiments, mice were pretreated with the GABA(B) antagonists CGP36742 (1, 3, 10, or 30 mg kg(-1)) or CGP56433 (0.1, 0.3, 1.0, or 3.0 mg kg(-1)), or saline, 30 min before the test under ethanol. Rapid tolerance was evaluated 24 h after the first ethanol injection, by injecting all animals with ethanol and retesting them on the rota-rod. RESULTS: The results showed that (-)-baclofen (5 mg kg(-1)) significantly (ANOVA + Tukey's test) blocked rapid tolerance, whereas CGP36742 (3 and 10 mg kg(-1)) and CGP56433 (0.3, 1, and 3 mg kg(-1)) facilitated rapid tolerance in a dose-dependent way. The blockade of rapid tolerance by (-)-baclofen was antagonized by previous administration of CGP36742 or CGP56433. CONCLUSIONS: The current results suggest that rapid tolerance to ethanol is subjected to inhibition by a GABAergic GABA(B) receptor-mediated system in the mouse.

Animals↗
PubMed2006

Stability of cocaine dose-response functions at different inter-dose intervals.

Past research has found that daily administration of cocaine can lead to tolerance to its behavioral effects, and that tolerance can develop even when the dose is varied from day to day. The present experiment examined effects of administering varied doses of cocaine at a variety of inter-dose intervals ranging from once per week to everyday. Pigeons pecked on a fixed-ratio 20 schedule of reinforcement. A dose-response function for cocaine was assessed eight consecutive times during each of four phases of the experiment to assess the stability of effects of each dose. In Phase 1, subjects were administered a dose of cocaine or saline vehicle every seventh day. One subject developed tolerance by the end of this phase and was not studied further. In Phase 2, doses were administered every fourth day. During Phase 3, doses were administered every 2 days. In the final phase, doses were administered everyday. Dose-response curves were generally similar both within and across phases, regardless of inter-dose interval. No subjects developed tolerance during Phases 2, 3, and 4, suggesting that some aspect of the drug regimen prevented the development of tolerance when cocaine was given frequently.

Animals↗
PubMed1992

One way cross tolerance between cromakalim and salbutamol in the uterus of the rat in vivo.

1. Cross tolerance between the potassium (K+) channel opener, cromakalim and the beta 2-adrenoceptor agonist, salbutamol, was investigated in the uterus of the non-pregnant rat in vivo. Uterine sensitivity to salbutamol was similar in both vehicle-treated and cromakalim-tolerant rats. In salbutamol-tolerant rats, uterine responses to cromakalim were markedly decreased compared with saline-infused rats, such that maximum inhibition of uterine contractions was less than 40%. 2. Propranolol treatment and salbutamol tolerance each produced similar reductions in sensitivity of the uterus to salbutamol of approximately 10 fold. The same dose of propranolol did not influence uterine sensitivity to cromakalim, which suggests that the relaxant action of cromakalim is not due to a direct or indirect activation of uterine beta 2-adrenoceptors. 3. Salbutamol produced a marked (11.7 fold) increase in uterine adenosine 3':5'-cyclic monophosphate (cyclic AMP) concentrations measured ex vivo, which was completely inhibited by propranolol pretreatment, but was unaffected by glibenclamide pretreatment. Cromakalim did not increase uterine cyclic AMP concentrations, suggesting that stimulation of adenylate cyclase is not significant in the uterine relaxant action of cromakalim. 4. The lack of propranolol antagonism of cromakalim and of cromakalim-induced changes in uterine cyclic AMP concentrations suggests that the cross tolerance observed between salbutamol and cromakalim may be at the level of K(+)-channels.

Albuterol↗
PubMed1987

Environmental modification of tolerance to morphine discriminative stimulus properties in rats.

The development of tolerance to the discriminative stimulus properties of morphine was examined in rats trained to discriminate saline and 3.2 mg/kg morphine under a multiple timeout 15 min, 5 min fixed-ratio 30 schedule of food delivery. Generalization gradients were generated by administering increasing doses of morphine before successive timeout periods within the experimental session. Over the course of the study, the minimal discriminable dose (MDD) of morphine under control conditions fluctuated but did not systematically increase or decrease. Acute pretreatments of 3.2-17.8 mg/kg morphine 4-24 h before a generalization test resulted in minor changes in the MDD. To examine development of tolerance, supplemental doses of morphine (17.8 mg/kg) or saline were administered twice daily while discrimination training was either suspended or continued. Tolerance was assessed by weekly generalization tests. Greater tolerance developed to the morphine stimulus when training was suspended than when training was continued. For both training conditions, response rates during generalization tests were markedly suppressed during supplemental morphine administration, and original generalization gradients were recaptured within 2 weeks after termination of supplemental morphine administration. Supplemental saline administration did not alter the discriminative or rate-altering effects of morphine under either training condition. Thus, the magnitude of tolerance to a morphine discriminative stimulus reflected an interaction of supplemental drug treatment with the training conditions imposed during that treatment.

Animals↗
PubMed1979

Interactions between personal expectations and naloxone: effects on tolerance to ischemic pain.

Sixteen healthy subjects participated in an investigation of the interactive effects of naloxone and personal expectations of control, stress, and anxiety, on time tolerance to ischemic pain. Control and anxiety levels provided no significant naloxone-saline discriminations, but there was a significant interaction between stress levels and naloxone-induced reduction in tolerance to ischemia. This finding suggests that activity in the opiate system may be a function of the modifying influences of variable attitudes to environmental stress. A primary analgesic role for the endorphins is challenged, however, by the findings that tolerance levels failed to reveal naloxone reactors and stress levels were not significantly associated with differences in tolerance. The latter, on the other hand, correlated significantly with control and anxiety levels, indicating that further research is needed to clarify the complex relationship between these three variables and their effects on the modulation of pain perception.

Adult↗
PubMed2004

Estrous cycle stage-dependent expression of acute tolerance to morphine analgesia in rats.

Both baseline pain sensitivity and the response to antinociceptive treatment are sensitive to an animal's sex and estrous cycle stage. Sex differences are also observed in the development of antinociceptive tolerance induced by repetitive exposure to opiate drugs such as morphine. Conventional tolerance study protocols do not assess the impact of the estrous cycle stage. The present study aimed to compare the development of acute tolerance to morphine-induced antinociception in male and female (cycling and ovariectomized) Wistar rats using the tail-flick test. Acute tolerance was induced by two consecutive subcutaneous injections of morphine (10 mg/kg) or saline separated by an interval of 6 h. It was found that rats pretreated with morphine were tolerant to the second morphine dose. Tolerance was most pronounced in proestrous female rats and, to a lesser degree, in male rats. It was absent in ovariectomized rats as well as during the estrus, metestrus and diestrus phases. Thus, the estrous cycle exerts dramatic effects on the induction of acute tolerance to morphine-induced antinociception. These results suggest that pain management strategies can be optimized through the use of sex- and estrous cycle-specific techniques.

Analgesics, Opioid↗
PubMed2001

Substance P endopeptidase-like activity is altered in various regions of the rat central nervous system during morphine tolerance and withdrawal.

In this study the level of a substance P endopeptidase (SPE)-like activity was measured in different regions of the rat central nervous system (CNS) after chronic administration of morphine. Male rats (200-220 g) were randomly divided into four groups. Two groups were injected (s.c.) with morphine (10 mg/kg) twice daily, whereas the other two received saline under identical conditions. After 8 days, when animals were completely tolerant to morphine, one of the morphine-treated groups and one group of saline-injected rats were given naloxone (s.c. 2 mg/kg). Withdrawal signs were observed and recorded. The enzyme activity was measured in extracts of the various CNS tissues by following the conversion of synthetic substance P (SP) to its N-terminal fragment SP(1-7) using a radioimmunoassay detecting this product. In discrete CNS areas including periaqueductal grey, spinal cord, substantia nigra and ventral tegmental area (VTA) a significant increase in enzyme activity was observed in the withdrawal group, while tolerant rats exhibited decreased SPE-like activity in the striatum (see Table 1). The enhanced enzyme activity during withdrawal is in agreement with our previous observation that the levels of SP(1-7) in rat brain are affected following naloxone precipitated withdrawal. In some tissues, including VTA, a correlation between the SPE-like activity and the intensity of the opioid abstinence was observed. Our result suggests that the elevated SPE-like activity is responsible for enhanced release of SP(1-7) in rats during morphine withdrawal, affirming a modulatory or regulative role of this enzyme in this state of opioid dependence.

Animals↗
PubMed1987

Gastric emptying, glucose tolerance, and insulin response after duodenojejunostomy.

We investigated the impact of direct jejunal delivery of various meals on gastric emptying, glucose tolerance, and insulin response in a chronic dog model following duodenojejunostomy. Ten beagle dogs underwent duodenal transection 2 cm distal to the pylorus and end-to-side duodenojejunostomy 20 cm distal to the ligament of Treitz. Three months after operation each dog underwent gastric emptying studies using radiolabeled normal saline, 20% glucose solution, and standardized mixed solid meal. Glucose tolerance tests with plasma insulin determinations were obtained using the glucose meal. After duodenojejunostomy both the rapid exponential pattern of emptying of normal saline and the slower linear pattern of glucose emptying seen in intact dogs were preserved. The linear gastric emptying of the solid meal which was slower than gastric emptying of either of the liquid meals was also preserved. Although integrated plasma glucose levels over 2 hr were 484.8 +/- 40.4 and 456.6 +/- 30.4 mg X hr/dl in intact and duodenojejunostomy dogs, respectively (P greater than 0.05), the initial rate of rise of plasma glucose was significantly delayed in the duodenojejunostomy dogs. But integrated plasma insulin levels over 2 hr differed significantly (P less than 0.05) between the intact (71.6 +/- 9.2 microU X hr/nl) and duodenojejunostomy (48.3 +/- 6.2 microU X hr/nl) dogs. We conclude that duodenojejunostomy (jejunal delivery) preserved the patterns of gastric emptying of saline, glucose, and mixed solid meals; retarded initial plasma glucose response to the glucose meal; and blunted plasma insulin response to the glucose load.

Animals↗
PubMed2003

Induction of salt tolerance in Bacillus subtilis IFO 3025.

Salt tolerance was induced in Bacillus subtilis IFO 3025 cells when a moderate osmotic stress was imposed by incubation in the presence of compatible solutes and 0.5 M NaCl or 0.8 M sorbitol. The optimum condition for inducing salt tolerance was observed when the cells were incubated in a solution containing 5 mM glutamate, 2.5 mM KCl, and 0.5 M NaCl or 0.8 M sorbitol. After 60 min incubation, the cells were able to form colonies on an agar plate with high salinity. It was confirmed that the cells acquired salt tolerance by accumulating glutamate and potassium ions in the cytoplasm as the main solute and ion, respectively.

Journal Article↗
PubMed1997

Changes in hypothalamic oxytocin levels during morphine tolerance.

The role of hypothalamic oxytocin neurons in the hypothalamus-pituitary-adrenal (HPA) axis adaptation during opioid tolerance has not been explored. In this study the modification of oxytocin levels in different hypothalamic nuclei was determined after acute or chronic morphine exposure. Male rats were implanted with placebo (naïve) or morphine (tolerant) pellets for 7 days. On day 8, groups of rats received an acute injection of either saline i.p. or morphine (30 mg/kg i.p.) and were sacrificed 30 min later. In morphine-tolerant rats, there was a decrease in the oxytocin content in the median eminence (ME) and in the supraoptic nucleus (SO) after acute injection of saline or morphine. No modifications were seen in the paraventricular nucleus (PVN). The present study demonstrates that chronic morphine administration alters the brain oxytocin system, which suggests that this peptide might contribute to the behavioural, emotional and neuroendocrine responses to opioids.

Animals↗
PubMed2005

[Insulin resistance and effects of intravenous acute saline load on renal production of prostaglandin I2 and thromboxane A2 in salt-sensitive hypertensive patients].

OBJECTIVE: To investigate insulin resistance and the effects of intravenous acute saline load on renal production of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) in salt-sensitive hypertensive patients. METHODS: The 24-hour excretion of urinary 6-keto-prostaglandin F (PGF) 1alpha and thromboxane B(2) were measured before and after intravenous acute saline load in 53 hypertensive patients whose salt sensitivity had been determined. Oral glucose tolerance test and insulin release test were performed in all the subjects. RESULTS: after intravenous acute saline load, the 24-hour excretions of urinary 6-keto PGF 1alpha were significantly lower in salt-sensitive (SS) hypertensive patients than that in non-salt-sensitive (NSS) ones (316+/-57 pg/min vs 371+/-68 pg/min, P<0.01), and the decrease from baseline was much greater in SS group than that in NSS group (197+/-99 pg/min vs 136+/-101 pg/min, P<0.01). Both 24 hour urinary excretion of TXA(2) and the increase in urinary excretion of TXA(2) were significantly greater in SS hypertensive patients than those in NSS ones after salt loading (394+/-32 pg/min vs 359+/-44 pg/min, P<0.01, and 80+/-47 pg/min vs 47+/-45 pg/min, P<0.01, respectively). The plasma glucose and insulin concentrations in every time point were much higher in SS hypertensive subjects than that in NSS ones, and the former group had lower insulin sensitivity index than the latter (0.013+/-0.003 vs 0.018+/-0.004, P<0.01) CONCLUSION: Saline load produces significantly different effects on renal production of PGI(2) and TXA(2) in SS and NSS hypertensive patients, and these changes may be related to the pathophysiology of SS hypertensive patients after acute salt loading. Insulin resistance is greater in SS hypertensive patients than in NSS ones.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

An integrated theory of the no-reflow phenomenon and the beneficial effect of vascular washout on no-reflow.

OBJECTIVES: No-reflow is failure of perfusion in free tissue transfer despite adequate arterial inflow. The objectives of this study were to construct a theory of interactive mechanisms of the no-reflow phenomenon and to determine whether preischemic vascular washout could increase flap ischemia tolerance. STUDY DESIGN: The evidence for the role of various mechanisms in the development of no-reflow is reviewed, and an integrated network proposed. A rat-groin free flap model is used to test preischemic vascular washout with normal saline, heparinized normal saline, lactated Ringer's solution, Tis-U-Sol, and Viaspan. METHODS: The mean ischemia tolerance of this flap without any therapeutic intervention was first determined, using 22 animals. An additional 50 animals were used to compare with the control group the ischemia tolerance of flaps washed out with the above fluids before their ischemic period. RESULTS: The critical ischemia time 50 (time after which half of the flaps are expected to survive and half, die) of the untreated flap is 23.4 hours in this model (P<.05). Flaps washed out with normal saline or lactated Ringer's solution have significantly worse ischemia tolerance (P<.0001). Flaps washed out with Tis-U-Sol or Viaspan behave similarly to the control group (P>.57). Flaps receiving preischemic washout with heparinized normal saline (4,000 units/L) had a significantly better outcome than the control group (P<.027). CONCLUSIONS: Preischemic washout with normal saline, lactated Ringer's solution, or heparinized Tis-U-Sol is detrimental for flap survival after ischemia, Tis-U-Sol- and Viaspan-treated flaps do have ischemia tolerance similar to the control group, and flaps washed out with heparinized normal saline have a survival advantage in this model.

Animals↗
PubMed1997

Characterization of neonatal rat morphine tolerance and dependence.

The administration of morphine and fentanyl by continuous intravenous infusion has been shown to produce analgesic tolerance and physical dependence in human neonates. In animals, daily repeated morphine bolus injections is a common method of inducing neonatal rat tolerance and dependence. Yet this method differs from the intravenous route reported to affect human neonates. Alzet osmotic minipumps were implanted in postnatal day 14 rats to provide a continuous morphine infusion more closely mimicking the clinical picture. Rats remained naive or were infused with saline or morphine (0.7 mg/kg/h) for 72 h. Morphine's antinociceptive potency was similar between naive and saline-infused animals, while morphine-infused animals were tolerant. Gender did not contribute to the degree of tolerance observed. Naloxone precipitated withdrawal in the morphine pump-implanted rats was similar to that reported by others. Thus, minipumps provide a useful model for assessing the tolerance and dependence liability of different opioids.

Analgesics, Opioid↗
PubMedDate not supplied

Are mummy characteristics reliable indicators of diapause and cold tolerance in the parasitoid wasp Aphidius rhopalosiphi (Braconidae, aphidiinae) ?

Many insect species have evolved different overwintering survival strategies such as cold tolerance or diapause. This study investigated the relationship between Aphidius rhopalosiphi mummy colour and cold tolerance and diapause. Mummy colour was insufficient to discriminate diapausing from non-diapausing individuals. This phenotypic character seems to reflect environmental conditions rather than direct developmental time and cocoon thickness (identification criteria of diapause). There is, however, a relationship between cold tolerance and mummy colour. Dark mummies exhibited significantly higher water content, survival at low temperature and lower supercooling point values than pale mummies. Mummy colour in Aphidius rhopalosiphi seems to be a phenotypic indicator of the cold tolerance.

Adaptation, Physiological↗
PubMed2000

Does the formation of lipopolysaccharide tolerance require intact vagal innervation of the liver?

The study was designed to test whether intact vagal innervation of the liver is required for the formation of tolerance to lipopolysaccharide (LPS). Wistar rats were subjected to either denervation of the liver (transection of the hepatic and both celiac branches of the abdominal vagus) or sham surgery. Two weeks later, each rat had an osmotic pump implanted subcutaneously. The pump was filled with either a suspension of Escherichia coli LPS (18 mg/ml) in saline or saline alone. Via a catheter, the pump delivered its content into the right jugular vein at a rate of approximately 0.72 microl/kg/h (approximately 13 microg/kg/h of LPS) over 28 d. On day 25 of the infusion, each animal had another catheter implanted into the left jugular vein. Three days later, each rat was injected with a lethal bolus dose of LPS (15 mg/kg) and had its colonic temperature recorded. The saline-infused sham-operated rats responded to the bolus injection of LPS with hypothermia followed by a fever (mean response magnitude 1.0+/-0.2 degrees C); 91% of the animals died within 24 h. The LPS-primed shams developed marked tolerance: When challenged with a lethal dose of LPS, they exhibited a significantly smaller thermal response (magnitude 0.5 +/- 0.2 degrees C) and none died. No group of the vagotomized animals, whether LPS- or saline-primed, became tolerant: Both groups exhibited similar hypothermic responses to the bolus LPS injection and a substantial mortality rate (40 and 100%, respectively). The study shows that prolonged infusion of low doses of LPS leads to the formation of tolerance and that vagal denervation of the liver by hepato-celiac vagotomy suppresses this process. The mechanisms of vagal control of the formation of LPS tolerance remain speculative.

Animals↗
PubMed2002

Effect of a dose of ethanol on acute tolerance and ethanol consumption in alcohol drinker(UChB) and non-drinker (UChA) rats.

Acute tolerance that develops within minutes of ethanol exposure appears to influence the apparent acute behavioral sensitivity of laboratory animals to ethanol actions. The existence of a correlation between voluntary ethanol consumption and the speed of acquiring acute tolerance has been proposed. In the present paper we investigated the effect of an acute dose of ethanol on tolerance development and on ethanol voluntary consumption in our two selected bred strains, UChA (low ethanol drinker) and UChB (high ethanol drinker) rats. Acute tolerance developed to motor impairment induced by a dose of ethanol of 2.3 g/kg. administered intraperitoneally was evaluated by the tilting plane test. Voluntary ethanol consumption was compared in rats receiving the ethanol dose, to rats receiving a saline intraperitoneal (i.p.) injection. The results show that UChB rats receiving an intoxicating dose of ethanol develop more tolerance and they significantly increased their ethanol consumption compared to the same line that received a saline injection, while no change in acute tolerance and voluntary ethanol consumption were obtained in UChA rats. In conclusion, a possible mechanism by which UChB rats drink high amounts of ethanol appears to be the development of tolerance to the pharmacological effects of ethanol.

Alcohol Drinking↗
PubMed1999

Alteration of spinal protein kinase C expression and kinetics in morphine, but not clonidine, tolerance.

Antinociceptive synergism between spinally administered morphine and clonidine decreases to an additive interaction in morphine- and clonidine-tolerant mice. Spinally administered protein kinase C (PKC) inhibitors also decrease the synergism to addition. To determine whether chronic morphine or clonidine treatment alters spinal PKC activity, the present studies measured PKC activity and expression of PKC isoform proteins in spinal cord cytosol and membrane fractions. Mice were treated for 4 days with either placebo pellets, morphine pellets, s.c. saline, or s.c. clonidine. Morphine pellet-implanted mice were tolerant to morphine-induced tail flick antinociception, but not cross-tolerant to clonidine. Clonidine-pretreated mice were tolerant to clonidine, but not cross-tolerant to morphine. Induction of morphine tolerance produced a 2-fold lower Km value for PKC (8.24 +/- 1.67 microM in placebo pellet vs 4.43 +/- 1.24 microM in morphine pellet) in cytosol, but not membrane fractions from spinal cord. Vmax values were not different. No difference in Km or Vmax values was found between proteins from saline- and clonidine-pretreated animals. Immunoreactive cPKCalpha, betaI, and gamma isoforms decreased 14, 26, and 17%, respectively, in cytosol from morphine-tolerant animals. No difference in PKC isoforms was found in the membranes or in fractions from clonidine-tolerant mice. Morphine tolerance, but not clonidine tolerance, enhanced PKC activity while decreasing protein expression.

Analgesics↗
PubMedDate not supplied

Induction of oral tolerance, in mice, to gum arabic.

As part of a programme of research on the immunological properties of the exudate gums, the capacity of gum arabic to induce immunologic hyporesponsiveness when fed (oral tolerance) has been examined. Inbred mice were fed saline or gum arabic; 1 week later all were systemically immunized with the antigen emulsified in complete Freund's adjuvant. Mice which had been fed the antigen had significant suppression of the humoral (P less than 0.01) and cell mediated (P less than 0.01) immune responses to the antigen. These results demonstrate that although gum arabic is a complex, proteinaceous polysaccharide antigen, it is tolerogenic when an animal encounters it by the natural route, via the gut.

Animals↗