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Ontogenetic studies of tolerance development: effects of chronic morphine on the hypothalamic-pituitary-adrenal axis.

Endogenous opiates are important regulators of the hypothalamic-pituitary-adrenal (HPA) axis in rats. Tolerance clearly develops to morphine-induced stimulation of the HPA axis in adult rats (Ignar and Kuhn 1990). The goal of the present study was to determine whether tolerance to morphine-induced stimulation of the HPA axis developed in neonatal and weanling rats treated chronically with morphine. Rats were injected with morphine or saline between days 4-8 postnatal (pups) or days 21-25 (weanlings) and tolerance assessed by determining dose-response curves for ACTH and corticosterone secretion following an acute morphine challenge. Weanlings displayed marked tolerance to the stimulation of ACTH and corticosterone secretion by morphine. Tolerance was also observed in pups to morphine-stimulated ACTH and corticosterone release. These findings suggest that the relative adaptability of the HPA axis to chronic morphine in neonatal and weanling rats is similar.

Adrenocorticotropic Hormone↗

[Studies of salt tolerance of alloplasmic wheat].

Using Aegilops crassa cytoplasm wheat as test material, salt tolerance of alloplasmic wheat was identified by tissue culture, nutrient solution culture and artificial saline pond, from calli, seeding stage, recovering stage and mature period. The results showed Ae. crassa cytoplasm lines indicated the difference of salt tolerance in varying degree; the difference of cytoplasm effect among different nucleoplasm combinations showed certain nucleoplasm interaction relation. The salt tolerance of (Ae. crassa)-jian 26 was stronger than that other tested alloplasmic lines. The result demonstrated that at recovering date and at mature period indicated salt tolerance of alloplasmic lines was not only stronger than its nuclear parent but also over control variety. As compared with common wheat, lines having strong salt tolerance were more proportions in tested alloplasmic lines. The study of alloplasmic wheat should be significant for breeding salt tolerance wheat.

Cytoplasm↗

Differentiation of opiate receptors in the brain by the selective development of tolerance.

The selective development to either the delta-opiate receptor agonist D-Ala2,D-Leu5-enkephalin (DADL) or the mu-agonist sufentanyl (SUF) has been studied in the central nervous system of rats by use of osmotic minipumps for chronic administration of the drugs. The opiate-sensitive parameters analgesia and catatonia were investigated. Chronic intracerebroventricular infusion of DADL for 7 days produced a 15-fold shift in that for catatonia. In these rats, the potency of SUF in inducing analgesia and catatonia did not differ between DADL-treated animals and saline-infused controls. Similarly, chronic infusion of SUF resulted in tolerance towards SUF for both analgesia and catatonia. In these animals, DADL displayed a similar degree of tolerance w.r.t. its ability to evoke analgesia, whilst no tolerance could be detected for DADL-induced catatonia. The data indicate that prolonged stimulation of specific opiate receptors in the brain by selective agonists may bring about the selective development of tolerance for particular receptors. The data conflict with the notion that mu-receptors specifically mediate analgesia and delta-receptors catatonia.

Animals↗

Behavioral analysis indicates benzodiazepine-tolerance mediated by the benzodiazepine binding-site at the GABA(A)-receptor.

1. GABA(A)-receptor induced changes in locomotion and anxiety-like behaviors were studied in rats using an open-field and an elevated plus-maze. Acute and chronic doses of the benzodiazepine diazepam without and in combination with the GABA uptake inhibitor SKF-89976A were investigated. 2. Fifty-six male rats of the strain PVG/OlaHsd (PVG; 180-200 g body wt) were used to assess the influence of the benzodiazepine binding-site to the development of tolerance. Rats were divided into six groups: The first receiving saline (0.9%), the second and third diazepam (10.0 mg/kg) daily for 23 days with or without an acute challenge of 2.0 mg/kg diazepam. The fourth group received diazepam (10.0 mg/kg) daily and acutely SKF-89976A (15.0 mg/kg) plus diazepam and the fifth and sixth group received acute treatment with diazepam (2.0 mg/kg) or SKF-89976A (15.0 mg/kg). 3. Under chronic treatment with diazepam the animals became tolerant to acute doses of diazepam in activity and anxiety-related behaviors. Acute treatment with SKF-89976A increased exploration. Parameters expressing anxiolytic-like behaviors were increased, too, but not all of them significantly. In diazepam tolerant animals SKF-89976A produced anxiolytic-like behaviors 4. We conclude that the BZ- and not the GABA-binding site at the GABA(A)-receptor is involved in the development of BZ-tolerance.

Animals↗

The effect of glucagon-like peptide I (GLP-I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones.

Glucagon-like peptide I (GLP-I) decreases plasma glucose in type II diabetic patients and in healthy subjects indirectly by stimulation of insulin and inhibition of glucagon secretion, whereby the hepatic glucose production decreases. However, recent studies indicate that GLP-I may also directly influence peripheral and hepatic glucose uptake. We infused somatostatin (SS) intravenously (500 or 1,000 microgram/h) in 13 healthy subjects to suppress insulin and glucagon secretion from the endocrine pancreas, together with infusion of either GLP-I (50 pmol / kg / h) or saline intravenously. After 30 min, a 25-g intravenous glucose tolerance test (IVGTT) was carried out, and plasma concentrations of glucose, insulin, glucagon, and GLP-I were measured during the following 2 h. IVGTT together with GLP-I infusion significantly elevated insulin during 500 microgram/h SS but not during 1,000 microgram/h SS. Plasma glucagon was strongly depressed in all experiments. During 500 microgram/h SS, the glucose disappearance constant, Kg, was 0.49 +/- 0.03% per minute with GLP-I and 0.39 +/- 0.04% per minute with saline (n = 8, P = 0.004). With 1,000 microgram/h SS, Kg was 0.42 +/- 0.03% per minute with GLP-I and 0.40 +/- 0.03% per minute without (NS). In conclusion, when endogenous insulin secretion is held at a constant low level, which may be accomplished only with very large doses of SS, GLP-I has no effect on glucose elimination. Thus, an insulin-independent effect of GLP-I on glucose disposal could not be demonstrated.

Adult↗

Effects of poly (ADP-ribose) synthetase inhibitor on B-cells of a canine pancreas after massive pancreatectomy.

Nicotinamide, a poly (ADP-ribose) synthetase inhibitor, was administered intravenously to massive pancreatectomized dogs (NA group), whereas saline was administered intravenously to massive pancreatectomized dogs (saline group). Stathmokinetic studies were done to clarify the regenerating activities of B-cells. Nicotinamide significantly increased mitotic indices of B-cells after pancreatectomy (p less than 0.01). On the second day after pancreatectomy, mitotic index of B-cells in the NA group (2.00 +/- 0.20%) was higher than that in the saline group (0.25 +/- 0.10%). Though insulin content of pancreatic tissue decreased 2 d after pancreatectomy in the both groups, recovery of insulin content was significantly more immediate and more sufficient in the NA group. Intravenous glucose tolerance tests showed a significantly greater increase of insulin release on the 31st and 62nd day after pancreatectomy, and better glucose tolerance on the 62nd day in the NA group compared with the saline group. These results are considered to be attributed to the regenerating and protecting effects of nicotinamide on B-cells after pancreatectomy, and suggest a clinical value of nicotinamide also in man, especially for Sandmeyer's diabetes.

Animals↗

Blockade of morphine-induced analgesia and tolerance in mice by MK-801.

The effect of MK-801 on morphine-induced analgesia, tolerance and opioid binding sites was examined in mice. In analgesia studies, mice received either naloxone or MK-801. Controls were injected with saline. Mice were then injected with morphine 10 or 30 min following naloxone or MK-801, respectively, and tested for analgesia (tail flick assay) 45 min later. Pretreatment with naloxone or MK-801 blocked morphine-induced analgesia. In tolerance studies, mice were pretreated with either saline or MK-801. Thirty minutes later, mice were injected with either saline or morphine (acutely or chronically) and tested for analgesia 24 h later. Pretreatment with MK-801 partially or completely blocked the development of acute and chronic tolerance, respectively. In binding studies, MK-801 displaced [3H]naloxone poorly compared to naloxone or morphine. Together, these data suggest a role for NMDA receptors in morphine-induced analgesia and tolerance. The poor inhibition of the [3H]naloxone binding sites by MK-801 supports the possibility that MK-801 might not act directly on the opioid receptors, but rather, inhibits morphine-induced analgesia and tolerance by some other mechanisms.

Analgesia↗

Cocaine tolerance and cross-tolerance.

Pharmacological mechanisms by which tolerance develops to the behavioral effects of cocaine were assessed by examining cross-tolerance to specific drugs. Daily experimental sessions were conducted in which rats were trained to press a key under a fixed-ratio 30-response schedule of food reinforcement (each 30th response produced food). Each of the drugs studied decreased rates of responding before initiating daily (10 mg/kg, i.p.) treatment with cocaine. Treatment with cocaine produced a small, significant shift to the right in the cocaine dose-effect curve; the ED50 values changed from 13.3 to 21.7 mg/kg. Cross-tolerance was not conferred to the indirect agonist, d-amphetamine, the direct agonist apomorphine, the D1-selective agonists SKF 38393 or fenoldopam, or the D2-selective agonists quinpirole or (-)-NPA. Cross-tolerance was conferred to the close structural analog of cocaine, WIN 35,428, but not to another dopamine uptake inhibitor, GBR 12909. Tolerant rats showed no change in specific binding of [3H]SCH 23390 to D1 receptors, [3H]spiperone to D2 receptors, [3H]GBR 12935 to dopamine uptake sites in striatum, [3H]paroxetine to serotonin uptake sites or [3H]mazindol to norepinephrine uptake sites in cortex or hippocampus. In addition, there were no changes in transmitter levels indicative of neurotoxicity. Serum levels of cocaine were not appreciably different in groups of cocaine- and saline-treated rats. The present results suggest that the modest tolerance that can develop to the behavioral effects of cocaine does not confer significant functional or metabolic changes in the effects of drugs acting on dopaminergic systems. Importantly, the tolerance produced by repeated administration of cocaine does not produce a cross-tolerance to GBR 12909, suggesting differences in mechanism among different structural forms of dopamine uptake inhibitors.

Animals↗

The effect of salinity on the acute toxicity of cadmium to the tropical, estuarine, hermaphroditic fish, Rivulus marmoratus: a comparison of Cd, Cu, and Zn tolerance with Fundulus heteroclitus.

The mangrove-dwelling fish, Rivulus marmoratus, is the only vertebrate that is a synchronous, internally self-fertilizing hermaphrodite. This unique reproductive mode yields offspring with little genetic variation, which offers significant advantages for the use of this species in bioassays. We conducted acute (96 h) LC50 tests of Cd toxicity under four different water chemistry conditions, representing fresh water (low [Ca+Mg] and low [Na+K]), 14 ppt sea water simulated with Cl salts (high [Ca+Mg] and high [Na+K]) and two artificial conditions (high [Ca+Mg], low [Na+K] and low [Ca+Mg], high [Na+K]). Two replicates were conducted at different times for each of the four treatments and the results were very reproducible. The mean LC50's as mg total Cd/L were 2.96 (fresh water), 21.12 (high [Ca+Mg], high [Na+K]), 17.86 (high [Ca+Mg], low [Na+K]) and 12.67 (low [Ca+Mg], high [Na+K]). An additional test in 14 ppt sea water (made up from Instant Ocean salts) yielded a 96h LC50 of 24.48 mg Cd/L, and was thus similar to the high [Ca+Mg]-high [Na+K] treatment, despite some differences in anion and cation concentrations. The degree to which [Ca+Mg], [Na+K] and [Cl] interact to determine Cd toxicity is still unclear, although the role of [Cl] is likely to be equal to or greater than that of [Ca+Mg]. When all solutes are high, it is likely that the formation of a Cd complex with Cl (248 mM) leads to the observed reduction in Cd toxicity in comparison with hard fresh water, not the increased divalent [Ca+Mg] levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

An analysis of the effects of contextual cues on the development of morphine tolerance in rats.

Tolerance to morphine analgesia was determined daily by exposing rats either to the same box or to different boxes by a repeated administration of morphine (5 mg/kg). In the Acquisition Phase, the rats received either morphine or saline in the same or different boxes for four consecutive days, and the process of tolerance development was assessed by a hot-plate test. Marked tolerance developed in the group exposed to the same contextual cue, whereas tolerance was attenuated in the group exposed to different cues. In the Extinction Phase, all rats received saline injections in the box exposed on Day 1 for four days. On the first day, hyperalgesia was observed only in the rats injected with morphine in the same contextual cue. In the Retest Phase, the rats underwent a second morphine injection and to some extent showed recovery from tolerance. In the Acquisition Phase, the number of animals showing abnormal activity with morphine injection increased monotonically in the group that was administered morphine in the same box (Group M-S) before injection, but in the group administered the drug in different boxes (Group M-D), no systematic development of the activity occurred. These results indicate that the hindering of a rat's ability to associate with environmental cues under the effect of morphine slows the development of tolerance, and the withdrawal and anticipatory symptoms, and the tolerance of morphine involves psychological and pharmacological factors.

Analgesics, Opioid↗

Tomato plant-water uptake and plant-water relationships under saline growth conditions.

Growth and water uptake both decreases when tomato plants are irrigated with saline water. To determine the relative contribution of physiological traits to these decreases plant fresh and dry weight, leaf area, leaf water (Psi(w)) and osmotic (Psi(Pi)) potentials, gas exchange parameters, stomatal density, leaf chlorophyll and Na content were investigated in the tomato (Lycopersicon esculentum) cultivars, Daniela and Moneymaker. Plants were grown in greenhouse, in sand culture, and irrigated with a complete nutrient solution supplied with 0 (control), 35 and 70 mM NaCl over a period of 2 months. Salinity reduced plant dry weight, height and number of leaves even at 35 mM NaCl. Leaf Psi(w) and Psi(Pi) decreased with salinity but leaf turgor pressures were significantly higher in salinised than in control plants which suggests that bulk tissue turgor did not limit growth under the saline conditions tested. Increasing salinity in the irrigation solution led to both morphological changes [(reduction of plant leaf area and stomatal density) and physiological changes [reduction of stomatal conductance, transpiration, and net CO(2) assimilation (A(CO(2)))] Plant water uptake, measured as the difference between volume of nutrient solution supplied and drainage collected, was closely related to transpiration, stomatal conductance, and stomatal density. Chlorophyll content per unit of leaf area increased with salinity. Reduction of net A(CO(2)) with salinity was explained in higher degree by stomatal conductance and stomatal density than by Na accumulation in the leaves. Although plant water uptake was similar for the two cultivars, Daniela transported, per unit of water uptake, more Na to the leaves than did Moneymaker. However, Daniela reduced leaf area less than did Moneymaker. Water use efficiency, calculated either as the ratio between total plant dry matter and total plant water uptake, or as the ratio between net A(CO(2)) and transpiration, did not change under our saline growth conditions. The contribution of the observed salt-responses to reduction in shoot water loss, plant water uptake and salt loading, while keeping water use efficiency, is discussed in relation to salt tolerance. Because some of these salt-responses take a long time to develop, growing seedlings in seedbeds with saline media could be of interest to better tolerate further salty conditions in the field or greenhouse.

Journal Article↗

Increased brain P-glycoprotein in morphine tolerant rats.

The objective of this study was to determine whether chronic morphine exposure increased P-glycoprotein in rat brain. Male Sprague-Dawley rats were treated with morphine, saline, or dexamethasone for 5 days. On day 6, antinociceptive effect was measured to evaluate the extent of functional tolerance to morphine. Brain P-glycoprotein was detected by Western blot analysis of whole brain homogenate. Morphine- and dexamethasone-treated rats exhibited decreased antinociceptive response when compared to saline-treated controls. Brain P-glycoprotein was approximately 2-fold higher in morphine-treated rats compared to saline controls based on Western blot analysis. Chronic morphine exposure appears to increase P-glycoprotein in rat brain. P-glycoprotein induction may enhance morphine efflux from the brain, thus reducing morphine's pharmacologic activity. Induction of P-glycoprotein may be one mechanism involved in the development of morphine tolerance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Conditioning and extinction of tolerance to the hypothermic effect of ethanol in rats.

The contribution of classical conditioning to tolerance to the hypothermic effect of ethanol was examined. During the tolerance acquisition phase, rats were exposed at 4-day intervals to a distinctive set of environmental cues paired with injections of ethanol (1.4 g/kg, ip). Interspersed between these drug trials were exposures to an alternate set of cues paired with injections of saline. In addition, three groups experienced different amounts of stimulation and activity during drug exposure in order to determine whether "behavioral augmentation" of tolerance would occur. In subsequent tests, the rats were tolerant only in the presence of cues previously paired with ethanol. Moreover, this environmentally specific tolerance was associated with a conditioned hyperthermic response to placebo (saline) injections in the drug environment. An extinction procedure designed to weaken tolerance mediated by classical conditioning was also found to be effective. Evidence for conditioned tolerance was weakest in animals experiencing low levels of activity during the initial drug exposure periods.

Animals↗

Effects of chronic intraventricular administration of angiotensin II on drinking behavior and blood pressure.

Angiotensin II was continuously infused into the lateral cerebral ventricle of rats, and the effects on daily food and water consumption, urine volume, and aortic blood pressure were studied. All was infused at a rate of 10 ng/hr for seven days, using subcutaneously implanted osmotic minipumps. An intraventricular (IVT) control group was infused with only the saline vehicle, while a third group received AII subcutaneously. IVT AII rats showed a four-fold increase in water consumption, to a mean of 171 ml/day during Days 2-4 of infusion, whereas water intake of the other groups did not change from preinfusion levels. Urine volume showed a similar pattern to water intake, increasing five-fold in the IVT AII group during Days 2-4. These measures declined during the final three days of AII infusion, but significant tolerance was not observed. Food intake decreased markedly in both saline and IVT AII groups after implantation of the pumps, but the latter resumed normal food intake more slowly than the former, and body weight remained below preinfusion levels throughout the AII period. Aortic blood pressure of the IVT AII rats showed a slight, but progressive, rise during the infusion period, but it did not significantly exceed that of the saline rats. These results indicate that continuous, low-level, intraventricular infusion of AII may markedly increase water intake without significantly increasing fluid retention or blood pressure.

Angiotensin II↗

Tolerance to adenosine's accentuation of ethanol-induced motor incoordination in ethanol-tolerant mice.

Our previously published reports have provided data that have supported a functional correlation between ethanol-induced changes in the characteristics of adenosine receptor, adenosine uptake and release in the brain, and ethanol-induced motor incoordination. The present data demonstrated a cross-tolerance between ethanol and adenosine further supporting the hypothesis that brain adenosine modulates the motor impairing effects of ethanol. Mice that received (-)-N6-cyclohexyladenosine (CHA) [0.25 mg/kg/day, intraperitoneally (ip)] for 10 days exhibited marked attenuation (cross-tolerance) to acute ethanol-induced motor incoordination compared with chronic saline (ip) controls. The attenuation of acute ethanol-induced motor incoordination was essentially same in animals that received CHA (25 ng/5 microliters/day for 10 days) by the intracerebroventricular (icv) route as opposed to the controls that chronically received artificial cerebral spinal fluid by the same route. Similarly, tolerance was exhibited to acute CHA (0.125 mg/kg ip and 12.5 ng/5 microliters icv) by animals fed liquid ethanol (19.5 g/kg/24 hr) for 10 days compared with none in the pair-fed sucrose controls. Scatchard plots using cerebellar tissue homogenates from animals given chronic CHA or chronic ethanol indicated no change in Bmax and/or Kd values for CHA binding when compared with CHA binding in tissues from their respective controls. However, a lack of any change in the binding characteristics cannot rule out the involvement of adenosine receptors in the observed cross-tolerance between ethanol and CHA. The results may suggest desensitization of adenosine A1 receptors due to chronic CHA and ethanol as an alternate possible explanation in the development of cross-tolerance between adenosine (CHA) and ethanol.

Adenosine↗

First human studies with a high-molecular-weight iron chelator.

The release of free, reactive iron from cellular iron stores has been implicated as an important contributor to tissue damage in a variety of clinical situations, including ischemia and reperfusion injury, hemorrhagic shock, and burn injury. Deferoxamine mesylate (DFO), the only iron chelator currently approved for clinical use, is used for the treatment of iron overload, including acute iron poisoning and treatment of chronic iron overload in transfusion-dependent anemias such as beta-thalassemia. However, it is not suitable for acute care situations because of its toxicity, primarily hypotension when given at high intravenous doses, and its short plasma half-life. We have produced a high-molecular-weight iron chelator by chemically coupling DFO to hydroxyethyl starch. This novel chelator (HES-DFO) was administered to healthy male subjects by intravenous infusion over a 4-hour period. The drug was well tolerated, and signs of DFO acute toxicity were not observed. Maximum plasma chelator levels of approximately 3 mmol/L were achieved with HES-DFO, which is more than an order of magnitude higher than has been reported with injections of DFO. Drug residence time in plasma was markedly prolonged, with an initial half-life of 22 to 33 hours. Urinary iron excretion was 7.1 +/- 2.2 mg in 48 hours in the highest dose group, as compared with 0.06 +/- 0.15 mg in control subjects who received normal saline infusions. Intravenous infusion of HES-DFO is well tolerated, produces substantial and prolonged plasma chelator levels, and markedly stimulates urinary iron excretion.

Adult↗

Effect of salt stress on nodulation and nitrogen fixation in legumes.

It is now well established that almost all phases of root nodule development in legumes are adversely affected by saline conditions in the rooting medium. There is also a general agreement that the rhizobia are more tolerant to salt stress than the host plant, but they show considerable strain variability in growth and survival under saline conditions. Inhibitory effect of salinity on nodulation has been attributed to decrease in rhizobial colonisation and shrinkage and lack of root hair formation. Salt stress also induces premature senescence of already formed nodules. Both N2-fixation activity and nodule respiration are inhibited sharply on exposure of plants to saline conditions. The decrease in N2-fixation has been ascribed to direct effect on nitrogenase activity or an indirect effect through decrease in leghemoglobin content, respiratory rate, malate concentrations in nodules and photosynthate availability. Salinity increases oxygen diffusion resistance in the nodules and alters their ultrastructure. Decrease in N2-fixation in nodules under salinity is also accompanied by parallel decrease in the activity of H2O2-scavenging enzymes like catalase, ascorbate peroxidase and the level of antioxidants like ascorbic acid. Nodules appear to undergo osmoregulation under saline conditions by accumulating physiologically compatible solutes like proline, sugars (pinnitol) and lactic acid. The intensity of the adverse effects of salinity on nodule functioning depends on plant species, rhizobial strain, duration of exposure to saline conditions, nature, concentration and mode of salt application.

Fabaceae↗

Rice GTPase OsRacB: potential accessory factor in plant salt-stress signaling.

As the sole ubiquitous signal small guanosine triphosphate-binding protein in plants, Rop gene plays an important role in plant growth and development. In this study, we focus on the relationship between the novel rice Rop gene OsRacB and plant salt tolerance. Results show that OsRacB transcription is highly accumulated in roots after treatment with salinity, but only slightly accumulated in stems and leaves under the same treatment. Promoter analysis showed that OsRacB promoter is induced by salinity and exogenous salicylic acid, not abscisic acid. To elucidate its physiological function, we generated OsRacB sense and antisense transgenic tobacco and rice. Under proper salinity treatment, sense transgenic plants grew much better than the control. This suggests that overexpression of OsRacB in tobacco and rice can improve plant salt tolerance. But under the same treatment, no difference could be observed between OsRacB antisense plants and the control. The results indicated that OsRacB is only an accessory factor in plant salt tolerance.

Abscisic Acid↗