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PubMed1999

Epinephrine and endotoxin tolerance differentially modulate serum cytokine levels to high-dose lipopolysaccharide challenge in a murine model.

BACKGROUND: The epinephrine tolerance state has been demonstrated to increase survival in endotoxic shock and was claimed to have cross-tolerance with endotoxin tolerance. With use of these data, we aimed to determine the effect of epinephrine and endotoxin tolerance on major cytokine levels in a lipopolysaccharide challenge in mice. METHODS: Epinephrine tolerance was induced by beginning with a low dose and gradually increasing to a lethal dose. Endotoxin tolerance was induced by injecting saline solution for 4 days and lipopolysaccharide 1 mg/kg on the fifth day. After these procedures, saline solution or 20 mg/kg lipopolysaccharide was injected into animals. Peak serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta, interleukin 6 (IL-6), interleukin 10 (IL-10), and interleukin 12 (IL-12) were assayed. RESULTS: The lipopolysaccharide injection increased the levels of all the cytokines in the control and epinephrine-tolerant animals. TNF-alpha, IL-6, and IL-10 levels were lower in endotoxin-tolerant animals compared with controls. Epinephrine-tolerant animals had higher levels of TNF-alpha, IL-6, and IL-12 than the controls did. CONCLUSION: Epinephrine tolerance primes for an exaggerated release of TNF-alpha, IL-6, and IL-12 in response to lipopolysaccharide challenge, suggesting anti-inflammatory and immunosuppressive effects by epinephrine. The anti-inflammatory effect was not mediated through increased IL-10 release. Endotoxin tolerance selectively modulated cytokine release.

Animals↗
PubMed2005

Gene expression and metabolite profiling of Populus euphratica growing in the Negev desert.

BACKGROUND: Plants growing in their natural habitat represent a valuable resource for elucidating mechanisms of acclimation to environmental constraints. Populus euphratica is a salt-tolerant tree species growing in saline semi-arid areas. To identify genes involved in abiotic stress responses under natural conditions we constructed several normalized and subtracted cDNA libraries from control, stress-exposed and desert-grown P. euphratica trees. In addition, we identified several metabolites in desert-grown P. euphratica trees. RESULTS: About 14,000 expressed sequence tag (EST) sequences were obtained with a good representation of genes putatively involved in resistance and tolerance to salt and other abiotic stresses. A P. euphratica DNA microarray with a uni-gene set of ESTs representing approximately 6,340 different genes was constructed. The microarray was used to study gene expression in adult P. euphratica trees growing in the desert canyon of Ein Avdat in Israel. In parallel, 22 selected metabolites were profiled in the same trees. CONCLUSION: Of the obtained ESTs, 98% were found in the sequenced P. trichocarpa genome and 74% in other Populus EST collections. This implies that the P. euphratica genome does not contain different genes per se, but that regulation of gene expression might be different and that P. euphratica expresses a different set of genes that contribute to adaptation to saline growth conditions. Also, all of the five measured amino acids show increased levels in trees growing in the more saline soil.

Desert Climate↗
PubMed1987

Salt tolerance in suspension cultures of sugar beet : induction of na/h antiport activity at the tonoplast by growth in salt.

Cell suspension cultures of sugar beet were grown at various salinities (0-200 millimolar NaCl). Their tolerance to Na(+) was comparable to that of the intact plant. Tonoplast vesicles were prepared by sucrose density gradient centrifugation of microsomal membranes and shown to be highly purified. The vesicles were subjected to a pH jump in the presence of acridine orange and the rate of recovery of fluorescence after addition of Na(+) was used as a measure of Na(+)-dependent H(+) efflux. In the presence of K(+) and valinomycin, the Na(+)/H(+) antiport showed saturation kinetics. Increasing Na(+) in the growth medium did not change the apparent K(m) for Na(+), but increased V(max) to about twice the control value, suggesting a specific induction of antiport synthesis by salt.

Journal Article↗
PubMed1994

Role of alkali cations (K+ and Na+) in cyanobacterial nitrogen fixation and adaptation to salinity and osmotic stress.

Cyanobacteria occupy almost every possible ecological niche on earth, being tolerant to a large number of environmental stresses, including salinity and drought. Many of them also fix atmospheric nitrogen. They are responsible for a significant share of biosolar energy conversions on this planet and make substantial contributions to the carbon and nitrogen status of both oceans and soils. Sodium and potassium are two of the most prevalent cations on this planet. While K+ is an essential macronutrient in most life-forms, Na+ is strongly discriminated by means of highly selective alkali cation transport systems, favouring K+ over Na+. Although a nutritional requirement for K+ has not been specifically investigated, rapid accumulation of K+ during salt/osmotic stress has been observed in several cyanobacteria. Genes and proteins constituting a membrane-bound, turgor- and osmo-inducible, Kdp-ATPase-like system in Anabaena strains that may help in their early K+ responses to salt/osmotic stress have been identified. An unusual, specific and absolute requirement for trace quantities of sodium has been documented in cyanobacteria. Work done in our laboratory, and elsewhere, has elucidated the mechanisms underlying such a unique requirement. It has long been believed that cyanobacteria scavenge and immobilise sodium. We have, however, shown that sodium exclusion brought about by curtailment of influx and active efflux of Na+ forms the basis of salt tolerance in these microbes and that the inherent salt tolerance can be modified by factors that modulate Na+ fluxes in cyanobacteria. Identification of genes affecting the cation relationships in nitrogen-fixing cyanobacteria is currently in progress.

Adaptation, Physiological↗
PubMed2006

Antigen-induced, tolerogenic CD11c+,CD11b+ dendritic cells are abundant in Peyer's patches during the induction of oral tolerance to type II collagen and suppress experimental collagen-induced arthritis.

OBJECTIVE: Although oral tolerance is a well-known phenomenon, the role of dendritic cells (DCs) is not well characterized. This study was conducted to better understand the differential role played by each Peyer's patch DC subset in the induction of oral tolerance to type II collagen (CII) in murine collagen-induced arthritis (CIA). METHODS: CII was fed 6 times to DBA/1 mice beginning 2 weeks before immunization, and the effect on arthritis was assessed. We compared the proportion of CD11c+,CD11b+ DCs and CD11c+,CD8alpha+ DCs in the Peyer's patches of CII-fed tolerized and phosphate buffered saline-fed nontolerized mice after the induction of CIA. The immunosuppressive properties of each DC subset were determined using fluorescence-activated cell sorter analysis for intracellular interleukin-10 (IL-10) and IL-12 and mixed lymphocyte culture. The ability of each DC subset to induce CD4+,CD25+ T regulatory cells was also examined. Mice were injected with CII-pulsed CD11c+,CD11b+ DCs isolated from Peyer's patches of tolerized mice, and the effect on CIA was examined. RESULTS: The severity of arthritis was significantly lower in tolerized mice. The proportion of CD11c+,CD11b+ DCs was increased in the Peyer's patches of tolerized mice and those DCs exhibited immunosuppressive characteristics, such as increased IL-10 production, inhibition of T cell proliferative responses to CII, and CD4+,CD25+ regulatory T cell induction. Furthermore, the CD11c+,CD11b+ DCs suppressed the severity of arthritis upon adoptive transfer. CONCLUSION: Our observations demonstrate that CD11c+,CD11b+ DCs, which are abundant in Peyer's patches during the induction of oral tolerance to CII, are crucial for the suppression of CIA and could be exploited for immunotherapy of autoimmune diseases.

Adoptive Transfer↗
PubMed1998

Routine use of saline hysterosonography in 500 consecutive, unselected, infertile women.

Saline hysterosonography was attempted as a routine, first-line screening test of uterine structure in 500 consecutive, unselected, infertile women. The procedure was completed in 96.8% (484/500) women and the observations were interpretable in 483 of these women. Intrauterine pathology was suspected in 67/499 (13.4%) women on plain ultrasound scan and 58/484 (12%) women with saline hysterosonography. Ultrasound alone had a superior specificity (96.3%) to sensitivity (81.8%) and better negative (97.6%) than positive (73.8%) predictive value for the detection of any intrauterine abnormality, using saline hysterosonography as the reference procedure. Suspected pathology at saline hysterosonography led to hysteroscopy in 20 women, after a median of 5.7 months (range, 1-14). The overall concordance rate between the two procedures was 65% with lesions suspicious of intrauterine polyps not present at subsequent hysteroscopy on six occasions. Criteria were established to help identify women with potentially self-limiting lesions, in whom a re-scan should be considered before resorting to hysteroscopy. The procedure was well tolerated with no significant complications. Saline hysterosonography appeared to be an acceptable first-line screening procedure for uterine structure which enhanced the predictive power of ultrasound alone for uterine anomalies and provided additional information which was potentially of value when planning operative hysteroscopy.

Adult↗
PubMed2003

Antagonism of N-methyl-D-aspartate receptors reduces the vulnerability of the immune system to stress after chronic morphine.

It has been shown that morphine-tolerant animals have an altered immunological sensitivity to stress. Although the glutamatergic system has been implicated in the neuroadaptive process underlying this tolerant state, its potential role in development of the altered immunological sensitivity consequent to chronic morphine treatment is not known. To determine this, a morphine-tolerant state was induced by 10-day administration of an escalating dose of morphine from 10 to 40 mg/kg (s.c., b.i.d.), and lymphocyte proliferative response to a T-cell mitogen was measured. Morphine challenge (10 mg/kg s.c.) after days of treatment was gradually less immunosuppressive, and this tolerance progression was delayed by concurrent administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (0.1 mg/kg s.c.) with chronic morphine. The effect was independent of glucocorticoid level changes and was not a result of an acute interaction of the drugs or the prolonged presence of the antagonist alone. Subsequent to chronic treatment, animals were subjected to opioid withdrawal and water stress. Both stressors induced 50% immunosuppression in morphine-tolerant animals compared with saline-treated controls. Increased immunological sensitivity to these stressors was attenuated when MK-801 was administered with chronic morphine as demonstrated by an accelerated recovery rate and lack of immunosuppression from opioid withdrawal and water stress, respectively. Together, these findings provide the first evidence that the neuroadapted state of the immune response after chronic morphine can be modified by NMDA receptor antagonism, as illustrated by a temporal deceleration of the development of immunological tolerance during chronic treatment that is associated with an attenuation of the immunological vulnerability of morphine-tolerant animals to stress.

Animals↗
PubMed1992

Maintenance of acute morphine tolerance in mice by selective blockage of kappa opioid receptors with norbinaltorphimine.

In this study we investigated the effect of the highly selective kappa opioid antagonist, norbinaltorphimine (norBNI) on the development of tolerance to a single dose of morphine. Mice were pretreated with 100 mg/kg of morphine sulfate (morphine), s.c. and 2 h later, norBNI (20 mg/kg s.c.) was administered and various times after this pretreatment, antinociceptive ED50 value of morphine was determined in the tail-flick assay. Twenty-four and 72 h after morphine injection, ED50 values of morphine were significantly increased by about 2.5-fold from those of their control mice that received saline instead of the tolerance-inducing dose of morphine. In a second set of experiments, animals were pretreated similarly with morphine and norBNI and 72 h after morphine injection, various opioid agonists were applied by the i.c.v. or i.t. route to see whether or not any cross-tolerance had developed to these agonists. The ED50 of i.c.v.-administered morphine was significantly greater than that of the non-pretreated controls. A small degree of cross-tolerance was observed with U-50,488H but not with DPDPE [D-Pen2,D-Pen5]enkephalin (DPDPE) at the supraspinal site. At the spinal site, tolerance to morphine was not observed. These results suggest that antagonism at kappa opioid sites after morphine administration, modulates positively the development of opioid tolerance.

Animals↗
PubMed2004

Identification of cold-inducible downstream genes of the Arabidopsis DREB1A/CBF3 transcriptional factor using two microarray systems.

The transcriptional factor DREB/CBF (dehydration-responsive element/C-repeat-binding) specifically interacts with the dehydration-responsive element (DRE)/C-repeat (CRT) cis-acting element (A/GCCGAC) and controls the expression of many stress-inducible genes in Arabidopsis. Transgenic plants overexpressing DREB1A showed activated expression of many stress-inducible genes and improved tolerance to not only drought, salinity, and freezing but also growth retardation. We searched for downstream genes in transgenic plants overexpressing DREB1A using the full-length cDNA microarray and Affymetrix GeneChip array. We confirmed candidate genes selected by array analyses using RNA gel blot and identified 38 genes as the DREB1A downstream genes, including 20 unreported new downstream genes. Many of the products of these genes were proteins known to function against stress and were probably responsible for the stress tolerance of the transgenic plants. The downstream genes also included genes for protein factors involved in further regulation of signal transduction and gene expression in response to stress. The identified genes were classified into direct downstream genes of DREB1A and the others based on their expression patterns in response to cold stress. We also searched for conserved sequences in the promoter regions of the direct downstream genes and found A/GCCGACNT in their promoter regions from -51 to -450 as a consensus DRE. The recombinant DREB1A protein bound to A/GCCGACNT more efficiently than to A/GCCGACNA/G/C.

Arabidopsis↗
PubMedDate not supplied

Tolerability and efficacy of high-dose furosemide and small-volume hypertonic saline solution in refractory congestive heart failure.

Thirty patients aged 65-85 years, with refractory New York Heart Association (NYHA) class IV congestive heart failure (CHF) were treated with an intravenous infusion of furosemide (250-2000 mg/d) and small-volume hypertonic saline solution (150 mL of 1.4-4.6% NaCl) twice a day for 6 to 12 days. A daily fluid oral intake of 1000 mL and previous cardiac therapy were maintained. Clinical signs and symptoms of CHF, such as dyspnea, edema and weakness, improved, as did severity of illness as defined by NYHA class. The infusion was well tolerated. After a 12-month follow-up, 24 patients (80%) were alive and in the NYHA class assigned on discharge from the hospital. This therapeutic combination is effective and well tolerated and should represent an innovative approach to the management of refractory CHF.

Aged↗
PubMed2003

Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1- (9-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans.

Glucagon-like peptide 1 (GLP-1) is an insulin secretagogue synthesized in the intestine and released in response to meal ingestion. It is secreted primarily in two forms, GLP-1-(7-37) and GLP-1-(7-36)NH(2), both of which bind to a specific GLP-1 receptor (GLP-1r) on the pancreatic beta-cell and augment glucose-stimulated insulin secretion. Once secreted, GLP-1-(7-36)NH(2) is rapidly metabolized to GLP-1-(9-36)NH(2), which is the predominant form of GLP-1 in postprandial plasma because of its relatively slower clearance. Although no clear biological role for GLP-1-(9-36)NH(2) in humans has been identified, recent studies in animals suggest two potential effects: to antagonize the effects of intact GLP-1 and to promote glucose disappearance in peripheral tissues. In the studies reported here we compared the independent effects of GLP-1-(7-36)NH(2), GLP-1-(7-37), and GLP-1-(9-36)NH(2) on parameters of iv glucose tolerance and determined whether GLP-1-(9-36)NH(2) inhibits the insulinotropic actions of GLP-1. Ten healthy subjects underwent 4 separate frequently sampled iv glucose tolerance tests during infusions of GLP-1-(7-37), GLP-1-(7-36)NH(2), GLP-1-(9-36)NH(2), or saline. Results from the iv glucose tolerance test were used to obtain indexes of beta-cell function (acute insulin response to glucose) and iv glucose tolerance (glucose disappearance constant), and the minimal model of glucose kinetics was used to obtain indexes of glucose effectiveness and insulin sensitivity. Compared with control studies, both GLP-1-(7-36)NH(2) and GLP-1-(7-37) significantly increased acute insulin response to glucose, glucose disappearance constant, glucose effectiveness, and glucose effectiveness at zero insulin, but did not change the insulin sensitivity index. In contrast, none of the parameters of glucose tolerance was measurably affected by GLP-1-(9-36) amide. In a second set of experiments, 10 healthy subjects had glucose-stimulated insulin secretion measured during an infusion of GLP-1-(7-36)NH(2) alone or with a simultaneous infusion of GLP-1-(9-36)NH(2) that increased plasma levels approximately 10-fold over those produced by unmetabolized GLP-1. Augmentation of glucose-stimulated insulin secretion by GLP-1-(7-36)NH(2) was not altered by the coadministration of GLP-1-(9-36)NH(2). Based on these results we conclude that GLP-1-(9-36)NH(2) does not regulate insulin release or glucose metabolism in healthy humans.

Adult↗
PubMed1994

Gas Exchange and Carbon Partitioning in the Leaves of Celery (Apium graveolens L.) at Various Levels of Root Zone Salinity.

Both mannitol and sucrose (Suc) are primary photosynthetic products in celery (Apium graveolens L.). In other biological systems mannitol has been shown to serve as a compatible solute or osmoprotectant involved in stress tolerance. Although mannitol, like Suc, is translocated and serves as a reserve carbohydrate in celery, its role in stress tolerance has yet to be resolved. Mature celery plants exposed to low (25 mM NaCl), intermediate (100 mM NaCl), and high (300 mM NaCl) salinities displayed substantial salt tolerance. Shoot fresh weight was increased at low NaCl concentrations when compared with controls, and growth continued, although at slower rates, even after prolonged exposure to high salinities. Gas-exchange analyses showed that low NaCl levels had little or no effect on photosynthetic carbon assimilation (A), but at intermediate levels decreases in stomatal conductance limited A, and at the highest NaCl levels carboxylation capacity (as measured by analyses of the CO2 assimilation response to changing internal CO2 partial pressures) and electron transport (as indicated by fluorescence measurements) were the apparent prevailing limits to A. Increasing salinities up to 300 mM, however, increased mannitol accumulation and decreased Suc and starch pools in leaf tissues, e.g. the ratio of mannitol to Suc increased almost 10-fold. These changes were due in part to shifts in photosynthetic carbon partitioning (as measured by 14C labeling) from Suc into mannitol. Salt treatments increased the activity of mannose-6-phosphate reductase (M6PR), a key enzyme in mannitol biosynthesis, 6-fold in young leaves and 2-fold in fully expanded, mature leaves, but increases in M6PR protein were not apparent in the older leaves. Mannitol biosynthetic capacity (as measured by labeling rates) was maintained despite salt treatment, and relative partitioning into mannitol consequently increased despite decreased photosynthetic capacity. The results support a suggested role for mannitol accumulation in adaptation to and tolerance of salinity stress.

Journal Article↗
PubMed2026

Whole-genome sequencing and characterization of Pseudomonas stutzeri P1 endophyte isolated from potato unveils plant growth-promoting and other traits.

Endophytic bacteria play an important role in plant growth promotion and stress tolerance, offering sustainable alternatives to chemical inputs in agriculture. In this study, an endophytic bacterial strain P1 was isolated and identified as Pseudomonas stutzeri, a plant-associated bacterium exhibiting multiple plant growth-promoting traits (PGPTs). Biochemical (qualitative and quantitative) and in vitro analyses demonstrated nitrogen fixation, phosphate solubilization, ammonia production, indole-3-acetic acid (IAA) production, biofilm formation, and tolerance to abiotic stresses, including salinity and drought. Furthermore, the P1 strain displayed strong biocontrol activity against the fungal pathogen Fusarium oxysporum f. sp. cumini, indicating its potential to mitigate biotic stress. Whole-genome sequencing generated a high-quality complete genome of 4,758,235 bp. Functional annotation showed enrichment of metabolic pathways associated with plant-microbe interactions and environmental adaptation. Further analyses using KEGG and PGPT-pred data confirmed the presence of genes associated with direct and indirect PGPT, such as nitrogen fixation, phosphate solubilization, biofilm formation, and stress tolerance. The genome also contained genes related to CAZymes, adhesion, and motility, highlighting a strong plant association, whereas the genome lacked major virulence factors and antimicrobial traits, supporting the non-pathogenic nature of the P1 strain. Overall, these findings demonstrate the potential of P1 as a promising bioinoculant candidate for sustainable agriculture in the potato sector.

PGPT-associated genes↗
PubMed1991

Is tolerance to intrathecal morphine in intact rats supraspinally mediated?

The effect of repeated intrathecal (IT) injections of 5 micrograms of morphine on the tail flick (TF) was determined in rats that were tested either 0.5 h or 5.0 h after administration on each of five successive days. Tolerance developed rapidly in animals tested 5.0 h after each injection. Animals tested 0.5 h after each injection did not become tolerant. Animals that were tested 5.0 h after an intrathecal saline injection on the first four days were also tolerant to a 5 micrograms dose of morphine on the fifth day. These data are discussed in the context of previous conflicting reports concerning tolerance to intrathecal morphine. It is suggested that, under certain conditions, tolerance to intermittent intrathecal morphine administration may be due to a supraspinal opiate action.

Analgesics↗
PubMed2026

Desert-derived Ensifer sp. SA403 enhances potato salt tolerance by reshaping rhizosphere microbiome functions and host responses.

Soil salinization increasingly threatens global food security, and potato (Solanum tuberosum L.), a moderately salt-sensitive crop, is particularly vulnerable to saline soils. Plant growth-promoting rhizobacteria (PGPR) offer a promising strategy to improve crop performance, yet how PGPR interact with native microorganisms to enhance potato salt tolerance remains poorly understood. In this study, we identified a desert-derived PGPR strain, Ensifer sp. SA403, which substantially enhanced potato performance under high salinity across sterile, non-sterile and field conditions. Physiologically, inoculation with SA403 reduced shoot Na⁺ accumulation and increased the K⁺/Na⁺ ratio; notably, these effects were markedly stronger in non-sterile substrates than under sterile conditions, indicating that SA403-mediated ion homeostasis relies on cooperation with the resident microbiota rather than on the strain acting alone. Metagenomic profiling indicated that SA403 strain reshaped rhizosphere communities, significantly enriching beneficial taxa such as Priestia and Bradyrhizobium, and upregulated functional pathways involved in glutathione and sulfur metabolism. Furthermore, host transcriptomic analyses showed that SA403 modulated plant responses to salt stress, with differentially expressed genes enriched in jasmonic acid signaling, ethanolamine metabolism and amino-acid biosynthesis pathways. Field trials on saline soils confirmed that SA403 significantly increased seedling emergence and tuber weight. Together, our results demonstrate that SA403 functions as a biological mediator that optimizes rhizosphere microecology and coordinates ion balance and host signaling to enhance potato salt tolerance. These findings support the potential of SA403 as a robust PGPR-based tool for sustainable potato production on saline soils.

Rhizosphere↗
PubMed2026

Beyond the salt barrier: CRISPR-mediated DNA reprogramming to uncouple yield from tolerance in Rice: A review.

Rice (Oryza sativa L.) feeds half of humanity, yet its cultivation is increasingly threatened by soil salinization, which now affects 1.4 billion hectares globally. Decades of breeding and engineering have focused on Na+ exclusion, principally through the Saltol QTL and the xylem-unloading transporter OsHKT1;5, yet this strategy has reached a physiological ceiling. Excluder genotypes survive salinity but fail to fill grain, because the ATP-intensive cost of continuous ion extrusion starves reproductive sinks, while ABA-mediated stomatal closure imposes chronic carbon limitation. The resulting "survival-yield gap" exposes a fundamental flaw in single-trait approaches to a polygenic stress. In this review, we argue that durable, yield-stable salt tolerance requires a coordinated systems-level intervention spanning five mechanistic tiers: (i) CRISPR/Cas9-mediated removal of negative regulatory brakes (OsRR22, RST1, PC1) that suppress plant's latent stress-adaptive capacity; (ii) reinforcement of actin-myosin cytoskeletal transport to sustain SOS1, NHX1, and HKT1;5 delivery under ionic stress; (iii) importation of halophyte design principles from Oryza coarctata, including salt gland architecture and superior Na+ compartmentalization; (iv) recalibration of the ROS-photosynthesis axis via the DHHC09-STRK1-CatC molecular switch and stomatal density engineering; and (v) pyramiding these modules into a "Salt-Shield Rice" genotype through multiplex editing, marker-assisted introgression, speed breeding, and genomic selection. We propose a phased ten-year roadmap that integrates synthetic biology circuit design with conventional breeding to deliver field-ready, multi-module varieties with greater than 70% yield stability at 8-10 dS m-1. This remains an aspirational design target rather than a demonstrated outcome, as three of the five tiers-halophyte-derived structural traits, cytoskeletal reinforcement, and full multi-module pyramiding-remain unvalidated in rice.

CRISPR/Cas9↗
PubMed1982

Effects of pentobarbital and cocaine in rats expecting pentobarbital.

Rats received extensive exposure to pentobarbital in a distinctive environment, and were subsequently tested for tolerance to the sedative effects of pentobarbital either in the distinctive environment or in an environment previously associated only with saline. Rats tested when expecting pentobarbital (i.e., in the usual drug environment) were tolerant, but rats tested when not expecting the drug (i.e., in the saline environment) were not tolerant. These results extend demonstrations of conditional tolerance to the general behavioral arousal effects of a sedative hypnotic. Subsequently, the same rats were administered cocaine either when expecting pentobarbital or when not expecting pentobarbital. Rats administered cocaine when expecting pentobarbital exhibited more intense forms of cocaine-induced behavior than rats administered cocaine but not expecting pentobarbital. These results establish the phenomenon of conditional cross-potentiation between conditional drug states and unconditional drug-effects.

Animals↗
PubMed1992

Development of tolerance to endogenous opiates activated by 24-h food deprivation.

Four experiments assessed the effects of exposure to 24-h food deprivation on the tail-flick latency of rats exposed to a temperature stimulus. Confirming previous studies, Experiment 1 showed that food deprivation gave rise to analgesia, as indicated by increased tail-flick latencies, that was antagonized by naloxone. Experiment 2 found that analgesia was greatly reduced after five exposures to periods of 24-h food deprivation (alternating with 24-h free access to food), indicating the development of tolerance. Experiments 3 and 3a examined the development of tolerance to the analgesic effects of morphine following repeated morphine injections, saline injections, and exposure to 24-h food deprivation plus saline injections. The combined results of both experiments provided evidence that repeated exposures to either morphine or food deprivation, produced greater tolerance to morphine than did exposures to saline. That food deprivation was cross-tolerant with morphine indicated that tolerance to food deprivation-induced analgesia involved opioid mechanisms. The relevance of opioid tolerance to psychobiological models of feeding and to the development of an animal model of anorexia nervosa was discussed.

Analgesia↗