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PubMed1997

[Experimental study of selective muscarinic receptor antagonists on attenuation of morphine tolerance and dependence in rats].

OBJECTIVE: To characterize the role of muscarinic receptor subtype in the process of the morphine tolerance and dependence. METHODS: The morphine (Antinociception) tolerance was assessed by using hot-plate latency, and morphine dependence was characterized by naloxone-precipitated withdrawal. Intraperitoneal (i.p.) or intrathecal (i.t.) injection of muscarinic M1 selective antagonist pirenzepine or M2 selective antagonist methoctramine was carried out. RESULTS: Methoctramine (i.p.) for 6 days restored the sensitivity to morphine in male Sprague Dawley rats that are tolerant as a result of 6 days of b.i.d. morphine injection, in contrast, saline and pirenzepine (i.p.) did not increase the mean HP latency of morphine tolerant rats. Both methoctramine and pirenzepine in doses did not alter the baseline HP latency. Concurrent treatment with pirenzepine (i.t.) significantly attenuated the development of morphine tolerance produced by twice daily injection of morphine in a dose-dependent manner, however, methoctramine (i.t.) also decreased without dose-relation. In addition, the withdrawal symptoms precipitated by naloxone in morphine dependent rats were blocked by methoctramine (i.p.) or pirenzepine (i.t.) at single dose injection in a dose-dependent manner. Methoctramine (i.t.) at 200 micrograms/kg could partially inhibit the withdrawal symptoms. CONCLUSIONS: The data suggested that the muscarinic receptor subtype predominating M2 receptor at the peripheral and M11 in the spinal cord mediate the process of morphine tolerance and dependence in rat.

Animals↗
PubMed2004

Effects of cocaine on performance under fixed-interval schedules with a small tandem ratio requirement.

Daily administration of cocaine often results in the development of tolerance to its effects on responding maintained by fixed-ratio schedules. Such effects have been observed to be greater when the ratio value is small, whereas less or no tolerance has been observed at large ratio values. Similar schedule-parameter-dependent tolerance, however, has not been observed with fixed-interval schedules arranging comparable interreinforcement intervals. This experiment examined the possibility that differences in rate and temporal patterning between the two types of schedule are responsible for the differences in observed patterns of tolerance. Five pigeons were trained to key peck on a three-component multiple (tandem fixed-interval fixed-ratio) schedule. The interval values were 10, 30, and 120 s; the tandem ratio was held constant at five responses. Performance appeared more like that observed under fixed-ratio schedules than fixed-interval schedules. Effects of various doses of cocaine given weekly were then determined for each pigeon. A dose that reduced responding was administered prior to each session for 50 days. A reassessment of effects of the range of doses revealed tolerance. The degree of tolerance was similar across components of the multiple schedule. Next, the saline vehicle was administered prior to each session for 50 days to assess the persistence of tolerance. Tolerance diminished in all subjects. Overall, the results suggested that schedule-parameter-dependent tolerance does not depend on the temporal pattern of responding engendered by fixed-ratio schedules.

Animals↗
PubMed2003

Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza.

Influenza is an important cause of hospitalization due to lower respiratory tract involvement for which there is no specific antiviral treatment with proven efficacy. We conducted a double-blind, randomized, placebo-controlled trial to assess the tolerability and efficacy of nebulized zanamivir (16 mg four times a day) in combination with rimantadine compared to rimantadine with nebulized saline for treating influenza in adults hospitalized with influenza. Twenty patients tolerated the inhaled zanamivir (ZNV) plus rimantadine without decline in peak expiratory flow rates compared to the 21 who received inhaled saline. The study was terminated early because the approval of ZNV made further enrollment untenable. No significant differences were observed in the proportion of patients shedding virus by treatment day 3 (57% ZNV plus rimantadine, 67% placebo plus rimantadine), or in the durations of hospitalization and supplemental oxygen use. More ZNV plus rimantadine recipients exhibited no or mild cough on day 3 of treatment (94 vs 55%, P=0.01). Two rimantadine-resistant viruses emerged during rimantadine monotherapy; no ZNV resistance was observed. Nebulized ZNV appears to be well tolerated in this hospitalized population but further studies are needed to assess its efficacy.

Adult↗
PubMed2000

Stress responses in two genotypes of mulberry (Morus alba L.) under NaCl salinity.

Changes in biomass yield rates, cell membrane stability (CMS), malondialdehyde (MDA) content and in the levels of physiological stress markers such as proline and glycine betaine in two high yielding genotypes (S1 and ATP, salt tolerant and salt sensitive, respectively) of mulberry under NaCl salinity were studied. Biomass yield rates and CMS were significantly decreased in both the genotypes under stress conditions. Per cent of decrease in biomass yield rate and CMS was relatively less in S1 than in ATP. Salt stress results a significant increase in the accumulation of proline, by 6-fold in S1 and 4-fold in ATP. Glycine betaine content was also increased significantly in stressed plants. However, the per cent increase was more in S1 than in ATP. The level of lipid peroxidation as indicated by MDA formation was greater in ATP than in S1. These results clearly support the better salt tolerant nature of S1 compared to ATP genotype.

Betaine↗
PubMed1992

Repeated systemic administration of the mixed inhibitor of enkephalin-degrading enzymes, RB101, does not induce either antinociceptive tolerance or cross-tolerance with morphine.

The potent analgesic responses elicited by systemic administration of RB101, N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxopro pyl]- 1-oxopropyl]-L-phenylalanine benzyl ester, a prodrug able to inhibit enkephalin-degrading enzymes completely after in vivo bioactivation, has made it possible to investigate the development of antinociceptive tolerance after chronic potentiation of endogenous enkephalins. The ED50 values of RB101 obtained 10 min after i.v. injection were not significantly different in mice treated for 4 days with i.p. administered vehicle (ED50 = 9.50 (6.37-14.15) mg/kg), or with 80 mg/kg of RB101 twice daily (ED50 = 9.50 (5.86-15.39) mg/kg). In contrast, a parallel rightwards shift of the dose-response curves, corresponding to a significant 1.92 (1.49-2.52)-fold decrease in analgesic potency, was observed after i.v. administration of morphine in mice chronically treated with morphine (3 mg/kg, twice daily for 4 days) (ED50 = 3.10 (2.52-3.81) mg/kg) vs. saline (ED50 = 1.60 (1.22-2.09) mg/kg). No tolerance to RB101 was observed even after a longer period (8 days) of chronic treatment with the prodrug. Moreover, no cross-tolerance between morphine and RB101 appeared to occur since the ED50 values obtained after i.v. administration of RB101 were not significantly different in mice chronically pretreated with vehicle (ED50 = 9.50 (6.37-14.15) mg/kg) or with morphine (ED50 = 10.00 (6.62-15.10) mg/kg). The analgesic effect of RB101 observed in morphine-tolerant mice was antagonized by prior injection of naloxone, but not naltrindole (delta-selective antagonist), supporting a preferential involvement of mu-opioid receptors in the antinociceptive effect of RB101, at least in mice in the hot-plate test.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1989

Inhalation of hypertonic saline as a bronchial challenge in children with mild asthma and normal children.

The response to bronchial challenge with ultrasonically nebulized 4.5% saline was compared to the response to histamine and isocapneic hyperventilation in a group of children with mild asthma and control subjects. Challenge with 4.5% saline was found to have an accuracy of approximately 80%, compared to 90% for histamine and 80% for hyperventilation. The challenge test was well tolerated by all children. Increasing the dose of 4.5% saline delivered to the children by use of a nebulizer with a higher output improved the accuracy of challenge with 4.5% saline to approximately 90%. This finding suggests that the nebulizer output is an important determinant of the accuracy of bronchial challenge with 4.5% saline. Bronchial challenge with 4.5% saline appears to be a promising addition to the tests of bronchial responsiveness in children, but further studies, particularly documenting the reproducibility and the relationship to clinical asthma, are needed before it can replace the current standard tests.

Adolescent↗
PubMed2004

Overexpression of spermidine synthase enhances tolerance to multiple environmental stresses and up-regulates the expression of various stress-regulated genes in transgenic Arabidopsis thaliana.

Polyamines play pivotal roles in plant defense to environmental stresses. However, stress tolerance of genetically engineered plants for polyamine biosynthesis has been little examined so far. We cloned spermidine synthase cDNA from Cucurbita ficifolia and the gene was introduced to Arabidopsis thaliana under the control of the cauliflower mosaic virus 35S promoter. The transgene was stably integrated and actively transcribed in the transgenic plants. As compared with the wild-type plants, the T2 and T3 transgenic plants exhibited a significant increase in spermidine synthase activity and spermidine content in leaves together with enhanced tolerance to various stresses including chilling, freezing, salinity, hyperosmosis, drought, and paraquat toxicity. During exposure to chilling stress (5 degrees C), the transgenics displayed a remarkable increase in arginine decarboxylase activity and conjugated spermidine contents in leaves compared to the wild type. A cDNA microarray analysis revealed that several genes were more abundantly transcribed in the transgenics than in the wild type under chilling stress. These genes included those for stress-responsive transcription factors such as DREB and stress-protective proteins like rd29A. These results strongly suggest an important role for spermidine as a signaling regulator in stress signaling pathways, leading to build-up of stress tolerance mechanisms in plants under stress conditions.

Arabidopsis↗
PubMed2000

Genetic analysis of salt-tolerant mutants in Arabidopsis thaliana.

Stress caused by the increased salinity of irrigated fields impairs plant growth and is one of the major constraints that limits crop productivity in many important agricultural areas. As a contribution to solving such agronomic problems, we have carried out a large-scale screening for Arabidopsis thaliana mutants induced on different genetic backgrounds by EMS treatment, fast neutron bombardment, or T-DNA insertions. From the 675,500 seeds we screened, 17 mutant lines were isolated, all but one of which yielded 25-70% germination levels on 250 mm NaCl medium, a condition in which their ancestor ecotypes are unable to germinate. Monogenic recessive inheritance of NaCl-tolerant germination was displayed with incomplete penetrance by all the selected mutants, which fell into five complementation groups. These were named SALOBRENO (SAN) and mapped relative to polymorphic microsatellites, the map positions of three of them suggesting that they are novel genes. Strains carrying mutations in the SAN1-SAN4 genes display similar responses to both ionic effects and osmotic pressure, their germination being NaCl and mannitol tolerant but KCl and Na(2)SO(4) sensitive. In addition, NaCl-, KCl-, and mannitol-tolerant as well as abscisic-acid-insensitive germination was displayed by sañ5, whose genetic and molecular characterization indicates that it carries an extremely hypomorphic or null allele of the ABI4 gene, its deduced protein product lacking the APETALA2 DNA binding domain.

Abscisic Acid↗
PubMed2004

Over-expression of a transcription factor regulating ABA-responsive gene expression confers multiple stress tolerance.

Unfavourable environmental conditions, such as drought, freezing and high salinity, are major limiting factors of plant productivity. Plants perceive and respond adaptively to such 'abiotic stress' conditions, and the adaptive process is controlled mainly by the phytohormone, abscisic acid (ABA). The hormone, whose level increases under various stress conditions, functions as a signal to trigger adaptive responses that include changes in gene expression patterns. We have recently reported transcription factors that regulate the ABA-responsive gene expression. As ABA mediates adaptation to several common abiotic stresses, we investigated whether the transcription factors are involved in various stress responses. Here, we report that over-expression of ABF3, one of the factors, confers tolerance to chilling, freezing, high temperature and oxidative stress in addition to drought. Our results indicate that ABF3 is involved in multiple stress responses, and that it may be a useful genetic resource for the engineering of plant stress tolerance.

Journal Article↗
PubMed1991

Selenium tolerance, salt tolerance, and selenium accumulation in tall fescue lines.

High levels of soil salinity and Se concentration are coexisting problems in the San Joaquin Valley, California. Tall fescue is a potentially useful crop plant for land management in soils containing elevated concentrations of Se and salinity. Information regarding its physiological mechanism and genetic variation of Se accumulation in this species is scant. Thirteen tall fescue (Festuca arundinacea Schreb.) lines were examined for Se and salt tolerances and Se accumulation in nutrient solution culture. Genetic variation of both Se and salt tolerances was detected among six American cultivars and seven worldwide tall fescue lines. Selenium tolerance and salt tolerance are independent of each other and are negatively correlated with tissue Se and salt concentrations. These relationships suggest that an exclusion mechanism is responsible for the tolerance. This diversity of Se and salt tolerance and Se accumulation among the tall fescue lines is important for the application of this species for land management.

Genotype↗
PubMed1995

Role of drug-administration cues in the associative control of morphine tolerance in the rat.

This research investigated the role of injection procedures as a potential confound in the study of associative and nonassociative morphine tolerance development. Rats administered a series of morphine injections paired with a distinctive context environment can develop tolerance controlled associatively by the context. However, rats given morphine unpaired with the context may also develop some degree of tolerance. This study examined whether this tolerance represents an associative effect with animals using the injection ritual as a cue predictive of morphine delivery. Following 14 days of habituation to handling and injection stimuli, rats were given eight morphine injections (20 mg/kg, IP) explicitly paired or unpaired with a distinctive context. Animals were then tested for morphine analgesia in the context after either a 30-day rest condition or a 30-day period of daily saline injections. Analgesia was assessed by the tail-flick method, and tolerance was defined as the shift to the right of the dose-response curve of morphine-experienced relative to saline control animals. Paired animals across both retention conditions displayed tolerance, whereas tolerance retention in unpaired animals was observed only in those animals not given saline injections over the 30-day interval. Results support an associative interpretation of tolerance observed in unpaired conditions and suggest that the injection ritual may provide highly salient cues for the support of associative tolerance effects.

Analgesia↗
PubMed2006

Generation and analysis of expressed sequence tags from NaCl-treated Glycine soja.

BACKGROUND: Salinization causes negative effects on plant productivity and poses an increasingly serious threat to the sustainability of agriculture. Wild soybean (Glycine soja) can survive in highly saline conditions, therefore provides an ideal candidate plant system for salt tolerance gene mining. RESULTS: As a first step towards the characterization of genes that contribute to combating salinity stress, we constructed a full-length cDNA library of Glycine soja (50109) leaf treated with 150 mM NaCl, using the SMART technology. Random expressed sequence tag (EST) sequencing of 2,219 clones produced 2,003 cleaned ESTs for gene expression analysis. The average read length of cleaned ESTs was 454 bp, with an average GC content of 40%. These ESTs were assembled using the PHRAP program to generate 375 contigs and 696 singlets. The resulting unigenes were categorized according to the Gene Ontology (GO) hierarchy. The potential roles of gene products associated with stress related ESTs were discussed. We compared the EST sequences of Glycine soja to that of Glycine max by using the blastn algorithm. Most expressed sequences from wild soybean exhibited similarity with soybean. All our EST data are available on the Internet (GenBank_Accn: DT082443-DT084445). CONCLUSION: The Glycine soja ESTs will be used to mine salt tolerance gene, whose full-length cDNAs will be obtained easily from the full-length cDNA library. Comparison of Glycine soja ESTs with those of Glycine max revealed the potential to investigate the wild soybean's expression profile using the soybean's gene chip. This will provide opportunities to understand the genetic mechanisms underlying stress response of plants.

Arabidopsis↗
PubMed2001

Regular inhaled salbutamol : effect on airway responsiveness to methacholine and adenosine 5'-monophosphate and tolerance to bronchoprotection.

OBJECTIVE: Regular treatment with inhaled beta(2)-agonists increases airway responsiveness consistently to indirect bronchoconstrictors (allergen, exercise, hypertonic saline solution, etc) and inconsistently to direct bronchoconstrictors (histamine, methacholine). Studies demonstrating tolerance to beta(2)-agonist bronchoprotection against the indirect bronchoconstrictor adenosine 5'-monophosphate (AMP) have not examined changes in baseline AMP responsiveness. This study assessed the effect of regular salbutamol on AMP and methacholine responsiveness and on tolerance to bronchoprotection. DESIGN: Double-blind, randomized, crossover study. SETTING: University hospital bronchoprovocation laboratory. PATIENTS: Fourteen atopic asthmatic subjects with FEV(1) > 65% predicted, and methacholine provocative concentration causing a 20% fall in FEV(1) (PC(20)) < 8 mg/mL. INTERVENTIONS: Salbutamol, 100 microg, and placebo inhalers, two puffs qid, each for 10 days. MEASUREMENTS: Methacholine PC(20) and AMP PC(20) measured 12 h after blinded inhaler after each treatment period. Methacholine PC(20) and AMP PC(20) repeated 10 min after salbutamol, 200 microg (eight subjects). RESULTS: There was no difference between placebo and salbutamol treatment in geometric mean methacholine PC(20) (0.85 mg/mL vs 0.82 mg/mL, p = 0.86) or AMP PC(20) (22 mg/mL vs 17.4 mg/mL, p = 0.21; n = 14). The acute bronchoprotective effect of salbutamol was greater vs. AMP than vs methacholine (5.1 doubling concentrations vs. 3.5 doubling concentrations, p = 0.06) and loss of protective effect of salbutamol (mean +/- SD) was greater vs AMP than vs. methacholine (2.4 +/- 0.33 doubling concentration loss vs 0.8 +/- 0.21 doubling concentration loss, p = 0.008; n = 8). CONCLUSION: Regular salbutamol (mean +/- SD) treatment did not enhance airway responsiveness to either the indirect bronchoconstrictor AMP or the direct bronchoconstrictor methacholine. Compared to its effect on methacholine, salbutamol had a greater acute protective effect vs AMP and produced greater loss of protection vs AMP when used regularly.

Adenosine Monophosphate↗
PubMed2005

Dexamethasone modulates the development of morphine tolerance and expression of glutamate transporters in rats.

We recently demonstrated an increase in spinal cerebrospinal fluid (CSF) excitatory amino acids (EAAs) in morphine-tolerant rats after morphine challenge. The present study examined whether co-infusion of the glucocorticoid dexamethasone (DEX) co-infusion inhibited morphine tolerance and the morphine challenge-induced EAAs increase after long-term morphine infusion. Intrathecal (i.t.) catheters and one microdialysis probe were implanted to male Wistar rats. Rats were divided into four groups: i.t. morphine (15 microg/h), saline (1 microl/h), DEX (2 microg/h), or DEX (2 microg/h) plus morphine (15 microg/h) infusion for 5 days. Tail-flick responses were examined before drug infusion and daily after the start of infusion for 5 days. Moreover, on day 5 after morphine challenge (50 microg, i.t.), CSF EAAs was also measured. Rat spinal cords were removed on day 5, and prepared for Western blot analysis of different glutamate transporters (GTs). The AD50 (analgesic dose) on day 5 was 1.33 microg in saline-infused rats, 83.84 microg in morphine-tolerant rats, and 10.15 microg in DEX plus morphine co-infused rats. Single DEX (2 microg, i.t.) injection did not enhance morphine's antinociceptive effect in either naïve or morphine-tolerant rats. No difference in CSF EAA level was observed in all groups between baseline (before drug infusion) and on day 5 after tolerance developed. Surprisingly, on day 5, after morphine challenge, an increase in glutamate and aspartate (284+/-47% and 201+/-18% of basal) concentration was observed, and morphine lost its antinociceptive effect (maximum percent effect, MPE = 41+/-12%), whereas DEX/morphine co-infusion inhibited morphine-evoked EAA increase with a MPE = 97+/-2%. DEX co-infusion prevented the downregulation of glial glutamate transporters (GLAST (Glu-Asp transporter) and GLT-1 (Glu transporter-1)), but not the neuronal GT EAAC1 (excitatory amino acid carrier). Upregulation of GLT-1 was also observed (204+/-20% of basal). DEX co-infusion inhibits the morphine-challenge induced EAA increase and prevents the loss of morphine's antinociceptive effect after long-term morphine infusion.

Amino Acid Transport System X-AG↗
PubMed1996

Differential tolerance to the effects of chlordiazepoxide on unpunished and punished operant responding following chronic treatment.

Differential development of tolerance to the effects of benzodiazepines (BZs) is a common clinical phenomenon. To examine whether the development of tolerance to the response-suppressant and antipunishment effects of BZs were differentially regulated in animals, male Sprague-Dawley rats were treated chronically with either the BZ receptor agonist chlordiazepoxide (CDP, 25 mg/kg, IP, b.i.d.) or saline for 15 weeks and examined under a multiple schedule of operant behavior. Chronic administration of CDP produced tolerance to its suppressive effects on unpunished responding (RI 80 s) but no tolerance to its enhancing effects on punished responding. This conclusion is supported by three observations. First, repeated priming with CDP produced tolerance to its response-suppressive effects in the RI 80-s schedule and revealed increases in punished responding. Second, baseline levels for punished responding remained elevated over the 15-week treatment period. Third, tolerance developed to the response-suppressant effects of CDP under the RI 80-s schedule, as indicated by a sixfold shift to the right in the dose-response curves for rats treated chronically with CDP when compared to saline-treated controls. However, tolerance did not develop to the antipunishment effects of CDP, as indicated by no differences in the dose-response curves for punished responding. Discontinuation of chronic treatment disrupted unpunished responding only on the first day, and reversed the increase in punished responding. Taken together, these results indicate that differential regulation occurs for the development of tolerance to the response-suppressant and antipunishment effects of BZs.

Animals↗
PubMed1998

Antinociceptive tolerance to the mu-opioid agonist DAMGO is dose-dependently reduced by MK-801 in rats.

Morphine has been used in previous studies that investigate interactions between the spinal cord mu-opioid and N-methyl-D-aspartate (NMDA) receptors in mechanisms of antinociceptive tolerance. Although morphine acts primarily on the mu-receptor, it also activates other subtypes of opioid receptors. In the present study, the selective mu-opioid agonist, D-Ala2-N-Me-Phe4,Gly-ol5-enkephalin (DAMGO), was used to further test the hypothesis. Repeated intrathecal (i.t.) administration of 6 microg DAMGO (twice daily) in rats for 7 days resulted in an approximately 17-fold rightward shift of the cumulative dose-response curve (the tail-flick test) on Day 8 compared to that on Day 1. This rightward shift of the dose-response curve was prevented by the i.t. co-administration with DAMGO of the NMDA receptor antagonist MK-801 (10 = 5 > 2.5 >> 1.25 nmol > saline). Further, a lower dose range of MK-801 (2.5 > 1.25 nmol > 0.625 > 0.313 = saline) was effective to prevent the antinociceptive tolerance to a lower dose (1.5 microg) of DAMGO using the same i.t. administration regimen. Thus, the present results provide further evidence supporting a cellular and intracellular model of opioid tolerance involving interactions between the mu-opioid and the NMDA receptors in the spinal cord.

Analgesics↗
PubMed1992

Fluid retention after oral loading with water or saline in camels.

When dehydrated camels are offered water they drink volumes of water exceeding their body water loss during the water deprivation period. The excess water is excreted during 2-4 days. To investigate the ability to retain fluid in the body, normohydrated camels were loaded with water or isotonic saline (0.1 l/kg body wt) by esophageal tube. After water loading plasma osmolality decreased and a water diuresis was seen, but it took 3 days until the body weight returned to prehydration level. Plasma aldosterone concentration (PAC) increased, but plasma renin activity (PRA) and plasma atrial natriuretic peptide (ANP) concentration did not change. After the saline loading plasma osmolality increased and total plasma proteins and hematocrit decreased. Renal Na excretion increased 4 h after the saline load, but the magnitude of the natriuresis was small, and the camels had not regained their body weight 6 days after the load. PAC and PRA decreased after saline loading, while plasma ANP concentration did not change. These data show that camels are able to retain excess water within the body and to tolerate blood hyposmolality for a relatively long time. With saline the retention of fluid lasts even longer despite an attenuation of PAC.

Administration, Oral↗
PubMed1996

Behavioral contingencies modulate tolerance to discriminative stimulus effects of morphine.

Experiments examined how learning processes modulate tolerance to discriminative stimulus effects of morphine. Rats were trained to discriminate saline and 3.2 mg/kg morphine, and the doses of morphine required to mimic the training dose were determined before, during and after repeated treatment with saline or high doses of morphine (10 mg/kg, b.i.d.). In one set of experiments, training was either suspended or continued with saline and the original training dose during a 2-week treatment regimen. When training was suspended, high-dose morphine treatment increased the dose of morphine required for stimulus effects approximately 3-fold. Tolerance persisted 2 days after treatment ended, but disappeared within 7 days. In contrast, continued training with saline and 3.2 mg/kg morphine during high-dose treatment both attenuated development of tolerance and transferred control to lower doses. Transfer of control to lower doses appeared conditional upon recent termination of high-dose treatment, as it disappeared within 7 days. Treatment with saline did not change the doses of morphine required for stimulus effects under either training condition. A final experiment examined whether high-dose treatment could transfer control to higher doses of morphine. The treatment dose of 10 mg/kg morphine itself was used as the training dose during a 2-week treatment regimen. The dose of morphine required for stimulus effects increased 2- to 4-fold during treatment, but quickly returned to control values when treatment ended. These results extend previous findings that conditioning and pharmacodynamic processes jointly regulate development of tolerance to discriminative effects of morphine.

Animals↗