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PubMed2002

Mercury and lead tolerance in hypersaline sulfate-reducing bacteria.

Sulfate-reducing bacteria (SRB) HSR1, HSR4, and HSR14 isolated from the salt pans of Goa grew best at 90-100/1000 salinity on substrates like formate, acetate, lactate, butyrate, ethanol and benzoate. They were gram negative, non-sporulating, non-motile rods lacking in desulfoviridin and cytochromes. Examination of these isolates for heavy metal tolerance and response studies in terms of growth and sulfate-reducing activity (SRA) were carried out using HgCl2 and Pb(NO3)2 at final concentration of 50, 100, and 200 and 100, 200 and 500 microg ml(-1) respectively. With Hg, HSR1 showed approximately 80% of the control's growth at 100 and 200 microg ml(-1) but SRA reached only 60% of the control values at the end of 14 days. HSR14 could reach >100% of the control's growth at 200 microg ml(-1) but the SRA reached only up to 60% of the control without metal at 100 microg ml(-1). Though the concentration of Pb was double that of Hg, HSR4 could grow and respire better than the control, the growth being stimulated by 160% and respiration by 170% in the presence of 500 microg ml(-1) of Pb(NO3)2. It is probable that some hypersaline SRB are more tolerant to heavy metals than the mesohaline counterparts and could be more effectively used for precipitating these metals in bioremediatory measures. Further examination of their responses to varied concentration of metals under different salinities would indicate their range of applicability.

Adaptation, Physiological↗
PubMed2002

Gastric distension and duodenal lipid infusion modulate intestinal gas transit and tolerance in humans.

OBJECTIVE: Patients with unexplained abdominal complaints often attribute their symptoms to intestinal gas and indicate that symptoms are exacerbated by ingestion of a meal. However, the mechanisms responsible are unknown. Our aim was to analyze the specific influence of two meal-related factors, gastric distension, and intestinal nutrients, on intestinal gas dynamics and tolerance. METHODS: In 35 healthy subjects, gas evacuation and perception of jejunal gas infusion (12 ml/min) were measured for 3 h, during simultaneous duodenal infusion of saline, as control, lipids at 1 Kcal/min, or gastric distension. RESULTS: Infusion of lipids into the duodenum induced gas retention (584 +/- 154 ml, p < 0.05 vs 161 +/- 86 ml after saline infusion) without perception (2.2 +/- 0.5 score), whereas gastric distension induced perception (score 5.6 +/- 0.4, p < 0.05 vs score 1.9 +/- 0.4 after saline) without gas retention (7 +/- 205 ml). CONCLUSIONS: Different meal-related factors exert specific effects on intestinal gas dynamics and tolerance, and these mechanisms may interact to produce postprandial gas symptoms.

Abdominal Pain↗
PubMed1994

Pavlovian inhibitory conditioning and tolerance-reversal to scopolamine-induced adipsia in rats.

In the present experiment the effect of a conditioned inhibitory stimulus on tolerance to scopolamine-induced adipsia was evaluated. Long-Evans rats were injected with 0.6 mg/kg scopolamine bromidrate in the presence of a tone or a noise, and physiological saline with a compound tone-odor. A summation test with the compound stimulus noise-odor showed a tolerance reversal effect to scopolamine adipsic effects in tolerant subjects. This reduction of tolerance was similar to adipsia produced by the first scopolamine administration, only when the odor stimulus was present. However, the inhibitory stimulus alone has no effect upon water intake. Results confirmed that a Pavlovian conditioned inhibition procedure can reduce conditioned tolerance to a drug.

Animals↗
PubMed1995

Morphine-3-glucuronide: evidence to support its putative role in the development of tolerance to the antinociceptive effects of morphine in the rat.

Antinociceptive tolerance to morphine (MOR) was induced in groups of Sprague-Dawley rats receiving continuous intravenous infusions of morphine sulphate administered by 3 different MOR dosing regimes. At appropriate intervals throughout each infusion period, antinociceptive testing was performed using the tail-flick latency test and blood samples were collected. Groups of saline (SAL)-infused control rats also underwent antinociceptive testing and blood sample collection. Complete antinociceptive tolerance developed during each MOR infusion period and was characterized by a marked decline in the degree of antinociception from values greater than 90% of the maximum possible effect (%MPE) to pre-dosing baseline values. By contrast, %MPE values in SAL-infused control animals and in sham-operated rats were not significantly different from pre-dosing values throughout the infusion period, indicating that the experimental procedures themselves did not contribute to the development of antinociceptive tolerance to MOR. In addition, the rate of MOR tolerance development was inversely proportional to the MOR infusion rate. A very significant inverse relationship was observed between the mean degree of antinociception (%MPE) and the mean plasma molar concentration ratio, [morphine-3-glucuronide]/[MOR], for each of the 3 MOR dosing regimes and for the cumulated data. This relationship showed that near-maximum antinociception was attainable at ratio values less than approximately 0.50, whilst at ratio values above approximately 1.5, little or no antinociception was observed. Although %MPE was highly inversely correlated with the mean plasma morphine-3-glucuronide (M3G) concentrations for rats receiving regimes A and B, this was not the case for rats receiving regime C where antinociceptive tolerance was partially reversed by an increase in the morphine infusion rate part-way through the infusion period. In addition, a poor relationship was observed between %MPE and the mean plasma MOR concentration, possibly due to the confounding presence of M3G in all samples. Thus, we may conclude from this study in Sprague-Dawley rats that irrespective of the rate of antinociceptive tolerance development, the level of antinociception achievable appears to be highly inversely correlated with the mean [M3G]/[MOR] plasma molar concentration ratio and poorly correlated with the plasma MOR concentration, consistent with the notion that it is perhaps the balance between the excitatory effects of M3G and the inhibitory effects of MOR at the functional level which is the important determinant. Further research is required in carefully conducted studies in cancer patients to evaluate the possible contribution of the MOR metabolites, M3G and morphine-6-glucuronide (MbG), to increasing dosing requirements of MOR.(ABSTRACT TRUNCATED AT 400 WORDS)

Analgesics↗
PubMed2005

Increased salinization of fresh water in the northeastern United States.

Chloride concentrations are increasing at a rate that threatens the availability of fresh water in the northeastern United States. Increases in roadways and deicer use are now salinizing fresh waters, degrading habitat for aquatic organisms, and impacting large supplies of drinking water for humans throughout the region. We observed chloride concentrations of up to 25% of the concentration of seawater in streams of Maryland, New York, and New Hampshire during winters, and chloride concentrations remaining up to 100 times greater than unimpacted forest streams during summers. Mean annual chloride concentration increased as a function of impervious surface and exceeded tolerance for freshwater life in suburban and urban watersheds. Our analysis shows that if salinity were to continue to increase at its present rate due to changes in impervious surface coverage and current management practices, many surface waters in the northeastern United States would not be potable for human consumption and would become toxic to freshwater life within the next century.

Chlorides↗
PubMedDate not supplied

Acute adaptation of mice to hypoxic hypoxia.

Tolerance to hypoxia in vivo and in vitro was significantly increased by acute and repetitive exposure of mice to autoprogressive hypoxia. The average tolerance times of the successive 2nd, 3rd, 4th and 5th runs of exposure were, respectively, 2, 4, 6 and 8 times as long as that of the first exposure. The survival times under hypobaric chamber and cyanide toxification in the 4th exposure were, respectively, 10 (and even as much as 86) and 4 times those in control mice without exposure to hypoxia. Mandibular respiration and spinal reflex in vitro in hypoxia-resistant animals lasted 5-6 times as long as in control animals not previously exposed to hypoxia. Animals that received brain homogenate from hypoxia-resistant mice remained alive in a hypobaric chamber 2 times as long as those that received homogenate from controls and those that received saline. These results indicate that a kind of quickly developing adaptation with increased tolerance is achieved by acute and repetitive exposure of mice to progressive autohypoxia and some plastic or adaptive changes occur in the brain of hypoxia-resistant animals, including the production of some kind of water-soluble antihypoxic factors.

Adaptation, Physiological↗
PubMed1980

Modification of the behavioral effects of phencyclidine by repeated drug exposure and body weight changes.

In the first experiment, the effects of phencyclidine (PCP) on intake of sweetened condensed milk by rats were compared before and during a period of repeated daily injections of PCP or saline. A shift to the right in the PCP dose-effect function was found in rats receiving daily PCP injections indicating tolerance development to the effects of PCP on milk intake. The dose-effect function of PCP was shifted to the right in animals receiving daily saline as well. However, when body weight changes were controlled for in this groups of animals, the effects of PCP were the same as they had been initially, implicating body weight as a determinant of the behavioral effects of PCP. In the second experiment, a direct comparison of the behavioral effects of PCP in high- and low-weight animals revealed diminished effects of PCP in high-weight animals. When these animals were treated with 3H-PCP, brain total radioactivity as well as 3H-PCP in the high-weight animals were significantly lower than those in the low-weight animals.

Animals↗
PubMed2002

Photosynthetic limitations of a halophyte sea aster (Aster tripolium L) under water stress and NaCl stress.

To understand the mechanisms of salt tolerance in a halophyte, sea aster ( Aster tripolium L.), we studied the changes of water relation and the factors of photosynthetic limitation under water stress and 300 mM NaCl stress. The contents of Na(+) and Cl(-) were highest in NaCl-stressed leaves. Leaf osmotic potentials ( Psi(s)) were decreased by both stress treatments, whereas leaf turgor pressure ( Psi(t)) was maintained under NaCl stress. Decrease in Psi(s) without any loss of Psi(t) accounted for osmotic adjustment using Na(+) and Cl(-) accumulated under NaCl stress. Stress treatments affected photosynthesis, and stomatal limitation was higher under water stress than under NaCl stress. Additionally, maximum CO(2) fixation rate and O(2) evolution rate decreased only under water stress, indicating irreversible damage to photosynthetic systems, mainly by dehydration. Water stress severely affected the water relation and photosynthetic capacity. On the other hand, turgid leaves under NaCl stress have dehydration tolerance due to maintenance of Psi(t) and photosynthetic activity. These results show that sea aster might not suffer from tissue dehydration in highly salinized environments. We conclude that the adaptation of sea aster to salinity may be accomplished by osmotic adjustment using accumulated Na(+) and Cl(-), and that this plant has typical halophyte characteristics, but not drought tolerance.

Adaptation, Physiological↗
PubMed2004

Opiate tolerance by heroin self-administration: an fMRI study in rat.

Functional MRI (fMRI) was employed to determine whether repeated heroin self-administration (SA) produces tolerance or sensitization in the brain of heroin-SA rats. Twelve rats were evenly divided into saline and heroin (0.06 mg/kg, 4 hr/day) SA groups. There was a progressive increase in drug-SA behavior and daily heroin intake during the 8-9 days of heroin-SA training. Within 24 hr after the last session of daily SA, acute heroin (0.1 mg/kg) administration induced regional blood oxygen level-dependent (BOLD) signals in both groups of rats. The positive BOLD signals appeared mainly in the cortical regions, including the prefrontal cortex, cingulate, and olfactory cortex, while the negative BOLD signals were predominantly located in subcortical regions such as caudate and putamen, nucleus accumbens, thalamus, and hypothalamus. However, the number of activated voxels or BOLD-signal intensity was significantly less in heroin-SA rat in regions of prefrontal cortex, nucleus accumbens, and thalamus, etc., compared to the changes in the saline control rats. Application of gamma-vinyl GABA (100 mg/kg), an irreversible GABA-transaminase inhibitor, failed to block opiate actions in the heroin-SA rats. Together, these data suggest that repeated heroin-SA produces tolerance or desensitization of opiate actions in the rat brain, which may in turn potentiate drug SA behavior and drug intake.

Animals↗
PubMed2001

Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial.

BACKGROUND: Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis. Alternate-day treatment, if equally effective, would reduce the drug cost. Hypertonic saline improved lung function to the same degree as rhDNase in short-term studies. We compared the effectiveness of daily rhDNase, hypertonic saline, and alternate-day rhDNase in children with cystic fibrosis. METHODS: In an open cross-over trial, 48 children were allocated in random order to 12 weeks of once-daily rhDNase (2.5 mg), alternate-day rhDNase (2.5 mg), and twice-daily 5 mL 7% hypertonic saline. The primary outcome was forced expiratory volume in 1 s (FEV(1)). Secondary outcomes were forced vital capacity, number of pulmonary exacerbations, weight gain, quality of life, exercise tolerance, and the total costs of hospital and community care. FINDINGS: Mean FEV(1) increased by 16% (SD 25%), 14% (22%), and 3% (21%) with daily rhDNase, alternate-day rhDNase, and hypertonic saline, respectively. There was no difference between daily and alternate-day rhDNase (2% [95% CI -4 to 9], p=0.55). However, daily rhDNase showed a significantly greater increase in FEV(1) than hypertonic saline (8% [2 to 14], p=0.01). The average difference in 12-week cost between daily and alternate-day rhDNase was pound513 (95% CI -546 to 1510) and that between daily rhDNase and hypertonic saline was pound1409 (440 to 2318). None of the secondary clinical outcomes showed significant differences between treatments. INTERPRETATION: Hypertonic saline, delivered by jet nebuliser, is not as effective as daily rhDNase, although there is variation in individual response. There is no evidence of a difference between daily and alternate-day rhDNase.

Adolescent↗
PubMed2004

The effects of NMDA and GABAA pharmacological manipulations on acute and rapid tolerance to ethanol during ontogeny.

BACKGROUND: Sensitivity to several ethanol effects increases during ontogeny, perhaps in part because of a notable decline in acute tolerance. In contrast, rapid tolerance to ethanol-induced sedation emerges slowly during ontogeny. This study tested the hypothesis that ontogenetic differences in glutamate and/or gamma-aminobutyric acid systems influence tolerance expression. METHODS: Sprague-Dawley rats at postnatal day (P)26 or P70 received (+)MK-801, muscimol, or saline before ethanol (3.5 or 4.5 g/kg) or saline on day 1 and ethanol only on day 2. Loss of and time to regain the righting reflex and blood alcohol levels at recovery were recorded. The presence of acute tolerance was indicated as a positive slope of the linear regression of blood alcohol levels at recovery versus ethanol dose. Rapid tolerance was estimated on day 2 by comparing animals given ethanol only on day 2 with those given ethanol on both days. RESULTS: Acute tolerance on day 1 only was observed at P26; this was disrupted by (+)MK-801 but not muscimol. Evidence for acute tolerance also emerged in adults on day 2. Whereas both drugs increased ethanol sedation at both ages, they did not facilitate ontogenetic expression of rapid tolerance: rapid tolerance was not evident at P26 regardless of pretreatment when indexed in terms of recovery time. CONCLUSIONS: These data provide further evidence for an ontogenetic dissociation in the expression of acute and rapid tolerance to ethanol-induced sedation. Pharmacological attenuation of the expression of acute tolerance was sufficient but not necessary to delay recovery of righting after ethanol. The greater propensity of young animals to develop acute tolerance, seemingly modulated in part by NMDA receptors, may contribute to their relative resistance to ethanol, although other factors, including pharmacokinetic factors, also contribute to their more rapid recovery from ethanol sedation.

Aging↗
PubMed1995

Balloon test occlusion of the internal carotid artery with hypotensive challenge.

PURPOSE: To evaluate the usefulness of provocative testing with hypotensive challenge during balloon test occlusion of the internal carotid artery before carotid sacrifice and to correlate tolerance of balloon test occlusion with clinical outcome after carotid artery sacrifice. METHODS: Forty-seven consecutive cases of balloon test occlusions performed at our institution during the past 4 years were retrospectively reviewed. Occlusion was performed under normotensive conditions with distal perfusion of heparinized saline for 20 minutes, or until a deficit was perceived. If 20 minutes of normotension was tolerated, hypotension was induced to two thirds of mean arterial pressure for 20 minutes, or until a deficit was perceived. RESULTS: Of 47 patients, 4 (9%) had deficits at normotension. Of the remaining 43 patients, 9 (21%) had deficits at hypotension. One patient with a positive hypotensive test occlusion underwent carotid artery sacrifice after extracranial-intracranial bypass without sequelae. In one of the 19 patients who clinically tolerated test occlusion with hypotension and had carotid sacrifice (surgical ligation of the intracranial carotid artery), a mild embolic stroke developed, probably from the giant carotid wall aneurysm. This patient fully recovered; MR imaging showed mild changes consistent with emboli distal to the aneurysm. Symptomatic complications were noted in 2 (4%) patients, and asymptomatic arterial dissections were noted in 3 (6%) patients. CONCLUSION: Balloon test occlusion with hypotensive challenge is safe, economical, and greatly increases the sensitivity of balloon test occlusion. The predictive value of a negative test is high. However, to determine the test's specificity compared with quantitative imaging, controlled trials will be necessary.

Adult↗
PubMed2000

Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance.

The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. Possible abnormal pain and spinal antinociceptive tolerance were evaluated after intrathecal administration of [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO), an opioid mu agonist. Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion) and a decrease in antinociceptive potency and efficacy of spinal opioids (tolerance), signs also characteristic of nerve injury. Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the mu receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal administration of dynorphin A(1-17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels (i.e., antinociception). Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive potency and efficacy of spinal morphine. Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.

Analgesics↗
PubMed1988

Tolerance to and cross tolerance between ethanol and nicotine.

Female DBA mice were subjected to one of four treatments: ethanol-containing or control diets, nicotine (0.2, 1.0, 5.0 mg/kg/hr) infusion or saline infusion. After removal from the liquid diets or cessation of infusion, the animals were challenged with an acute dose of ethanol or nicotine. Chronic ethanol-fed mice were tolerant to the effects of ethanol on body temperature and open field activity and were cross tolerant to the effects of nicotine on body temperature and heart rate. Nicotine infused animals were tolerant to the effects of nicotine on body temperature and rotarod performance and were cross tolerant to the effects of ethanol on body temperature. Ethanol-induced sleep time was decreased in chronic ethanol- but not chronic nicotine-treated mice. Chronic drug treatment did not alter the elimination rate of either drug. Chronic ethanol treatment did not alter the number or affinity of brain nicotinic receptors whereas chronic nicotine treatment elicited an increase in the number of [3H]-nicotine binding sites. Tolerance and cross tolerance between ethanol and nicotine is discussed in terms of potential effects on desensitization of brain nicotinic receptors.

Alcoholism↗
PubMed1990

Prolonged survival of tumor-bearing rats with repetitive low-dose recombinant tumor necrosis factor.

Tumor necrosis factor may be a mediator of the syndrome of cancer cachexia. Tachyphylaxis or tolerance to the cachectic effects of recombinant tumor necrosis factor (rTNF) has been previously described. In this study, we investigate whether repetitive exposure to rTNF can induce similar tolerance in tumor-bearing (TB) rats and ameliorate cachexia induced by the tumor. In experiment 1, non-tumor-bearing (NTB) and TB rats were randomized to either escalating low doses of rTNF or saline i.p. twice daily for 9 consecutive days. NTB rats treated with rTNF demonstrated a significant decline in food intake and weight change (P less than 0.00001) but soon developed tolerance to the cachectic effects of rTNF; they consumed significantly more food than on the first day of treatment and had weight change similar to NTB rats treated with saline. TB rats treated with rTNF showed a similar significant decline in food intake and weight change (P less than 0.0001) and also demonstrated similar tolerance to the cachectic effects of rTNF with continued treatment. Following treatment, TB rats that had been treated with rTNF ate significantly more and lost less weight than TB rats that had been treated with saline (P less than 0.00001). rTNF treatment of TB rats also demonstrated antineoplastic activity, as estimated tumor weight of tumors from rats treated with rTNF were significantly less than controls (P = 0.003). The anticachexia and antineoplastic effects of rTNF resulted in prolonged survival of TB rats treated with rTNF compared to control TB rats (P = 0.015). Experiment 2 utilized two different rTNF treatment regimens in TB rats: one group received 12 days of escalating doses of rTNF, and another group received 15 days of rTNF treatment. TB rats treated with rTNF again had a significantly greater food intake (P less than 0.00001) and delayed weight loss (P = 0.0001) posttreatment that was further augmented by additional doses of rTNF. Antineoplastic activity of rTNF was less clear, and overall tumor growth curves were not affected by rTNF treatment. Survival of TB rats treated with rTNF was again significantly increased in a dose-dependent manner (P = 0.006). Repeated administration of low doses of rTNF to TB rats induces mild reduction in tumor growth, tolerance to the cachectic effects of rTNF that results in tolerance to the cachectic effects of tumor, and prolongation of survival.

Animals↗
PubMed2003

Prevention of myosin-induced autoimmune myocarditis in mice by anti-L3T4 monoclonal antibody.

This study was aimed at studying the effect of the induction of immune tolerance to swine cardiac myosin from anti-L3T4 monoclonal antibody injection and whether the immune tolerance could protect mice with myosin-induced myocarditis from myocardial injury. Twenty-four Balb/c mice were divided into two groups at random. All of the mice were immunized with swine cardiac myosin on the 1st day, 14th, 28th, 42nd, and 52nd day. Immune tolerance was induced by triplicate injections of 400 microg anti-L3T4 McAb on the 0 day (intravenous), 1st day, and 2nd day (intraperitoneal) in McAb-treated group. In the saline-treated group, saline of the same volume as anti-L3T4 monoclonal antibody was used as a control. The sera and hearts biopsies of all mice were collected on the 58th day. The anti-cardiac myosin antibody was examined with ELISA, and pathological changes of heart were observed by light microscope. It was shown that mice immunized with swine cardiac myosin could produce anti-myosin antibody and the anti-cardiac myosin antibody was positive in most of the saline-treated group but negative in the McAb-treated group. Morphologically, myocardial degeneration, necrosis, and infiltration of inflammatory cells were found in the saline-treated group but not in the McAb-treated group. In conclusion, this study indicated that the immune tolerance to cardiac myosin was induced by the anti-L3T4 monoclonal antibody, and accordingly myocardial injury could be prevented by induction of immune tolerance.

Animals↗
PubMed1994

Preoperative local infiltration with ropivacaine for postoperative pain relief after cholecystectomy.

In a randomized, double-blind, placebo-controlled trial, we evaluated the use of preoperative local anesthesia with regard to postoperative pain. Before surgery in 66 patients scheduled for cholecystectomy, the abdominal wall along the proposed line of incision was infiltrated with 70 mL of 0.25% ropivacaine, 70 mL of 0.125% ropivacaine, or 70 mL of saline. Wound pain at rest, wound pain during mobilization, and pressure exerted to reach maximum pain tolerance were assessed after 6, 26, 50, and 74 h and after 7 days. Consumption of analgesics was recorded. At the 6-h assessment, there was a statistically significant dose-related decrease in wound pain during mobilization (P = 0.001) and an increase of pressure exerted to reach maximum pain tolerance (P < 0.001). The tests were two-tailed and performed at a significance level of P < 0.05. There were no significant differences between the groups at later pain control assessments. The median time to first request for postoperative analgesics was significantly shorter (P = 0.014) in the saline group than in the ropivacaine 0.25% group. These effects are suggested to be a residual anesthetic effect of ropivacaine. The study gives no support to the hypothesis that preoperative local anesthetics dampen the inflammatory response and ensuing hyperalgesia.

Acetaminophen↗
PubMed1989

Time course characteristics of tolerance development to continuously infused antinociceptive agents in rat spinal cord.

By using a constant-rate, fixed concentration intrathecal infusion model, the time course of change in hot plate (HP) response latencies over a 7-day period was examined in rats receiving constant infusion of saline (vehicle), morphine (MOR (2, 6 or 20 nmol/hr), sufentanil (SUF) (0.06, 0.2 or 0.6 nmol/hr), D-Ala2-MePhe4-Gly-ol5-enkephalin (DAMGO) (0.1, 0.3 or 1.0 nmol/hr) (mu opioids), D-Ala2-D-Leu5-enkephalin (DADLE) (2,6 or 20 nmol/hr) (delta opioid), ST-91 (3, 10 or 30 nmol/hr) (alpha-2 agonist) or the combination of ST-91 + MOR. Three important observations were made: 1) A concentration-dependent elevation in HP latency was observed on day 1 (order of potency: DAMGO = SUF greater than MOR greater than or equal to DADLE greater than or equal to ST-91 + MOR greater than or equal to ST-91) with a gradual return to saline-infused values observed for all concentrations of all drugs by 3 to 5 days. 2) The rate of tolerance development, estimated by calculation of the exponential decay half-life from peak day 1 HP, was not different as a function of drug dose. The area under the 7-day tolerance curve (response latency x day) was directly proportional to infusion concentration and to peak HP effect on day 1. These two calculations both suggest that the rate at which the tolerance adaptation of drug occurs to agonist effects is similar for agents acting upon mu, delta and alpha-2 receptors in rat spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗