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PubMed2005

Expression of opioid receptor-like 1 (ORL1) & mu opioid receptors in the spinal cord of morphine tolerant mice.

BACKGROUND & OBJECTIVE: The mechanism underlying the development of tolerance to morphine is not clearly understood though a number of factors have been implicated. One of the likely factors may be increased activity of anti-opioid peptides like nociceptin (also known as orphanin FQ or N/OFQ). N/OFQ and morphine bind to opioid receptor-like 1 (ORL1) receptor and muopioid receptor respectively. The present work was undertaken to investigate the density of ORL1 and mu (mu) receptor expression in the spinal cord of mice after inducing morphine tolerance. METHODS: Swiss albino mice were injected with either morphine (experimental group, n=15) or saline (control, n=15), twice a day for 9 days. The development of tolerance was noted by the hotplate test. Cryostat sections of the cervical region of spinal cord were labeled with specific ligands to localize ORL1 and mu receptors. The density of receptor expression over laminae I-II of spinal cord was evaluated using image analysis system. RESULTS: The morphine treated mice developed tolerance by day 9 as evident by the hot plate test. Both receptors were selectively expressed at a higher concentration over the superficial laminae (I-II) of the dorsal horn, indicating a role in pain processing. An increased expression of ORL1 receptors was also noted over the gray matter around the central canal. Quantitative analysis showed an increased expression of ORL1 and mu receptors though the increase was not statistically significant. INTERPRETATION & CONCLUSION: The present study showed that both, ORL1 and mu-opioid receptors were expressed in areas of the spinal cord, concerned with transmission of pain signals. The density of these receptors increased in the superficial laminae (I-II) though not significantly from control after morphine tolerance. The increase in ORL1 receptors could oppose the analgesic action of morphine, contributing to tolerance. Further studies need to be done to elucidate the mechanism of morphine tolerance.

Animals↗
PubMed1983

[Characteristics of reverse tolerance to ambulation-increasing effect of methylphenidate after repeated administration in mice].

Effects of repeated administration of methylphenidate (MPD) 2, 4, 8 and 16 mg/kg, sc on ambulatory activity in adult male mice of old strain were studied. The ambulatory activity of each mouse was measured by a tilting-type activity cage for 90-150 min after the drug administration. The repeated administration of MPD 2 and 4 mg/kg at intervals of 3-4 days, and 4 mg/kg at intervals of 7 days produced an augmentation in the sensitivity of the mice, i.e., a reverse tolerance, to the ambulation-increasing effect of the drug. However, the repeated administration of MPD 4 mg/kg at intervals of 1 day, and 8 and 16 mg/kg at intervals of 3-4 days did not produce the reverse tolerance to it. The mice repeatedly given 16 mg/kg at intervals of 3-4 days exhibited an augmentation in stereotyped behaviors. The reverse tolerance, once produced, was well maintained 45 days after cessation of the repeated administration. Only a little reverse tolerance to MPD was produced in the mice repeatedly given the drug in their home cage, in which the mice were group-housed, and the extent was significantly less than that observed in the mice given the drug in the activity cage. In addition, the mice showing the reverse tolerance to MPD demonstrated an increase in sensitivity to methamphetamine as compared with the saline-given control mice. The present results suggest that the characteristics of reverse tolerance to the ambulation-increasing effect of MPD is almost identical with that after methamphetamine.

Amphetamine↗
PubMed1991

Induction of tolerance to syngeneic IgE in neonatal mice.

We have previously shown that adult A/J mice are tolerant to syngeneic IgE at the level of T cells, but not B cells. T cells of mice are responsive until the age of 2 to 3 wk, which correlates with the time of appearance of serum IgE. Tolerance can be induced earlier by neonatal administration of IgE in saline. We report here that purified nonimmune adult B cells, but not T cells, can transfer the state of tolerance to neonatal mice. As few as 2 x 10(6) B cells are effective. If IgE-bearing or IgE-secreting cells prove to be responsible, the amount of cell-bound IgE that can induce tolerance must be very small. The results also indicate that suppressor T cells do not have a major role in maintenance of self-tolerance to IgE.

Animals↗
PubMed1998

Cecal intubation model in the rat that facilitates selective in vivo study of colonic epithelial biology: preliminary report.

PURPOSE: A free-living animal model with ready and repetitive access to selected regions of the large bowel and with minimally altered bowel anatomy and physiology would facilitate the in vivo study of luminal factors on the colonic mucosa in a steady-state environment. This study describes a novel model of large-bowel intubation in the rat. METHOD: Four Sprague-Dawley rats (240-260 g) had laparotomy and intubation of the distal colon and the cecum via a cecotomy with the use of two small tubes with restraints and transmural anchors. The tubes were tunneled and anchored to the back for infusion of fluid directly into the colon. Tube positions were studied when the animals were killed. Animals were fed on either a 10 percent fiber diet or a fiber-free diet. Stathmokinetic assessment of the distal colon was performed after one week of infusion with phosphate-buffered saline and sodium n-butyrate. RESULTS: The technique produced an easy access without affecting the weight gain of the animals after recovery. Tube positions were accurate after three weeks at the time the animals were killed. Infusions of phosphate-buffered saline and n-butyrate were well tolerated. n-Butyrate infusions twice daily for a week reversed the atrophy in the colonic mucosa induced by dietary fiber deprivation. CONCLUSION: An in vivo large-bowel intubation model permitting selective delivery of luminal factors provides an effective option for the study of colonic mucosal biology.

Animals↗
PubMed1998

5-HT3 serotonergic receptor mediation of hypoglycemia-induced arginine-vasopressin but not oxytocin secretion in normal men.

The present study was undertaken in order to establish the possible involvement of 5-HT3 serotonergic receptors in the control of basal and/or hypoglycemia-stimulated arginine vasopressin (AVP) and/or oxytocin (OT) secretion. For this purpose, 12 normal men were injected intravenously with a bolus of 4 mg ondansetron, a specific 5-HT3 receptor antagonist, under basal conditions (n = 6) or 30 min before insulin (0.15 IU/kg body weight) administration (n = 6) (insulin tolerance test (ITT)). Control experiments with normal saline instead of ondansetron treatment were performed. Furthermore, on a different occasion, the same subjects were tested in identical experimental conditions with 8 mg ondansetron. Our results showed that the hypoglycemic response to insulin was similar during the ITT and ondansetron plus ITT. Inhibition of 5-HT3 serotonergic receptors with ondansetron (4 or 8 mg) did not modify the basal secretion of AVP and OT and the OT response to insulin-induced hypoglycemia. In contrast, the administration of 4 or 8 mg ondansetron significantly reduced in a similar manner hypoglycemia-induced AVP rise. Mean peak level at 45 min after insulin injection was 2.25 times higher than baseline in the control ITT and 1.5 times higher than basal value in the ondansetron (4 or 8 mg) plus ITT. These data demonstrate that 5-HT3 serotonergic receptors at least partially mediate the AVP response to hypoglycemia, without modifying the simultaneous OT response. On the other hand, 5-HT3 receptors do not appear to be involved in the control of basal posterior pituitary hormone secretions.

Adult↗
PubMed1998

Clinical and manometric effects of combined external beam irradiation and brachytherapy for anal cancer.

This study evaluates anorectal function after combined tele- and brachytherapy for anal cancer using manometric measurements and a standardized questionnaire. Eight patients received 44 +/- 3 Gy external beam radiation followed by 20 +/- 4 Gy interstitial brachytherapy with iridium-192. Patients were examined 43 months (range 25-83) after therapy. Maximum anal basal pressure, squeeze pressure, and squeeze increment were significantly lower in patients (50, 163, 115 mmHg, respectively) than in control subjects (75, 285, 180 mmHg, respectively). Decreased anal elasticity was not observed. Anal prestretch "normalized" the contractility of the internal and external sphincter. Thus damage to the anal epithelium and hemorrhoidal cushions seems to be the most important mechanism explaining reduced anal closing pressure values. The rectoanal inhibitory reflex was observed in all but one patient. Rectal compliance was significantly reduced. Whereas all patients could retain a water filled rectal balloon until the maximum tolerable sensation level was reached, the rectal saline infusion test was strongly abnormal. Four patients were perfectly continent. Four patients were incontinent for gas and presented urgency in case of liquid stools with limited soiling occurring once weekly or less; three of them also had urgency for solids. Defecation frequency was increased but regular in most patients. Reduced anal closure together with reduced rectal compliance are at the basis of stool frequency, urgency and partial incontinence with occasional soiling. However, enough reserve sphincter function was maintained to preserve a clinically acceptable degree of anal continence in our patients.

Adenocarcinoma↗
PubMed1983

Vascular participation in deep cold pain.

As the magnitude of cold pain probably depends on blood flow and thus on internal limb temperature, the activated nociceptors should be close to or within the walls of veins. This hypothesis was tested by injecting small quantities (20 ml) of cold saline into an empty vein of the hand in 16 subjects. Saline temperatures below 26 degrees C elicited pure cold sensations whereas temperatures below 20 degrees C evoked both cold and pain sensations. Pain was mainly described as deep and it tended to radiate along the veins. With saline of 5 degrees C the pain tolerance level of several subjects was reached. Pain always appeared after cold and it disappeared before or together with cold. The results can be explained on the basis of two types of vascular receptors: a sensitive specific cold receptor and a nociceptor with a threshold around 20 degrees C.

Adult↗
PubMed2002

30-day intravenous administration of VRCTC-310-ONCO in rabbits.

VRCTC-310-ONCO, an agent based on the snake phospholipase A2 (crotoxin), is currently under clinical development. After phase I study in patients by intramuscular administration, the interest of intravenous (IV) dosing arose. To evaluate IV administration of VRCTC-310-ONCO in rabbits, ten animals were subjected to surgical implant of fixed jugular catheter, by which they received daily IV doses of 0.03 mg/kg body weight of VRCTC-310-ONCO for 30 days (n = 8) or saline (n = 2). The procedure was well tolerated in all rabbits. One of the animals died after the sixth dose of VRCTC-310-ONCO with CNS involvement; two additional rabbits required dose-reduction. All other rabbits achieved 30 days of treatment and were sacrificed. All rabbits (even controls) developed lymphocytosis and mild anaemia, without changes in blood neutrophils. No changes were found in serum transaminases (GOT and GPT), cholesterol, triglycerides, and y-glutamyl transpeptidase. At necropsy, chronic granulation tissue was found surrounding the implant in all rabbits. VRCTC-3 10-ONCO-treated rabbits presented generalised and marked swelling of hepatocytes, with areas of cytoplasmic vacuolisation. No abnormalities were found in kidney, heart, lung, spleen, adrenal gland, uterus, testes and ovary. Additional studies with IV route for VRCTC-310-ONCO, including humans, are required to define its toxicity in the clinical setting.

Adrenal Glands↗
PubMed2002

Nicotine-induced attentional enhancement in rats: effects of chronic exposure to nicotine.

Consistent with human literature, previous studies identified attention-enhancing effects of nicotine in rats, using a 5-choice task. The present study addressed the influence of repeated exposure to nicotine on these effects. Over six weeks, the effects of nicotine (0.0, 0.05 and 0.2 mg/kg) given ten min before sessions were tested each week. In addition, rats were injected daily two hours after sessions. In the first week, when these post-session injections were of saline for all rats, pre-session nicotine had profound rate-disruptive effects at the larger dose. In weeks 2-6, when half the rats received post-session injections of saline and the other half of nicotine (0.4 mg/kg), the disruptive effects of pre-session nicotine had disappeared and it enhanced attentional performance on all response indices. These effects did not differ significantly between post-session treatment groups or weeks, although they appeared less pronounced in the last two weeks. When tested under modified task parameters in weeks 9 and 10, nicotine (0.1 mg/kg) robustly enhanced performance in both groups despite continuing daily post-session administration of nicotine or saline. These studies provide evidence that, following tolerance to initial disruptive effects, the nicotine-induced attentional enhancement is stable across lengthy periods of chronic exposure. This is important for potential therapeutic applications of the drug and indicates that these effects can be a continuous motive for smoking behavior.

Animals↗
PubMed2004

Effects of intratracheal tumor necrosis factor-alpha plasmid vector on lipopolysaccharide lethality and lung injury in mice.

Bacterial lipopolysaccharide (LPS) causes acute lung injury (ALI) and contributes to inflammation in the acute respiratory distress syndrome (ARDS) and sepsis, making mechanisms of resistance to LPS critically important in clinical settings. The authors postulated that intratracheal administration of a plasmid (pcDNA3. 0-rTNFalpha) encoding rat tumor necrosis factor-alpha (TNF-alpha) would increase resistance of mice to LPS-induced ALI or mortality. They investigated the time course and dose-response for development of LPS-induced ALI in C57/BL6 mice and sought possible protective effects of 100 microg pcDNA3.0-rTNFalpha intratracheally 1, 2, or 3 weeks before LPS challenge. Lung myeloperoxidase (MPO) activity and alveolar lavage fluid (BALF) cell counts increased significantly 48 hours after intraperitoneal (IP) LPS challenges. After pcDNA3.0-rTNFalpha pretreatment, mice challenged with LPS had lower lung/body weight ratios than mice treated with pcDNA3.0; however, other indices of lung injury did not differ. Survival of mice challenged with lethal IP LPS 2 weeks after intratracheal pcDNA3.0-rTNFalpha vector improved significantly, compared to mice pretreated with the control vector, pcDNA3.0. However, pcDNA3.0-pretreated mice tolerated LPS challenge less well than saline-pretreated controls. LPS causes neutrophilic lung injury and mortality, but pcDNA3.0-TNFalpha does not prevent ALI due to LPS. Intratracheal pcDNA3.0-rTNFalpha pretreatment significantly improves survival of mice after LPS challenge, compared to those pretreated with pcDNA3.0.

Animals↗
PubMed1982

Effect of bethanechol on gastric acid secretion and serum gastrin concentration after proximal gastric vagotomy.

It has been suggested that maximal acid output decreases after vagotomy as a result of reduced cholinergic activity and that maximal acid secretion can be restored to prevagotomy levels with cholinergic agonists. To test this, a maximally tolerated dose of bethanechol (50 micrograms/kg/hr) or saline was infused intravenously in nine duodenal ulcer patients who had been treated by proximal gastric vagotomy. Bethanechol infusion significantly (p less than 0.05) increased basal acid secretion without affecting basal serum gastrin concentrations. Despite stimulation of basal acid secretion, bethanechol had no significant effect on maximal acid output in response to subcutaneous pentagastrin. Although bethanechol significantly increased maximal acid output in response to subcutaneous histamine, maximal acid secretion in response to histamine (or to pentagastrin) was not restored to the prevagotomy level in any patient. Thus, factors other than loss of cholinergic activity appear to be responsible for the large reduction in maximal secretory capacity after vagotomy.

Adult↗
PubMed2003

Sodium influx and accumulation in Arabidopsis.

Arabidopsis is frequently used as a genetic model in plant salt tolerance studies, however, its physiological responses to salinity remain poorly characterized. This study presents a characterization of initial Na+ entry and the effects of Ca2+ on plant growth and net Na+ accumulation in saline conditions. Unidirectional Na+ influx was measured carefully using very short influx times in roots of 12-d-old seedlings. Influx showed three components with distinct sensitivities to Ca2+, diethylpyrocarbonate, and osmotic pretreatment. Pharmacological agents and known mutants were used to test the contribution of different transport pathways to Na+ uptake. Influx was stimulated by 4-aminobutyric acid and glutamic acid; was inhibited by flufenamate, quinine, and cGMP; and was insensitive to modulators of K+ and Ca2+ channels. Influx did not differ from wild type in akt1 and hkt1 insertional mutants. These data suggested that influx was mediated by several different types of nonselective cation channels. Na+ accumulation in plants grown in 50 mM NaCl was strongly reduced by increasing Ca2+ activity (from 0.05-3.0 mM), and plant survival was improved. However, plant biomass was not affected by shoot Na+ concentration, suggesting that in Arabidopsis Na+ toxicity is not dependent on shoot Na+ accumulation. These data suggest that Arabidopsis is a good model for investigation of Na+ transport, but may be of limited utility as a model for the study of Na+ toxicity.

Arabidopsis↗
PubMed2005

A novel, long-acting agonist of glucose-dependent insulinotropic polypeptide suitable for once-daily administration in type 2 diabetes.

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with a potentially therapeutic role in type 2 diabetes. Rapid degradation by dipeptidylpeptidase IV has prompted the development of enzyme-resistant N-terminally modified analogs, but renal clearance still limits in vivo bioactivity. In this study, we report long-term antidiabetic effects of a novel, N-terminally protected, fatty acid-derivatized analog of GIP, N-AcGIP(LysPAL(37)), in obese diabetic (ob/ob) mice. Once-daily injections of N-AcGIP(LysPAL(37)) over a 14-day period significantly decreased plasma glucose, glycated hemoglobin, and improved glucose tolerance compared with ob/ob mice treated with saline or native GIP. Plasma insulin and pancreatic insulin content were significantly increased by N-AcGIP(LysPAL(37)). This was accompanied by a significant enhancement in the insulin response to glucose together with a notable improvement of insulin sensitivity. No evidence was found for GIP receptor desensitization and the metabolic effects of N-AcGIP(LysPAL(37)) were independent of any change in feeding or body weight. Similar daily injections of native GIP did not affect any of the parameters measured. These data demonstrate the ability of once-daily injections of N-terminally modified, fatty acid-derivatized analogs of GIP, such as N-AcGIP(LysPAL(37)), to improve diabetes control and to offer a new class of agents for the treatment of type 2 diabetes.

Animals↗
PubMed1988

Extremely thermophilic fermentative archaebacteria of the genus desulfurococcus from deep-sea hydrothermal vents.

Two strains of extremely thermophilic, anaerobic bacteria are described that are representative of isolates obtained from a variety of oceanic hydrothermal vent sites at depths from 2,000 to 3,700 m. The isolates were similar in their requirements for complex organic media, elemental sulfur, and seawater-range salinities (optimum, 2.1 to 2.4%); their high tolerance for sulfide (100 mM) and oxic conditions below growth-range temperatures (50 to 95 degrees C); and their archaebacterial characteristics: absence of murein, presence of certain diand tetraethers, and response to specific antibiotics. The two strains (S and SY, respectively) differed slightly in their optimum growth temperatures (85 and 90 degrees C, optimum pHs for growth (7.5 and 7.0), and DNA base compositions (52.01 and 52.42 G+C mol%). At their in situ pressure of about 250 atm (25,313 kPa), growth rates at 80 and 90 degrees C were about 40% lower than those at 1 atm (101.29 kPa), and no growth occurred at 100 and 110 degrees C, respectively, at either pressure. In yeast extract medium, only 2% of the organic carbon was used and appeared to stem largely from the proteinaceous constituents. According to physiological criteria, the isolates belong to the genus Desulfurococcus.

Journal Article↗
PubMed1993

Induction of reactivation of herpes simplex virus in murine sensory ganglia in vivo by cadmium.

Herpes simplex viruses maintained in a latent state in sensory neurons in mice do not reactivate spontaneously, and therefore the factors or procedures which cause the virus to reactivate serve as a clue to the mechanisms by which the virus is maintained in a latent state. We report that cadmium sulfate induces latent virus to reactivate in 75 to 100% of mice tested. The following specific findings are reported. (i) The highest frequency of induction was observed after two to four daily administrations of 100 micrograms of cadmium sulfate. (ii) Zinc, copper, manganese, or nickel sulfate administered in equimolar amounts under the same regimen did not induce viral reactivation; however, zinc sulfate in molar ratios 25-fold greater than those of cadmium induced viral replication in 2 of 16 ganglia tested. (iii) Administration of zinc, nickel, or manganese prior to the cadmium sulfate reduced the incidence of ganglia containing infectious virus. (iv) Administration of cadmium daily during the first week after infection and at 2-day intervals to 13 days after infection resulted in the recovery from ganglia of infectious virus in titers 10- to 100-fold higher than those obtained from animals given saline. Moreover, infectious virus was recovered as late as 11 days after infection compared with 6 days in mice administered saline. (v) Administration of cadmium immediately after infection or repeatedly after establishment of latency did not exhaust the latent virus harbored by sensory neurons, inasmuch as the fraction of ganglia of mice administered cadmium and yielding infectious virus was similar to that observed in mice treated with saline. We conclude that induction of cadmium tolerance precludes reactivation of latent virus. If the induction of metallothionein genes was the sole factor required to cause reactivation of latent virus, it would have been expected that all metals which induce metallothioneins would also induce reactivation, which was not observed. The results therefore raise the possibility that in addition to inducing the metallothionein genes, cadmium inactivates the factors which maintain the virus in latent state.

Animals↗
PubMed1989

Inhibition of basal insulin secretion induces insulin resistance in normal man: evidence for a tonic effect of insulin on carbohydrate metabolism.

Insulin resistance has been demonstrated both in insulin deficiency and insulin excess in man and in animals. This study was carried out in normal man to evaluate the role of insulinopenia in the pathogenesis of insulin resistance. Insulin suppression was obtained by 4 h somatostatin (SRIF) infusion. Insulin receptors on circulating monocytes were evaluated before and after SRIF infusion; an insulin tolerance test (ITT) was performed after SRIF, saline or SRIF and replacing basal insulin secretion. Insulin binding to circulating monocytes did not change after 4 h insulinopenia (2.19 +/- 0.30 vs. 2.35 +/- 0.80%), while insulin sensitivity appeared decreased after SRIF (KITT = 0.97 +/- 0.13) as compared with saline (KITT = 3.30 +/- 0.42), and this effect was prevented by insulin (KITT = 2.46 +/- 0.38). A relationship was detected between KITT and plasma insulin concentration before ITT (r = 0.85, p less than 0.01), suggesting that insulin deficiency is the main cause of the phenomenon observed. The present data suggest that basal insulin concentration plays an essential role in the control of insulin sensitivity. If insulin binding on monocytes mimics the behavior of major insulin target tissues, it is possible that the impaired insulin action after 4 h of insulin deficiency is related to a post binding effect.

Adult↗
PubMedDate not supplied

MR dacryocystography: comparison with dacryocystography and CT dacryocystography.

BACKGROUND AND PURPOSE: Several techniques have been used to image the nasolacrimal system, providing functional (dacryoscintigraphy) or morphologic (dacryocystography, CT dacryocystography [CTD]) information. Using gadopentetate dimeglumine-diluted solution injected into the lacrimal canaliculus or instilled into the conjunctival sac, we compared the sensitivity of MR dacryocystography (MRD) with that of CTD. METHODS: Eleven healthy volunteers and 25 patients affected by primary epiphora (21 patients) or postsurgical recurrent epiphora (four patients) underwent MRD after the topical administration of contrast media or cannulation of the lacrimal canaliculus. The MR imaging findings were compared with irrigation and CTD data. All patients underwent surgical treatment (dacryocystorhinostomy), which served as a standard of reference for confirming the MRD findings. RESULTS: The topical administration of contrast-enhanced saline solution and the injection of contrast-enhanced saline solution after cannulation were always well tolerated. In healthy volunteers, outflow of contrast media was always revealed by MRD. Eight (32%) of 25 patients with epiphora had stenosis proximal to the lacrimal sac revealed by MRD, whereas 17 (68%) of 25 showed a dilated lacrimal sac and nasolacrimal duct stenosis, as confirmed by surgical findings. The findings of MRD after the topical administration of contrast medium and MRD after cannulation of the lacrimal canaliculus were comparable with irrigation or CTD data for all patients except one. CONCLUSION: In patients with epiphora, MR imaging performed after the topical administration of diluted contrast material can reveal stenosis of the lacrimal apparatus and can be added to the standard orbital imaging protocol when lacrimal system involvement is suspected.

Constriction, Pathologic↗
PubMed1981

Cross-tolerance to phenobarbital following chronic ethanol polydipsia.

Using contingent food pellet delivery, rats were trained on a discriminative motor control task requiring that a force transducer be held steadily within a force band. Motor performance following pre-task doses of phenobarbital (40, 60 or 80 mg/kg) both before and after 4 months fo chronic ethanol polydipsia (mean intake = 11.1 g/kg/kay)indicated the development of cross-tolerance from ethanol to phenobarbital. Days on which saline control injections were given in place of phenobarbital injections (on injection days ethanol was withdrawn 5 hr pre-injection) revealed the development of a mild physical dependence on ethanol at this level of ethanol polydipsia. Chronic ethanol polydipsia did not alter the time course of phenobarbital elimination from the serum, indicating that the cross-tolerance probably was due to central nervous system changes.

Alcoholism↗