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Biomedical subjects

G Schulteis

Publications and source records attributed to G Schulteis.

47 records · Page 3Linked to original sources
PubMed1988

Enkephalins and learning and memory: a review of evidence for a site of action outside the blood-brain barrier.

A series of studies indicate that enkephalins exert dramatic influences on learning and memory in rats and mice, when studied with conditioning tasks that are both negatively and positively motivated. Pharmacological analysis of these enkephalin actions on conditioning suggests that the [leu]enkephalin acts through a delta opioid receptor which is located outside the blood-brain barrier. Control studies indicate that enkephalins do not simply affect the performance of a conditioned response through actions on shock sensitivity or locomotor activity. Characterization of the peripheral enkephalin mechanism that affects behavior suggests an action through an enzymatic system that controls the concentrations of enkephalin present at its receptors in the periphery. This enzymatic mechanism is sensitive to experience, since its activity changes following conditioning, which suggests that it may be a regulatory mechanism for behavior.

Adrenal Glands↗
PubMed1988

Stimulation and antagonism of opioid delta-receptors produce opposite effects on active avoidance conditioning in mice.

The effects of opioid delta-receptor activation on conditioning in a one-way active avoidance paradigm were investigated in mice. Peripheral administration of 30 and 100 micrograms/kg of [Leu5]enkephalin (LE) and 11.6 micrograms/kg of [D-Pen2,D-Pen5]enkephalin (DPDPE), a synthetic enkephalin analog with high delta-selectivity, impaired acquisition of avoidance responding. The dose response functions for both peptides were U-shaped. Deficits in responding were also present 24 hours after training, which suggests that the impaired performance observed during training was not an impairment in the ability of the mice to perform. Also, neither LE nor DPDPE decreased footshock sensitivity or open-field activity, which rules out analgesia and decreased activity levels as likely explanations for the deficits in conditioning. Finally, antagonizing endogenous ligands with the delta-selective antagonist ICI 154,129 enhanced acquisition, an effect opposite that produced by LE and DPDPE. The results suggest that activation of delta-receptors is normally involved in the modulation of active avoidance learning.

Animals↗
PubMedDate not supplied

Plasma uptake and in vivo metabolism of [Leu]enkephalin following its intraperitoneal administration to rats.

To understand better how [Leu]enkephalin (LE) acts to modulate learning and memory in rats, the plasma uptake, disappearance, and metabolism of LE were investigated following its intraperitoneal administration. Concentrations of [3H]-LE and its radioactive metabolites were determined by thin layer chromatography in plasma samples withdrawn from rats at various times after injection of peptide. As measured in rats receiving an IP injection of a dose of LE (3 micrograms/kg) that impairs active avoidance conditioning, the LE was very rapidly metabolized, with greater than 95% of plasma [3H] in the form of metabolites by 1 min after injection. Despite this rapid metabolism, low but measurable quantities of intact LE were detectable in plasma at all sampling times. Consistent with a greater potency of D-Ala2-[D-Leu5]enkephalin (DADLE) than of LE in modulating avoidance conditioning, DADLE was less rapidly metabolized than was LE following its IP administration. The metabolism of DADLE and LE in vivo was more rapid than it was in plasma in vitro, suggesting a role for membrane bound enzymes in the metabolism of IP-administered enkephalins. The data demonstrate that, despite a rapid hydrolysis of LE in vivo, sufficient LE is present in plasma following IP administration of a behaviorally active dose to support a role of circulating intact LE in the modulation of avoidance conditioning.

Animals↗
PubMedDate not supplied

Uptake and metabolism of [3H]-Leu-enkephalin following either its intraperitoneal or subcutaneous administration to mice.

The uptake and metabolism of 30 micrograms/kg [3H]-Leu-enkephalin ([3H]-LE) following either intraperitoneal (IP) or subcutaneous (SC) administration to Swiss Webster mice was examined. Uptake of [3H] was rapid, with peak levels of radioactivity in plasma observed at 5 or 10 min following IP or SC peptide injection, respectively. The majority (80-99% +/- 0.8) of plasma radioactivity at all postinjection plasma collection time points was in the form of tyrosine-containing enkephalin metabolites, indicating a substantial and rapid in vivo hydrolysis rate for exogenously administered LE. Leu-enkephalin is metabolized in vivo faster than previously reported in vitro in mouse plasma. However, despite this extensive hydrolysis, levels of intact LE remaining in plasma following its systemic administration are within or above endogenous LE plasma levels.

Animals↗
PubMedDate not supplied

Experience-dependent regulation of Leu-enkephalin hydrolysis in rat plasma.

We examined experience-dependent alterations in the production of individual enkephalin metabolites during Leu-enkephalin hydrolysis in rat plasma in vitro. High performance liquid chromatography separation and electrochemical detection were used to quantify accumulation of the primary N-terminal products of enkephalin hydrolysis, Tyr and Tyr-Gly-Gly. Blood was sampled from rats through indwelling femoral artery catheters before, during, and after active avoidance training or appropriate control treatments. Avoidance training increased Tyr production, as did handling and exposing animals to the novel avoidance chamber without foot-shock training. On the other hand, Tyr-Gly-Gly production was elevated by blood sampling alone, by handling/novelty, and by training, but the effect of training was significantly greater than the effects of either of the other treatments. Interestingly, Tyr-Gly-Gly production was highly correlated (r = -0.885) with a measure of escape performance. Since the enzymes that participate in enkephalin hydrolysis act upon a number of peptides, regulation of enzyme activity may be one mechanism whereby an organism can modulate levels of circulating peptides in response to environmental experiences; this may contribute to the expression of appropriate behavioral responses to those environmental experiences.

Amino Acid Sequence↗
PubMedDate not supplied

Individual variability in Tyr-Gly-Gly formation from enkephalin hydrolysis in mouse plasma.

We examined the effects of captopril (an angiotensin-converting enzyme inhibitor) and phosphoramidon (a selective enkephalinase inhibitor) on Tyr-Gly-Gly production during Met-enkephalin hydrolysis in plasma samples taken from individual outbred Swiss-Webster and inbred C57BL/6J and DBA/2J mice. Discriminant analysis procedures identified three distinct plasma profiles of Tyr-Gly-Gly production in all strains of mice: a captopril-sensitive/phosphoramidon-insensitive profile, a captopril-insensitive/phosphoramidon-sensitive profile, and a moderate captopril and phosphoramidon sensitivity profile. The abilities of captopril and phosphoramidon to inhibit Tyr-Gly-Gly production in the same mouse plasma sample were highly inversely correlated (r = -0.938). Plasma of Swiss-Webster mice whose cages and bedding had been changed 24 h prior to sample collection was significantly more likely to exhibit the captopril-sensitive/phosphoramidon-insensitive profile than the plasma of mice whose cages/bedding had not been changed for at least 5 days. The results suggest that environmental novelty may dramatically alter the activity of a plasma dipeptidyl carboxypeptidase system, and thereby regulate behavioral and physiological responses to novel experiences.

Amino Acid Sequence↗
PubMedDate not supplied

Time-dependent quantifiable withdrawal from ethanol in the rat: effect of method of dependence induction.

The importance of temporal factors on the presence and severity of ethanol withdrawal signs in the rat was quantified using rating scale, tremor, and acoustic startle paradigms. Ethanol dependence was induced in naive male Wistar rats by liquid diet administration (n = 21) or vapor inhalation (n = 13). Subjects were analyzed for intensity and duration of physiological ethanol dependence in repeated-measures trials conducted over 72 h post-ethanol withdrawal. Indices of dependence included CNS hyperexcitability manifested as observable withdrawal signs increased acoustic startle reactivity, and tremor activity. Data analysis revealed that withdrawal signs, observed and elicited, generally reached peak intensities between 12 and 24 h postwithdrawal and were more readily observed following vapor inhalation than liquid diet administration, probably because of the higher BALs attained with the inhalation procedure. Results suggest a difference in time course observed with the different behavioral paradigms. In particular, a possible sensitization to startle stimuli was exhibited independent of both startle intensity and dependence induction method. The neural substrates governing these behavioral time course differences remain to be determined.

Administration, Inhalation↗
PubMedDate not supplied

Behavioral assessment of forgetting in aged rodents and its relationship to peripheral sympathetic function.

Observation of age-related memory deficits in rodents is often dependent on the behavioral task used to assess these changes, rather than being universal to all memories. A review of studies using aversively-motivated multiple trial training paradigms suggests that the apparent acquisition deficits common to older animals may instead be due to a confounding tendency of these animals to behavioral rigidity or perseveration. Data obtained using single trial training paradigms, such as the one-trial passive avoidance task, indicate that young and old rodents can learn tasks with equal facility, that retention in young and old animals is similar at short training-testing intervals, but that retention is impaired in aged animals at longer training-testing intervals. We suggest that the adrenal medulla, a peripheral source of catecholamines, secretes catecholamines that act outside the blood-brain barrier to modulate memory processes. Further, we review evidence suggesting that the ability of the adrenal medulla to respond to the stresses of footshock during aversively-motivated training are impaired in aged rodents, and that this impairment may contribute to the rapid forgetting observed in senescent animals.

Adrenal Medulla↗
PubMedDate not supplied

Effect of oral mexiletine on capsaicin-induced allodynia and hyperalgesia: a double-blind, placebo-controlled, crossover study.

BACKGROUND AND OBJECTIVES: Mexiletine is a sodium channel blocker that has been used for the treatment of a variety of neuropathic pain syndromes. A recent double-blinded placebo-controlled study concluded that it was ineffective in the treatment of allodynia associated with neuropathic pain. However, this study failed to achieve adequate plasma levels of mexiletine. This was a study in healthy volunteers that sought to push the drug to dose-limiting side effects and then evaluate the effects on human experimental pain. METHODS: Twelve healthy volunteers were studied using a randomized, double-blind, placebo-controlled crossover study. The subjects were titrated to a maximum dose of 1,350 mg/d or dose-limiting side effects, whichever occurred first. At baseline and day 10 and 17, neurosensory testing, train-of-three thermal pulses, and side-effect measurements were performed and on day 17, intradermal capsaicin was injected on the volar aspect of the forearm and the pain and secondary hyperalgesia to von Frey hair, stroking, and thermal stimuli were measured. RESULTS: Peak plasma levels occurred on day 10 and were 0.36 +/- 0.21 microg/mL. All subjects experienced dose-limiting side effects. The mean maximum tolerable daily dose achieved was 859 mg (range, 300 to 1,350 mg). The side effects reported by the subjects included nausea, lightheadedness, muscle twitching and weakness, blurred vision, headache, tremors, difficulty concentrating, dysphoria, sedation, pruritus, and rash. These side effects occurred at an average daily dose of 993 mg (range, 600 to 1,350 mg). Compared with placebo, mexiletine had no significant effects on any of the neurosensory thresholds and pain scores after intradermal capsaicin. There was a significant reduction in the area of secondary hyperalgesia to von Frey hair stimulation only. There was a significant correlation between plasma mexiletine level and flare response. CONCLUSIONS: Mexiletine has minimal effects on human experimental pain. It is severely limited by side effects and tolerable doses seem to be void of effects on normal neurosensation and facilitated pain induced by capsaicin and thermal heat pulses.

Administration, Oral↗
PubMedDate not supplied

Topical delivery of lidocaine in healthy volunteers by electroporation, electroincorporation, or iontophoresis: an evaluation of skin anesthesia.

BACKGROUND AND OBJECTIVES: This study was designed to compare the onset, duration, and depth of local anesthesia after the topical delivery of lidocaine using electroporation (EP), electroincorporation (EI), and iontophoresis (IP) in healthy volunteers. EP and EI were performed with prototype devices and IP with a commercial drug/device product. METHODS: A double-blind, crossover study design was used for 10 randomized volunteers selected for EP treatment with either 4%, 10%, or 20% lidocaine or placebo normal saline. Because it was impossible to blind between IP, EP, and EI, an open label study with randomized volunteers was selected for IP and EP treatments. Onset and duration of anesthesia was determined by measuring warm sensation, cool sensation, and hot pain; depth of anesthesia was determined by measurement of pain sensation to a 27-gauge needle passed through the skin. RESULTS: For EP, all concentrations of lidocaine produced significant changes from baseline on 2 or 3 efficacy measures, however, the 4% concentration appeared to be the most efficacious when delivered by the EP method. The EP and EI methods produced a significant elevation in all 3 thermal thresholds, whereas IP produced significant elevations in cool and warm thresholds only. However, IP resulted in a greater depth of anesthesia. Plasma lidocaine levels were undetectable. CONCLUSIONS: The transdermal delivery of lidocaine by IP, EP, and EI results in similar surface skin anesthesia; however, IP results in a greater depth of anesthesia. Reg Anesth Pain Med 2001;26:229-238.

Administration, Topical↗