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S H Roth

Publications and source records attributed to S H Roth.

At least 37 records · Page 2Linked to original sources
PubMed1997

Nocifensive reflex thresholds in rats: measures of central nervous system effects of barbiturates.

PURPOSE: To characterize the pharmacodynamic relationships between plasma pentobarbitone and thiopentone concentrations and nocifensive reflexes during emergence from anaesthesia. METHODS: Forty-nine rats were studied. Plasma barbiturate concentrations were measured with high performance liquid chromatography. Nocifensive reflexes were assessed with the hindlimb withdrawal latency (WL) to heat and the somatic motor response threshold (SMRT) to tail pressure. In Protocol I, SMRT, WL, sedation, and the presence of paw-licking and the righting reflex were assessed in unrestrained rats before and every 10 min for two hours after an intraperitoneal injection of pentobarbitone (30 mg.kg-1). Plasma pentobarbitone kinetics were determined in a separate group of rats. In Protocol II, SMRT and drug concentrations were measured concurrently in partially restrained animals before and for 35 min after a computer-controlled i.v. bolus of thiopentone. In Protocol III the SMRT-plasma thiopentone relationship was determined during increasing and decreasing plasma thiopentone concentrations. RESULTS: Enhancement of both nocifensive reflexes was observed in the unrestrained animals. Enhancement of SMRT was maximal [175% (153-197) of control values] at a mean plasma thiopentone concentration of 11 (9-13) micrograms.ml-1. The SMRT-plasma thiopentone curve showed a mean efflux-influx difference in plasma thiopentone concentration of 4(2.3-5.7) micrograms.ml-1. CONCLUSIONS: Barbiturate-associated nocifensive reflex enhancement occurs in unrestrained animals with both thermal and pressure stimuli. The SMRT-plasma thiopentone concentration relationship during emergence from anaesthesia was similar to that observed previously during induction. The thiopentone plasma concentration-SMRT plot showed an equilibrium delay similar to that previously described by others for thiopentone at an electroencephalographic effect site.

Animals↗
PubMed1997

Sevoflurane modulates both GABAA and GABAB receptors in area CA1 of rat hippocampus.

It has been suggested that volatile anaesthetics enhance synaptic inhibition via gamma-aminobutyric acid (GABA) in the central nervous system. We have examined the effects of sevoflurane on GABAA and GABAB receptors in rat hippocampus in vitro. Extracellular recordings were used to record field potentials in rat CA1 pyramidal neurones of transverse hippocampal slices, stimulated electrically via stratum radiatum input. Sevoflurane 0.4-5.0 vol% decreased the amplitudes of population spikes (PS) of CA1 neurones in a concentration-dependent (calculated ED50 = 6.31 vol%) and reversible manner. The GABAA antagonist, bicuculline methiodide 5 x 10(-5) mol litre-1, induced oscillations (multiple spikes) and blocked the inhibitory actions of sevoflurane in the initial component (up to 24.8 ms) of the oscillation. The latter portion of the oscillation (greater than 24.8 ms) was depressed by sevoflurane. The GABAB antagonist, phaclofen 5 x 10(-4) mol litre-1 partially blocked the effects of sevoflurane on the latter portion of the bicuculline-induced oscillation. Sevoflurane 2.0 vol% significantly enhanced paired-pulse (PS2/PS1) facilitation (from 128.4% to 155.5% at an inter-stimulus interval of 37.9 ms); this enhancement was blocked by phaclofen. Stimulus-response relationships revealed that 2.0 vol% sevoflurane increased the intensity of threshold for PS generation to 109.8% of control. Both the GABAA agonist, muscimol 2 x 10(-5) mol litre-1 and the GABAB agonist, (+/-)-baclofen 10(-5) mol litre-1, potentiated the effects of sevoflurane. Sevoflurane enhanced thresholds by 137.1% and 138.5% of control in the presence of muscimol and (+/-)-baclofen, respectively. The results demonstrate that sevoflurane at clinical concentrations activated both GABAA- and GABAB-mediated inhibitions in area CA1 of the hippocampus, and that sevoflurane and GABA agonists (muscimol and baclofen) acted on different domains on the GABAA and GABAB receptors, respectively.

Anesthetics, Inhalation↗
PubMed1997

Pharmacodynamics of thiopentone: nocifensive reflex threshold changes correlate with hippocampal electroencephalography.

The electroencephalographic (EEG) effects of thiopentone have been used extensively in the pharmacodynamic and pharmacokinetic modelling of drug effects in the central nervous system (CNS). Thiopentone has a biphasic (enhancement followed by inhibition) effect on nocifensive reflexes that occurs in a dose range similar to that which activates the EEG. In this study we have used rats chronically instrumented with hippocampal EEG (hEEG) electrodes to simultaneously characterize the effects of thiopentone on the hEEG and nocifensive reflex thresholds. Enhancement of these two measures of CNS effect correlated well with plasma thiopentone concentrations of 10-30 micrograms ml-1 (35-75 mumol litre-1) but maximal reflex enhancement occurred at concentrations of 3 micrograms ml-1 (11 mumol litre-1) less than the peak hEEG effect. The results validate the usefulness of nocifensive reflex thresholds for measurement of the CNS effects of thiopentone at subanaesthetic concentrations.

Anesthetics, Intravenous↗
PubMed1997

The effects of sevoflurane on population spikes in CA1 and dentate gyrus of the rat hippocampus in vitro.

UNLABELLED: We studied the effects of sevoflurane on population spikes (PSs) in two synaptic pathways in rat hippocampal slices. Stimulating electrodes were placed on Schaffer collateral fibers or perforant path to activate inputs to CA1 pyramidal neurons or dentate gyrus (DG) neurons, respectively. Extracellular glass microelectrodes were used to record PSs. The paired-pulse stimulus was used to induce the paired-pulse facilitation (PPF). Sevoflurane (0.4-5.0 vol%) significantly decreased the amplitudes of PSs of CA1 and DG in a dose-dependent and reversible manner (25% effective dose values were 4.1 and 0.9 vol%, respectively). The stimulus-response relationships for PS amplitudes revealed that sevoflurane increased the threshold for PS generation in CA1 and DG. Sevoflurane (2.0 vol%) significantly enhanced PPF from 127% and 263% to 153% and 494% in CA1 and DG, respectively. The results imply that the effects of sevoflurane on PSs are greater in DG than in CA1 neurons, that sevoflurane enhances the PPF in both CA1 and DG, and that the actions of sevoflurane are not similar to those of other volatile or intravenous anesthetics previously reported in hippocampal preparations. IMPLICATIONS: The volatile anesthetic sevoflurane alters neural excitability of individual pathways in the hippocampus in a manner different from other general anesthetics. The results are consistent with a site-specific mechanism of action for general anesthesia.

Anesthetics, Inhalation↗
PubMed1996

Thiopentone induced enhancement of somatic motor responses to noxious stimulation: influence of GABAA receptor modulation.

PURPOSE: This study was conducted to determine whether hyperalgesic effects of subanaesthetic concentrations of thiopentone could be attributed to GABAA receptor effects. METHODS: All studies were performed on 50 rats in a prospective, randomized, blinded fashion using saline-injected animals as controls. Using a modified Randall-Selitto technique, the motor behavior stimulated by noxious stimulation was quantified by determining the lowest tail pressure required to provoke a withdrawal response (somatic motor response threshold, SMRT). In the first protocol (21 rats), we studied the effects of 0.5, 1.5 and 5 mg.kg-1 i.v. of the GABAA agonist, muscimol, on SMRT. In the second protocol (20 rats), the effects of administration of saline, muscimol 0.5 mg.kg-1, or the competitive GABAA antagonist, bicuculline 0.25 mg.kg-1, upon the SMRT-reducing effects of a standardized thiopentone infusion were observed. RESULTS: No dose of muscimol produced hyperalgesia. The highest dose of muscimol used (5 mg.kg-1) produced pronounced analgesic effects, raising the SMRT above 750 g. No change in SMRT was detected with the smaller doses of muscimol. Given in combination with muscimol (0.5 mg.kg-1), thiopentone produced analgesia, as shown by an increase in SMRT (P = 0.009). In the bicuculline treated animals, SMRT decreased linearly with increasing plasma thiopentone concentrations (P < 0.001). The slope of the relationship in the bicuculine group was not significantly different from that observed in the saline-treated group, indicating that bicuculline did not block the hyperalgesic effects of thiopentone. CONCLUSION: The results of these studies suggest that hyperalgesia associated with thiopentone is not mediated primarily by GABAA receptors.

Animals↗
PubMed1996

Effects of repeated exposures of hydrogen sulphide on rat hippocampal EEG.

Exposure to high levels of hydrogen sulphide (H2S) in humans has been associated with a number of respiratory and neurological symptoms. Acute toxicity following exposure to high concentrations is well-documented, however, there is little scientific information concerning the effects of exposure to low concentrations. The effects of low levels of H2S on electroencephalographic (EEG) activity in the hippocampus and neocortex were investigated on the freely moving rat (Sprague-Dawley). Hippocampal electrodes were implanted in the dentate gyrus (DG) and CA1 region. Activity was recorded for 10 min just prior to H2S exposure in the presence of air (pre-exposure). Rats were exposed to H2S (25, 50, 75, or 100 ppm) for 3 h/day; data was collected during the final 10 min of each exposure. The total power of hippocampal theta activity increased in a concentration-dependent manner in both DG and CA1; repeated exposures for 5 consecutive days resulted in a cumulative effect that required 2 weeks for complete recovery. The effects were found to be highly significant at all concentrations within subjects. Neocortical EEG and LIA (Large Amplitude Irregular Activity) were unaffected. The results demonstrate that repeated exposure to low levels of H2S can produce cumulative changes in hippocampal function and suggest selectivity of action of this toxicant.

Administration, Inhalation↗
PubMed1996

Evidence that GABA, serotonin, and norepinephrine are involved in the modulation of in vitro rhythmical activity in rat hippocampal slices.

Cholinergic agonists induce a rhythmical slow activity (RSA) in the in vitro rat hippocampus. RSA consists of bursts of activity separated by quiescent periods (interburst intervals). The activity involves activation of muscarinic receptors; however, the role of other neurotransmitter substances is still controversial. The present study demonstrates that 500 microM GABA, 15 microM serotonin (5HT), or 20 microM norepinephrine (NE) can alter the pattern of carbachol-induced RSA. Application of GABA, 5HT, or NE increases interburst interval; 5HT and NE also increase burst length. Total power of RSA is decreased by GABA and 5HT but increased by NE. None of the three receptor agonists alters RSA frequency. The pattern of RSA is also dependent upon carbachol concentration: low concentrations (0.5 and 1 microM) produce only population spikes, whereas concentrations of 3 to 100 microM produce burst activity (50 microM is optimal for the generation of RSA). Burst length and peak frequency of RSA are enhanced with increasing concentrations of carbachol, whereas interburst interval is decreased. The results illustrate that the pattern of RSA is not only dependent upon carbachol concentration but can be modulated by GABA, 5HT, and NE. This suggests that more than one neurotransmitter system contributes to the production and modulation of RSA.

Alpha Rhythm↗
PubMed1995

Hyperalgesia during sedation: effects of barbiturates and propofol in the rat.

Subhypnotic doses of thiopentone are considered to possess antianalgesic or hyperalgesic properties. In this study, we have tested the hypothesis that the coincidence of sedation and hyperalgesia is a property of both barbiturate and non-barbiturate anaesthetic agents. In a randomized, prospective, blinded study, the effects of slow (20 min) iv infusions of thiopentone, pentobarbitone, methohexitone or propofol on nociceptive threshold were measured in rats by tail pressure analgesimetry and compared with saline-infused control animals. Nociceptive thresholds were correlated with measurements of plasma drug concentrations and behavioural assessments. Comparison of pre-infusion nociceptive threshold with the lowest threshold obtained during drug infusion revealed decreases in all four treatment groups. As a percentage of the pre-infusion values, the decreases were: thiopentone: 42.5% (P < 0.001), pentobarbitone: 27.8% (P = 0.014), methohexitone: 24.9% (P = 0.013), propofol: 21.6% (P = 0.006). There were no changes in nociceptive threshold in the control groups. The relationship between nociceptive threshold and plasma drug concentration was usually characterized by an initial decline followed by a rise in nociceptive threshold as the plasma concentration and degree of sedation increased. The results support the hypothesis that hyperalgesia is a property of different anaesthetic agents when administered at sub-hynotic concentrations.

Animals↗
PubMed1995

Alteration of the morphology and neurochemistry of the developing mammalian nervous system by hydrogen sulphide.

1. Hydrogen sulphide (H2S) is a broad spectrum toxicant that occurs widely in nature and is also released by a variety of industrial activities and processes. 2. The central nervous system (CNS) appears to be the major target organ. 3. There is great potential for insult or injury to the developing or immature CNS. 4. The risk of chronic or repeated exposures to low concentrations have not been well defined. 5. Exposure to low concentrations of H2S to time-pregnant rats from day 5 postcoitus until day 21 postnatal results in architectural modification of cerebellar Purkinje cells, alteration of putative amino acid neurotransmitters and changes in monoamine levels in the developing rat brain up to day 21 postnatal. 6. H2S-induced alterations in monoamine tissue levels observed in the developing rat brain return to control values if exposure is discontinued during development, that is, at day 21 postnatal.

Animals↗
PubMed1995

From peptic ulcer disease to NSAID gastropathy. An evolving nosology.

Nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy is an important clinical entity, most commonly encountered in elderly female patients. The expanding use of NSAIDs in the elderly population has led to an increased incidence of NSAID-induced gastropathy. The risk of gastric bleeding in these patients is 7-fold higher than in the younger population. Long term NSAID therapy in the elderly is apparently associated with failure of normal gastric mucosal adaptation. Silent unidentified gastric lesions are likely to be common with long term NSAID therapy, as symptomatology does not parallel pathological progression. This gastropathy, in contrast to peptic ulcer disease, is responsive to prostaglandins and other cytoprotective agents. A new generation of prostaglandin-sparing NSAIDs (e.g. nabumetone), in addition to the older nonacetylated salicylates, may represent less gastrotoxic alternatives. Therefore, these agents may substantially reduce the risk of NSAID-induced gastropathy. The debate continues as to whether to use NSAIDs, and under which circumstances. More importantly, the cost-benefit implications and justification for concomitant therapy with gastroprotective agents cloud the picture. Currently, there is a definite consensus that NSAIDs should not be casually used on a chronic basis, especially in patients at risk for serious gastropathy complications. In all cases, where possible, gastric prostaglandin-sparing NSAIDs or nonacetylated salicylates should be used in lowest effective dosages. In special circumstances, gastroprotective co-therapy can be considered. NSAID therapy probably should not be used or continued in elderly patients with a history of bleeding ulcers or recent major gastric ulcer activity.

Aged↗
PubMed1994

Plasma, brain, and spinal cord concentrations of thiopental associated with hyperalgesia in the rat.

BACKGROUND: Although low doses of barbiturates are widely believed to increase sensitivity to pain, studies of the electrophysiologic effects of these drugs on the neurons involved in nociception in the spinal cord have detected only depressant effects. The goal of the studies reported here was to quantify the hyperalgesia resulting from low-dose thiopental infusions and to measure the associated concentrations of thiopental in the plasma, brain, and spinal cord. METHODS: Nociception was measured using the threshold for motor response to pressure stimulation of the tail (nociceptive threshold) and tail flick latency in the rat. Thiopental was administered by intravenous infusions designed to produce plasma concentrations that either slowly increased or remained at a steady state. Plasma and tissue thiopental concentrations were measured by high-performance liquid chromatography. RESULTS: We observed a reduction in nociceptive threshold that was correlated with the plasma thiopental concentration over the range 2-20 micrograms.ml-1 (7.6-76 microM). The relationship was nonlinear. Nociceptive threshold reached a nadir (36% less than control values) at a mean plasma thiopental concentration of 13.7 micrograms.ml-1 (51.9 microM). The steady-state study showed a similar reduction in nociceptive threshold, with an equilibrium plasma thiopental concentration of 7.6 +/- 1.3 micrograms.ml-1 (28.8 +/- 4.9 microM). Concentrations of thiopental in brain and spinal cord samples were 1.7 +/- 0.03 and 3.5 +/- 1.7 micrograms.g-1, respectively. CONCLUSIONS: These studies confirm previous reports of hyperalgesia in association with small doses of thiopental. Reductions in nociceptive threshold and tail flick latency were observed in association with spinal cord concentrations of thiopental in a range reported by others to depress the electrophysiologic activity of neurons involved in nociception.

Animals↗