Mechanisms of rapid growth in the neonatal pig heart

Physiological studies were conducted to examine the effects of noxious stimulation of one hindpaw or one forepaw on the latency of the withdrawal reflex in the tail-flick test in lightly anesthetized spinally intact or transected rats. Male Sprague-Dawley rats were anesthetized with an intraperitoneal injection of a mixture of Na-pentobarbital (20 mg/kg) and chloral hydrate (120 mg/kg). After baseline readings were taken in the tail-flick test, the effects of various noxious stimuli applied to remote body regions were assessed. The noxious stimuli included unilateral or bilateral hindpaw or unilateral forepaw thermal (immersion in water at 55 degrees C for 90 s), unilateral or bilateral chemical (subcutaneous hindpaw injection of 50 microliters of 5% formalin) and unilateral or bilateral mechanical (pinch with clamp exerting a force of 14.75 or 27 N) stimulation. Bilateral chemical and thermal, and unilateral thermal stimulation induced an antinociceptive response, consisting of an increase in tail-flick latency, peaking at 30 s after stimulation. Recovery to baseline levels occurred over the next 3-6 min. The antinociceptive effect of noxious thermal stimulation was attenuated or absent in chronically spinalized animals (T6/7) following hindpaw or forepaw immersion, respectively. Noxious mechanical stimulation had no effect on tail-flick latency. The data provide evidence that a noxious thermal or chemical stimulus produces a heterosegmental antinociceptive effect which is mediated in part via a supraspinal mechanism and in part via a local spinal mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ondansetron and Delta-9-Tetrahydrocannabinol Interfere With the Establishment of Lithium-Induced Conditioned Taste Avoidance in the House Musk Shrew (Suncus murinus).

Considerable evidence suggests that rats can learn to avoid a taste in the absence of nausea. The current experiments evaluated the potential of the antiemetic agents, ondansetron (OND) and delta-9-tetrahydrocannabinol (THC), to interfere with lithium chloride (LiCl)-induced taste avoidance in the house musk shrew, Suncus murinus, an insectivore that, unlike rats, is capable of vomiting. At a dose that did not modify saccharin (Experiment 1) or sucrose (Experiment 2) intake, OND prevented the establishment of LiCl-induced taste avoidance in the shrew. A low dose of THC (1 mg/kg), which did not modify sucrose intake during conditioning, also prevented the establishment of LiCl-induced taste avoidance in the shrew. Higher doses of THC were also effective, but they also suppressed sucrose consumption during conditioning. These results suggest that nausea is a necessary component of the unconditioned stimulus for the establishment of conditioned taste avoidance in the shrew, unlike the rat, which does not vomit when injected with a toxin. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pfiesteria in Maryland: preliminary epidemiologic findings

Nimesulide, a selective cyclooxygenase-2-inhibiting nonsteroidal anti-inflammatory drug, has been found to be a potent anti-inflammatory and analgesic drug, when administered orally, rectally or topically. The aim of the present study was to evaluate the comparative efficacy of intramuscularly injected nimesulide with that of diclofenac and to elucidate the pharmacokinetic profile of this formulation. Swiss albino mice were used in the experiment. Analgesic activity was tested using the acetic acid writhing test and the tail-flick latency test. Plasma levels of nimesulide and its active metabolite, hydroxynimesulide, were determined by a HPLC method. A peak analgesic effect was observed between 60 and 120 min, while Cmax (10.6 +/- 3.8 micrograms/ml) of nimesulide was reached at 60 min (Tmax). Analgesia was induced within 15 min of administration of nimesulide and was significantly higher than that of diclofenac at 90 and 120 min posttreatment in the writhing reflex and at 60 and 90 min in the tail-flick latency test. The results indicate that intramuscularly injected nimesulide may be an alternative mode of administration in uncooperative patients or when immediate analgesic effects are warranted.     

Inhibition of morphine-induced tolerance and dependence by a benzodiazepine receptor agonist midazolam in the rat

We investigated whether midazolam administration influenced morphine-induced antinociception and tolerance and dependence in the rat. Antinociception was assessed by the tail-flick (TF) and the hot-plate test (HP 52 degrees C). Morphine tolerance developed after daily single injections of morphine for 11 days. The effect of midazolam on morphine-induced antinociception and tolerance was assessed by giving daily injections of various doses of midazolam for 11 days. The first injection of saline or midazolam was given intraperitoneally and 30 min later morphine (10 mg/kg body weight) was administered subcutaneously. Antinociception was monitored by measuring TF and HP latencies 60 min after the second injection. Midazolam was injected at four different concentrations: 0.03, 0.1, 0.3, and 3 mg/kg body weight. Chronic administration of morphine resulted in the development of tolerance to antinociception in both TF and HP tests, with rats exhibiting baseline antinociception on Day 9. Animals treated with midazolam alone showed little antinociception on Days 3-9. However, midazolam administration in morphine-treated animals attenuated morphine-induced tolerance to antinociception on Days 1-11 as measured by the tail-flick test. Midazolam also decreased the jumping behavior following naloxone injections in morphine-dependent rats. These results suggest that midazolam may prolong the effects of morphine by delaying morphine-induced development of tolerance to antinociception. Midazolam also attenuated a decrease in weight gain induced by chronic injections of morphine.     

Quantitation of 5-fluorouracil catabolism in human liver in vivo by three-dimensional localized 19F magnetic resonance spectroscopy

The development of clinical applications of 19F magnetic resonance (MR) spectroscopy of 5-fluorouracil (5-FU) has been limited by the inability to localize 19F spectra to specific regions of interest, making it difficult to quantitate drug and metabolite concentrations accurately. To develop methodology for quantitation, we studied the liver of patients receiving rapid bolus i.v. injections of 5-FU. In serial studies, 5-FU disappeared from the liver within 17-26 min, and its catabolite, alpha-fluoro-beta-alanine (FBAL), rose to reach a plateau after 40 min. A high peak level of fluoro-ureido-propionic acid preceded that of FBAL in only one patient, and dihydrofluorouracil was never observed. During the plateau, we obtained MR imaging-directed 19F MR spectra localized using three-dimensional chemical shift imaging. The spin-lattice relaxation time of FBAL in liver, measured using a variable nutation angle method, was 1.6 +/- 0.2 s (mean +/- SD; n = 5). The concentration of FBAL at 60 +/- 10 min after injection was 1.0 +/- 0.2 mm in liver (mean +/- SD; n = 7). This amount represents approximately 20% of the injected dose and 1.4 times the initial hepatic 5-FU concentration. Our approach may permit one to obtain molar concentrations of fluoropyrimidine metabolites simultaneously in hepatic cancers and surrounding liver, and it helps expand pharmacokinetic modeling of fluoropyrimidine catabolism.     

Enflurane and isoflurane, but not halothane, protect against myocardial reperfusion injury after cardioplegic arrest with HTK solution in the isolated rat heart

To investigate the effects of halothane, enflurane, and isoflurane on myocardial reperfusion injury after ischemic protection by cardioplegic arrest, isolated perfused rat hearts were arrested by infusion of cold HTK cardioplegic solution containing 0.015 mmol/L Ca2+ and underwent 30 min of ischemia and a subsequent 60 min of reperfusion. Left ventricular (LV) developed pressure and creatine kinase (CK) release were measured as variables of myocardial function and cellular injury, respectively. In the treatment groups (each n = 9), anesthetics were given during the first 30 min of reperfusion in a concentration equivalent to 1.5 minimum alveolar anesthetic concentration of the rat. Nine hearts underwent the protocol without anesthetics (controls). Seven hearts underwent ischemia and reperfusion without cardioplegia and anesthetics. In a second series of experiments, halothane was tested after cardioplegic arrest with a modified HTK solution containing 0.15 mmol/L Ca2+ to investigate the influence of calcium content on protective actions against reperfusion injury by halothane. LV developed pressure recovered to 59%+/-5% of baseline in controls. In the experiments with HTK solution, isoflurane and enflurane further improved functional recovery to 84% of baseline (P < 0.05), whereas halothane-treated hearts showed a functional recovery similar to that of controls. CK release was significantly reduced during early reperfusion by isoflurane and enflurane, but not by halothane. After cardioplegic arrest with the Ca2+-adjusted HTK solution, halothane significantly reduced CK release but did not further improve myocardial function. Isoflurane and enflurane given during the early reperfusion period after ischemic protection by cardioplegia offer additional protection against myocardial reperfusion injury. The protective actions of halothane depended on the calcium content of the cardioplegic solution. IMPLICATIONS: Enflurane and isoflurane administered in concentrations equivalent to 1.5 minimum alveolar anesthetic concentration in rats during early reperfusion offer additional protection against myocardial reperfusion injury even after prior cardioplegic protection. Protective effects of halothane solely against cellular injury were observed only when cardioplegia contained a higher calcium concentration.     

Associative tolerance to nicotine analgesia in the rat: Tail-flick and hot-plate tests.

Previous assessments of associative nicotine tolerance may have confounded associative effects with novelty-induced stress effects, instrumental learning effects, or both. That is, subjects were tested in novel environments, allowed to practice the test response, or both during the tolerance development phase. In the first study, 32 male Sprague-Dawley rats were injected with various doses of nicotine and tested for nociception in the tail-flick and hot-plate tests to assess nicotine's analgesic effects. In the second study, 35 rats received nicotine explicitly paired or unpaired with a distinctive test context. All animals were equally preexposed to the test environment, and none had the opportunity to practice the test response. Paired rats developed greater nicotine tolerance than unpaired rats. This context-dependent (associative) tolerance effect was found with both tail-flick and hot-plate tests. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

5-HT3 receptor modulation of behavior during withdrawal from continuous or intermittent cocaine

The present experiments examined alterations in 5-HT3 receptors during withdrawal from continuous or intermittent cocaine. Rats were pretreated with 40 mg/kg/day cocaine for 14 days by either SC injections or osmotic minipumps. The rats were then withdrawn from the pretreatment regimen for 7 days. In Experiment 1, rats received 0-16 mg/kg IP injections of ondansetron, a selective 5-HT3 receptor antagonist. In Experiment 2, the rats received 0-16 mg/kg IP ondansetron in combination with a 15 mg/kg IP injection of cocaine. In Experiment 3, the subjects received 0-16 mg/kg IP injections of ondansetron in combination with a 7.5 mg/kg IP injection of cocaine. Following these injections, the subjects' behavior was rated using the Ellinwood and Balster (18) rating scale. The results of Experiment 1 indicated that ondansetron had no effect on the behavior of the subjects, nor was there a differential effect of pretreatment regimen the effects of ondansetron. The results of Experiment 2 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats, but did have a slight, statistically significant, suppressive effect in the injection rats. In contrast, ondansetron had a robust facilitative effect on cocaine-induced locomotion in the continuous infusion rats. The results of Experiment 3 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats or the cocaine injection pretreatment subjects. In the continuous infusion subjects, ondansetron did have a slight, statistically significant, facilitative effect on cocaine-induced locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the 5-HT3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure

The effect of the 5-HT3 antagonist ondansetron on ethanol self-administration was examined in a limited access paradigm. Acute administration of ondansetron (0.01 and 0.1 mg/kg) reduced ethanol intake in male Wistar rats by 35%, whilst water intake was unaffected. Both a lower (0.001 mg/kg) and higher dose (1 mg/kg) of ondansetron failed to modify ethanol consumption. Ondansetron did not, however, alter the pharmacokinetic profile of an orally administered dose of ethanol (1 g/kg) over the same dose range. To examine the generality of these findings and to determine if tolerance would develop to the suppressant effects of ondansetron on ethanol intake, male C57BL/6 mice were treated with ondansetron (0.001, 0.01 and 0.1 mg/kg) over 22 days, 30 min prior to scheduled access to ethanol. Both 0.01 and 0.1 mg/kg doses reduced ethanol intake; however, water intake was not altered by either dose. This finding confirms and extends the generality of the effects of 5-HT3 receptor antagonists on ethanol intake across different species and different paradigms of ethanol consumption. More importantly, the present study shows that the reduction in ethanol intake induced by ondansetron was maintained even after a prolonged period of treatment and is not due to an alteration in the absorption or metabolism of ethanol.     

Exposure to novelty induces naltrexone-reversible analgesia in rats.

The exposure of rats for 2 min to an open field, to a small box, or to inhibitory avoidance training in the small box was followed by a mild analgesia measured by the tail-flick method. The analgesia was observed as soon as 10 s after the exposure and lasted between 10 and 30 min. It was not observed in animals previously made familiar with the test situation, and it was reversed by the administration of naltrexone (0.1 mg/kg). The data suggest that novelty per se is a sufficient stimulus to activate an opioid-mediated analgesic stimulus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of general anesthetics on intercellular communications mediated by gap junctions between astrocytes in primary culture

BACKGROUND: Astrocytes represent a major nonneuronal cell population in the central nervous system (CNS) and are actively involved in several brain functions. These cells are coupled by gap junctions (GJ) into a syncytial-like network resulting in cellular communication through ionic and metabolic exchange between adjacent astrocytes. Whether anesthetics affect astrocyte function is not known. In the present study, the effects of general anesthetics on GJ permeability were investigated in primary cultures of mouse striatal astrocytes. METHODS: Junctional permeability was determined by using the fluorescent probe Lucifer yellow and the scrape loading/dye transfer technique. Confluent cells were preincubated 5 min with various concentrations of anesthetic agents and GJ permeability was estimated by measuring the area occupied by the dye from digitalized images taken 8 min after cell loading. RESULTS: Of the intravenous anesthetics tested, only propofol (P: 10(-4) M, P < 0.01 and 10(-5) M, P < 0.05) and etomidate (ET: 10(-4) M, P < 0.05, but not 10(-5) M) induced a significant reduction of GJ permeability. In contrast, diazepam (10(-5) M), morphine (10(-4) M), ketamine (10(-4) M), thiopental (10(-4) M), and clonidine (10(-7) M) did not affect junctional permeability. In addition, the halogenated anesthetics halothane, enflurane, and isoflurane induced a dose-dependent closure of GJ. For halothane, enflurane, and isoflurane, the maximum effect was achieved with a 10(-4) M, 1.6 x 10(-3) M, and 10(-3) M anesthetic concentration, respectively. Removal of volatile anesthetics resulted in the restoration of the control fluorescence area between 15 and 45 min. The time course of recovery of GJ permeability was examined more precisely for shorter periods of halothane administration (5 min, 1 mM). Under these conditions, the rate of dye spread returned to control values following anesthetic washout, while, during the same period of time, complete uncoupling of GJ was still observed in the presence of a 1 mM halothane concentration. CONCLUSIONS: These results indicate that general anesthetics differentially affect GJ permeability in cultured astrocytes. This uncoupling effect (closure of gap junctions) may contribute to the mechanisms of action of some anesthetic agents (primarily volatile anesthetics) at the level of the CNS by altering astrocyte communication.     

Glutamate-induced analgesia: blockade and potentiation by naloxone

Injection of 0.5 microliter L-sodium glutamate (60 mM) into the periaqueductal gray matter of the rat resulted in a short-lived analgesia as assessed by the tail-flick method. Naloxone (1 mg/kg) attenuated glutamate-induced analgesia when injected 30 min but not 5 min before testing. Paradoxically, a higher dose of naloxone (10 mg/kg) significantly potentiated glutamate analgesia when injected 5 min but not 30 min before testing. Moreover, this higher dose also potentiated analgesia when injected 5 min prior to 12 mM glutamate, a dose of glutamate previously found to be ineffective in causing analgesia. Microinjections of either 60 mM or 1 M KCl failed to elicit analgesia, indicating the specificity of the glutamate effect. Taken together with several other lines of evidence, the present findings suggest that glutamate-induced analgesia may be mediated by processes quite different from those underlying morphine analgesia. It is further suggested that a dose-related naloxone antagonism is not a necessary criterion for assessing endogenous opioid activity.     

The effect of blockade of the AMPA/kainate receptors of the nucleus accumbens on synaptic dopamine release during an emotional conditioned response

We studied the effect of combining prophylactic ondansetron (4 mg intravenously [IV]) to desflurane-based anesthesia in 90 ASA grade I or 11 women undergoing outpatient gynecological laparoscopy. Recovery after anesthesia, with special focus on postoperative nausea and vomiting (PONV), was assessed. Control groups received a similar desflurane anesthetic (placebo) or a propofol-infusion-based (active control) anesthetic. The study design was randomized, controlled, and double-blind (regarding ondansetron) and single-blind (regarding the anesthetic technique). Early recovery (eye opening, orientation, following commands, sitting) was similar in the three groups. However, overall home readiness (toleration of oral fluids, walking, pain tolerable by oral analgesics, no or only mild nausea) was achieved faster in the desflurane group receiving ondansetron (109 [21-937] min, P < 0.01) and in the propofol group (110 [33-642] min, P < 0.001) when compared to the desflurane only group (372 [45-723] min) (median [range]). The total incidence of PONV in the desflurane-only group was 80% (P < 0.01), compared to 40% and 20% in the desflurane group receiving ondansetron and the propofol group, respectively. The postoperative antiemetic requirements were consistently and significantly (P < 0.01) higher in the desflurane-only group compared to the other two groups. Postoperative sedation, analgesic requirements, and psychomotor recovery (assessed by the Maddox Wing and the Digit Symbol Substitution Tests) were similar in the three groups. Our results suggest that in order to achieve a propofol-like recovery profile in patients with a high likelihood of PONV, desflurane should be combined with a potent antiemetic (e.g., ondansetron).     

The effects of acute and repeated restraint stress on the nociceptive response in rats

The effects of acute and repeated restraint stress on nociception, as measured by the tail-flick latency, were studied in adult male and female rats. After the exposure to a single restraint session, both male and female rats presented an increased latency in the tail-flick test. On the other hand, chronically stressed females presented a performance similar to the control group, whereas chronically stressed male rats responded to restraint with a decrease in the tail-flick latency. This response could be determined by the chronic treatment itself or by the restraint done just before the measurement. Thus, the effect of chronic stress upon basal tail-flick latency was evaluated. In male rats, this latency was significantly decreased in the stressed animals compared with the control group. In female rats, no difference between those groups was observed. Therefore, the results suggest that: (a) acute restraint stress induces an analgesic response in both male and female rats, and (b) there is a gender-specific nociceptive response induced by repeated restraint stress with a hyperalgesic effect in response to stress only in males.     

Characterization and regional binding of human sperm monoclonal antibodies

Therapeutic effect of superoxide dismutase (SOD) and three derivatives: a conjugate with polyethylene glycol (SOD-PEG2), a cationized derivative (cSOD), and a mannosylated derivative (Man-SOD), on acute renal failure induced by ischemia/reperfusion was studied in rats. SOD and derivatives were administered intravenously to the rat after nephrectomy of the right kidney and before and after 60 min occlusion of the left renal artery. At 48 hr after reperfusion, the renal function was evaluated by determining the urinary excretion rate of 14C-inulin injected intravenously. No therapeutic effect on the impaired renal function was shown in the case of low dose SOD (2600 unit/kg) treatment. In contrast, administration of cSOD which was shown to be taken up by the isolated perfused kidney from its capillary side and SOD-PEG2 which maintained high plasma concentration exhibited significant therapeutic effect, as did SOD at ten-fold higher dose (26,000 unit/kg). On the other hand, renal damage was promoted by Man-SOD. Thus, the present study demonstrated that chemical modification may improve the therapeutic effect of SOD on the ischemic acute renal failure and increased SOD concentration in the renal vascular space is an important factor for the improved effect.     

Immunohistological demonstration of transforming growth factor-beta isoforms in the skin of patients with systemic sclerosis

The objective of the present study was to investigate whether oxytocinergic mechanisms may contribute to the antinociceptive effect of non-noxious, sensory stimulation. To test this hypothesis, oxytocin levels in plasma and cerebrospinal fluid (CSF) were measured in control rats as well as in rats exposed for 30 min to electro-acupuncture (2 Hz), thermal stimulation (40 degrees C) or vibration (100 Hz). All modes of stimulation induced significant elevations of oxytocin levels in plasma and/or in CSF, 30 or 90 min after the end of stimulation. Secondly, the antinociceptive effects of these treatments were investigated in the tail-flick test with and without prior administration of the oxytocin antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin (1 mg kg-1 i.p.). All three modes of stimulation caused a significant delay of the tail-flick latency to the same degree as that caused by injection of oxytocin 1 mg kg-1 i.p. (electro-acupuncture P < 0.01, thermal stimulation and vibration P < 0.05). In all cases, the delay was reversed by administration of the oxytocin antagonist (1 mg kg-1 i.p.). These findings suggest that analgesic effects induced by non-noxious sensory stimulation may, in part, be mediated through activation of oxytocinergic mechanisms.     

Antinociceptive responses to nicotinic acetylcholine receptor ligands after systemic and intrathecal administration in mice

The objective of this study was to determine which nicotinic receptor subtypes are involved in antinociception and their site of action. For that, the antinociceptive effects of several nicotinic receptor ligands were evaluated in the tail-flick test both after s.c. and intrathecal (i.t.) administration. Nicotine and other nicotine agonists increased tail-flick latencies in a dose-dependent manner after both routes of administration. Epibatidine enantiomers were the most potent agonists examined. Cytisine, a potent nicotinic ligand, failed to elicit antinociception when injected either i.t. or s.c. Despite some similarities in the effects of nicotinic agonists after i.t. and s.c. injections, their rank-order potency was different. In contrast to the s.c. results, the stereoselectivity of nicotine's effect after i.t. administration was minimal. When various nicotinic antagonists were compared after i.t. and s.c. administration, the results showed that mecamylamine and dihydro-beta-erythroidine differ in potency and their degree of antagonism of some of the nicotinic agonists given i.t. These data suggest that different subtypes of nicotinic receptors may exist in the spinal cord. A good correlation was found between binding affinity to [3H]-nicotine binding sites and analgesic potency after i.t. (r = 0.82), suggesting the involvement of alpha 4 beta 2 receptor subunits. In contrast, studies with MLA and alpha-BGTX suggested a minimal role for alpha-BGTX-sensitive receptors in the antinociceptive effect of nicotinic agonists.     

Modulation of endomorphin-2-induced analgesia by dipeptidyl peptidase IV

The tetrapeptide, endomorphin-2 (Tyr-Pro-Phe-PheNH2) possesses high affinity for mu opioid receptors, and produces potent analgesia in mice. Its structure appears to satisfy the substrate requirements of the proteinase, dipeptidyl peptidase IV which removes dipeptides from the amino terminus of peptides containing proline as the penultimate amino acid. A potent, stable and specific inhibitor of this enzyme, Ala-Pyrrolidonyl-2-nitrile, has been described which should potentiate endomorphin-2-induced analgesia. Further, since dipeptidyl peptidase IV has an absolute requirement for l-Pro, a more metabolically-stable d-Pro2-endomorphin-2 analog should produce longer analgesic actions at lower doses. The present study found that endomorphin-2 was degraded approximately twice as fast than the chromogenic substrate, Ala-Pro-2naphthylamide, by dipeptidyl peptidase IV, whereas d-Pro2-endomorphin-2 was totally resistant to this enzyme's action. d-Pro2-endomorphin-2 (ED50=0.05 microg) was more potent than endomorphin-2 (ED50=30 microg) in significantly increasing tail-flick latencies with longer durations of action. Both the peptide and analogue were equipotent (ED50=0.5 microg) in significantly increasing jump thresholds. Ala-Pyrrolidonyl-2-nitrile (10-75 nmol) elicited a dose-dependent analgesia, and potentiated the analgesic actions of endomorphin-2, particularly on the tail-flick test. Whereas systemic naltrexone (2.5, 10 mg/kg) dose-dependently eliminated each of the three forms of analgesia on the jump test as well as the peak (15 min) effect on the tail-flick test, analgesia elicited by either endomorphin-2, d-Pro2-endomorphin-2 or Ala-Pyrrolidonyl-2-nitrile returned after 30-60 min in naltrexone-treated rats on the tail-flick test. These data strongly suggest that dipeptidyl peptidase IV plays a role in the inactivation of endomorphin-2 in vivo, and thereby modulates its central analgesic actions.     

The enkephalinase mechanisms of the resistance and tolerance to the analgesic effect of morphine in rats. Differences in the effects of the action of D-phenylalanine in morphine-sensitive, morphine-tolerant and morphine-resistant rats

In morphine-sensitive (s.c. 1.5 mg/kg) Wistar rats (60%) i.p. inoculation of 300-600 mg/kg d-Phenylalanine (d-Pha) did not change the nociception (tail-flick test), but in morphine-resistant rats (40%) evoked a dose-dependent analgetic effect. In morphine-sensitive rats (40%) chronic morphine administration induced the tolerance and d-Pha injection evoked analgetic effect. Morphine injection just after d-Pha analgesia was over evoked analgetic effect in morphine-resistant and -tolerant rats. It is suggested that morphine-resistant rats have a congenital and morphine-tolerant rats an acquired high level of enkephalinase activity which blocked the morphine analgetic action.     

Context-sensitive half-times and other decrement times of inhaled anesthetics

The length of anesthetic administration influences the rate at which concentrations of anesthetics decrease after their discontinuation. This is true for both intravenous (I.V.) and inhaled anesthetics. This has been explored in detail for I.V. anesthetics using computer simulation to calculate context-sensitive half-times (the time needed for a 50% decrease in anesthetic concentration) and other decrement times (such as the times needed for 80% or 90% decreases in anesthetic concentration). However, decrement times have not been reported for inhaled anesthetics. In this report, published pharmacokinetic parameters and computer simulation were used to compare the context-sensitive half-times and the 80% and 90% decrement times of the expected central nervous system concentrations for enflurane, isoflurane, sevoflurane, and desflurane. The context-sensitive half-times for all four anesthetics are small (<5 min) and do not increase significantly with increasing duration of anesthesia. The 80% decrement times of both sevoflurane and desflurane are also small (<8 min) and do not increase significantly with duration of anesthesia. However, the 80% decrement times of isoflurane and enflurane increase significantly after approximately 60 min of anesthesia, reaching plateaus of approximately 30 and 35 min. The 90% decrement time of desflurane increased slightly from 5 min after 30 min of anesthesia to 14 min after 6 h of anesthesia. It remained significantly less than the 90% decrement times of sevoflurane, isoflurane, and enflurane, which reached values of 65 min, 86 min, and 100 min, respectively, after 6 h of anesthesia. IMPLICATIONS: The major differences in the rates at which desflurane, sevoflurane, isoflurane, and enflurane are eliminated occur in the final 20% of the elimination process.