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Biomedical subjects

R A Tasker

Publications and source records attributed to R A Tasker.

At least 19 recordsLinked to original sources
PubMed2006

Gender-based changes in cognition and emotionality in a new rat model of epilepsy.

Epilepsy research relies heavily on animal models that mimic some, or all, of the clinical symptoms observed. We have previously described a new developmental rat model of epilepsy that demonstrates both behavioural seizures and changes in hippocampal morphology. In the current study we investigated whether these rats also show changes in cognitive performance as measured using the Morris water maze task, and emotionality as measured using the Elevated plus maze task. In the water maze, significant differences between male and female rats were found in several performance variables regardless of treatment. In addition, female but not male rats, treated neonatally with domoic acid had significant impairments in learning new platform locations in the water maze. In the elevated plus maze, a significant proportion of female rats spent more time in the open arm of the maze following prior exposure to the maze whereas this effect was not seen in male rats. We conclude that perinatal treatment with low doses of domoic acid results in significant gender-based changes in cognition and emotionality in adult rats.

Animals↗
PubMed2004

Low doses of domoic acid during postnatal development produce permanent changes in rat behaviour and hippocampal morphology.

It is well established that the developing brain is a highly dynamic environment that is susceptible to toxicity produced by a number of pharmacological, chemical and environmental insults. We report herein on permanent behavioural and morphological changes produced by exposing newborn rats to very low (subconvulsive) doses of kainate receptor agonists during a critical window of brain development. Daily treatment of SD rat pups with either 5 or 20 microg/kg of domoic acid (DOM) from postnatal day 8-14 resulted in a permanent and reproducible seizure-like syndrome when animals were exposed to different tests of spatial cognition as adults. Similar results were obtained when animals were treated with equi-efficacious doses of kainic acid (KA; 25 or 100 microg/kg). Treated rats had significant increases in hippocampal mossy fiber staining and reductions in hippocampal cell counts consistent with effects seen in adult rats following acute injections of high doses of kainic acid. In situ hybridization also revealed an elevation in hippocampal brain derived neurotrophic factor (BDNF) mRNA in region CA1 without a corresponding increase in neuropeptide Y (NPY) mRNA. These results provide evidence of long-lasting behavioural and histochemical consequences arising from relatively subtle changes in glutamatergic activity during development, that may be relevant to understanding the aetiology of seizure disorders and other forms of neurological disease.

Animals↗
PubMed2000

On excitotoxicity.

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Gene Expression Regulation↗
PubMed1998

Development of an injectable sustained-release formulation of morphine: antinociceptive properties in rats.

The antinociceptive actions of morphine incorporated into an injectable chitosan-based gel were investigated in rats. Subcutaneous administration of 4.8 mg/kg morphine sulphate in a gel composed of N,O-carboxymethylchitosan (NOCC) and chitosan resulted in significant antinociception within 10 min that was maximal at 60 min and persisted for 6 h. In contrast, the same dose of morphine sulphate injected in sterile saline produced maximal responses at 30 min but only persisted for 2 h. NOCC/chitosan gel was easily injectable using a 22 guage needle and appears stable in long-term storage. No local or systemic adverse effects other than morphine-induced sedation were observed either at the time of injection or during the subsequent 48 h. We conclude that gels composed of chitosan and chitosan derivatives are effective matrices for sustained-release formulations of opioid analgesics capable of providing long-lasting antinociception.

Analgesics, Opioid↗
PubMed1997

Pharmacokinetics of an injectable sustained-release formulation of morphine for use in dogs.

This study investigated the pharmacokinetics of morphine sulphate in an injectable chitosan-based gel. Gels were made from a combination of N-O-carboxymethylchitosan (NOCC) and chitosan and were easily injectable via a 22 gauge needle and appeared stable during long-term storage. Groups of six beagles were injected subcutaneously (s.c.) with 1.2 mg/kg morphine sulphate, either in sterile saline or in sterilized gels, and serial blood samples were withdrawn via a jugular catheter and later analysed for morphine concentrations using radioimmunoassay. Data were analysed according to non-compartmental pharmacokinetics. NOCC-based gels resulted in significantly lower serum morphine concentrations at 10 and 30 min following injection but significantly higher concentrations at all points from 120 to 480 min post-injection. Dogs receiving morphine gel exhibited equivalent or lesser variability in serum morphine concentrations than dogs receiving conventional morphine sulphate. Pharmacokinetic analysis revealed that morphine release from the gel matrix was significantly prolonged but fully bioavailable. There were no significant differences in either distribution (Vd) or terminal elimination (t 1/2). Dogs experienced no adverse effects other than those normally associated with morphine administration at the time of injection but all dogs receiving the gel presented with an undefined stiffness the next day that resolved spontaneously within 48 h. We conclude that carboxymethylchitosan-based gels hold considerable promise for the development of injectable sustained-release formulations of opioid analgesics.

Animals↗
PubMed1997

Pharmacokinetics of oral morphine sulfate in dogs: a comparison of sustained release and conventional formulations.

The pharmacokinetics and bioavailability (F) of single dose sustained release morphine sulfate (OSRMS) and nonsustained release morphine sulfate (NSRMS) were compared to each other and to a bolus injection of morphine sulfate (MS) intravenously (i.v.) in dogs. Beagles (n = 6) were randomly assigned to 3 treatment groups: namely, OSRMS 15 mg orally, NSRMS 15 mg orally, and 15 mg i.v. Serum samples were drawn at intervals up to 480 min following oral and 420 min following i.v. administration. Serum was analysed for morphine concentration using a radioimmunoassay. Data were analysed using non-compartmental pharmacokinetics. The only statistically significant difference between OSRMS and NSRMS was maximum serum concentration (Cmax). There were trends toward longer time to maximum serum concentration (Tmax) and longer mean absorption time (MAT) for OSRMS when compared to NSRMS, but the differences were not statistically significant (P < 0.05). Pharmacokinetic parameters for both oral formulations exhibited large variability in the rate of absorption of MS from the gastrointestinal tract. Bioavailability of both OSRMS and NSRMS was low (15%-17%). As expected, the area under the concentration vs time curve (AUC) and Cmax for the i.v. data was significantly greater than for both oral groups, and Tmax and mean residence time (MRT) were significantly less following i.v. administration. There were no statistically significant differences among the 3 treatment groups for apparent volume of distribution at steady state (Vdss) or elimination parameters. The OSRMS formulation used in this study provided equivalent bioavailability to NSRMS in dogs, accompanied by large individual variability in drug absorption. It also did not appear that the sustained release formulation provided sufficiently prolonged release of morphine sulfate from the tablet matrix in dogs to allow prolonged dosing intervals compared to NSRMS.

Administration, Oral↗
PubMed1996

Selective reduction in domoic acid toxicity in vivo by a novel non-N-methyl-D-aspartate receptor antagonist.

Our objective was to characterize the neurotoxic actions of systemically administered domoic acid on different excitatory amino acid receptors, and to compare the receptor selectivity of domoate with the related compound kainic acid. Groups of mice were injected with various ligands selective for N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid-kainate (AMPA/kainate) receptors prior to injection of equitoxic doses of domoic acid or kainic acid. Domoic acid toxicity was not significantly altered by pretreatment with any NMDA receptor selective antagonists, with the exception of 3-(2-carboxypiperazine-4-yl)propyl-1 -phosphonic acid. Consistent with its characterization as an AMPA/kainate agonist, domoate toxicity was significantly antagonized by all non-NMDA receptor antagonists tested. Non-NMDA receptor antagonists that do not distinguish between high- and low-affinity [3H]kainic acid binding (i.e., quinoxalinediones) were equally effective at reducing domoic acid and kainic acid toxicity. However, the novel isatinoxime NS-102, which has been shown to interact selectively with low-affinity [3H]kainic acid binding sites, produced a selective dose-related antagonism of domoic acid toxicity relative to kainic acid. NS-102 produced significant reductions in overall toxicity, onset of motor seizures, and hippocampal CA3 cell damage induced by domoic acid at NS-102 doses that did not antagonize kainic acid induced toxicity. We conclude that domoic acid toxicity in vivo is mediated largely by a subclass of non-NMDA receptors that are selectively antagonized by NS-102.

Animals↗
PubMed1994

Rapid development of tolerance to morphine in the formalin test.

Previous reports have suggested that tolerance to the antinociceptive effects of morphine does not develop in the formalin test. To re-examine these findings, morphine was administered via multiple injections or continuous infusion from 0 to 4 days prior to testing with either the formalin or tail-flick test. Following twice daily injections (5.0 mg kg-1 s.c.), significant tolerance developed within 2 days with the formalin test but not until day 4 with the tail-flick test. Significant tolerance was noted with both tests 4 days following the implantation of osmotic mini-pumps (10 mg kg-1 day-1, s.c.). We conclude that in mice, tolerance to the analgesic effects of morphine develops rapidly with the formalin test.

Animals↗
PubMed1994

Pharmacokinetics of parenteral and oral sustained-release morphine sulphate in dogs.

The pharmacokinetics of single-dose morphine sulphate (MS) administered intravenously (i.v.) and intramuscularly (i.m.) and of oral sustained-release morphine sulphate (OSRMS) were studied in dogs. Beagles (n = 6) were randomly assigned to six treatment groups using a Latin square design. Treatments included MS 0.5 and 0.8 mg/kg i.v. and i.m. and OSRMS 15 and 30 mg orally (p.o). Serum samples were drawn at intervals up to 420 min following parenteral MS and 720 min following OSRMS. Serum was analysed for morphine concentration using a radioimmunoassay. Pharmacokinetic analysis of the results revealed that MS was eliminated by a first-order process best described by a two-compartment model. For i.v. and i.m. data there were no statistically significant differences (P < 0.05) between steady-state volume of distribution, half-life of elimination and plasma clearance. As expected, area under the concentration vs. time curve (AUC) was significantly greater for the 0.8 mg/kg dosage for i.v. and i.m. routes, and time to maximum serum concentration was significantly longer following i.m. administration. For OSRMS there were no significant differences between dosage for any parameter (AUC, Cmax, tmax, t1/2, F) and prolonged absorption of the drug occurred over approximately 6 h. Bioavailability (F) for both oral dosages was approximately 20%. The i.m. route is an effective method for rapid and complete delivery of MS to dogs. OSRMS may be useful in the provision of long-term analgesic therapy in dogs, but further work is required to verify the safety and effectiveness of this preparation.

Administration, Oral↗
PubMed1991

Hippocampal damage produced by systemic injections of domoic acid in mice.

The effect of systemic administration of domoic acid, a potent structural analogue of kainic acid, on the mouse hippocampus has been studied using light and electron microscopic techniques. Intraperitoneal injections of either domoic acid (4 mg/kg) or kainic acid (32 mg/kg) produced a series of behavioural changes including sedation, rigidity, stereotypy (scratching, head nodding), balance loss, and discrete or generalized convulsions. Both qualitative and quantitative histological analysis revealed similar but not identical patterns of neuronal damage in the hippocampal formation of domoic acid- and kainic acid-treated mice. With both toxins the most extensive damage was always observed in the CA3 region of the hippocampus, with lesser degrees of damage observed in other hippocampal regions (CA4 greater than CA1 greater than CA2 greater than dentate granule cells). In general, neuronal damage was more widespread following administration of kainic acid than domoic acid. In the CA3 region, however, the percentage of cells exhibiting damage was greater following domoic acid (82.1%) than kainic acid (58.8%) following systemic administration. No damage was found in the hippocampi of vehicle control-treated mice. Electron microscopy of the CA3 region following domoic acid revealed two subpopulations of damaged neurons: (1) swollen cells that exhibited vacuolization of their cytoplasm and (2) shrunken irregularly shaped electron-dense cells. Swollen processes of astroglial origin were observed surrounding electron-dense cells, and electron-dense processes were often found extending into the neuropil. These results suggest that although domoic acid and kainic acid produce similar changes in both open field behaviour and hippocampal neuropathology, responses to these toxins are not identical at equitoxic doses. Lesions in the domoic acid-treated mice are more selective for the CA3 hippocampal region than are those produced by kainic acid following systemic administration. Domoic acid may, therefore, be a better tool for studying certain aspects of excitatory amino acid neurotoxicity.

Animals↗
PubMed1991

Pharmacology of systemically administered domoic acid in mice.

Domoic acid, a structural analogue of kainic acid, has been identified as the toxin that poisoned people who consumed contaminated blue mussels harvested from eastern Prince Edward Island in December of 1987. To investigate the pharmacology of domoic acid in vivo we injected groups of mice with serial dilutions of extracts of contaminated mussels and verified domoic acid concentrations using high performance liquid chromatography. Mice progressed through a series of behavioural changes that were both reproducible and dose-dependent. These behaviours formed the basis of a rating scale that was used to reliably quantitate domoic acid concentrations as low as 20 micrograms/mL. This scale was then used to compare the relative toxicity of domoic acid contained in four formulations: namely, (1) extracts of contaminated mussels, (2) pure domoic acid, (3) extracts of noncontaminated mussels that were "spiked" with pure domoate, and (4) extracts of the algal source of domoic acid. Interpolation of the resulting dose-response curves produced median toxic dose (TD50) values of 2.9, 3.9, 4.9, and 4.2 mg/kg for the four formulations, respectively. Statistical analysis of these data revealed that curves for all formulations of domoic acid were parallel, but that extracts of contaminated mussels were significantly more potent than any of the other formulations at low and intermediate doses of domoic acid. We further compared domoic acid toxicity with that produced by kainic acid. Dose-response curves for both compounds were statistically parallel and both toxins were equally efficacious. The TD50 values were 3.9 and 31.9 mg/kg for pure domoic acid and kainic acid, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Tryptophan-morphine interactions and postoperative pain.

Patients undergoing abdominal surgery were infused with saline or the 5-hydroxytryptamine (5-HT) precursor tryptophan starting in the operating room and continuing for three hours in the recovery room. There was a nonsignificant trend for patients who received tryptophan to have higher pain scores. In the saline-treated patients, plasma tryptophan was below the range for normal healthy subjects, and there was a strong positive relationship between plasma tryptophan and morphine requirements. These data, taken together with animal data obtained using the formalin pain test, suggest that a 5-HT system in the brain can antagonize the dissociative state produced by morphine, which helps patients to tolerate pain. When plasma tryptophan falls below normal levels, brain 5-HT falls and morphine requirements are reduced. While tryptophan may potentiate spinal 5-HT function to decrease nociceptive afference in some circumstances, there may be clinical conditions in which the use of tryptophan is contraindicated.

Double-Blind Method↗
PubMed1989

Different alpha-receptor subtypes are involved in clonidine-produced analgesia in different pain tests.

Dose-response curves for clonidine-produced analgesia in rats were constructed using the tail-flick and formalin tests. Subsequently, the relative role of alpha 1 and alpha 2 receptors in clonidine analgesia in each of these tests was determined using systemic administration of vehicle controls, tolazoline, yohimbine and prazosin prior to injection of an ED50 dose of clonidine. Clonidine was found to be significantly more potent in the formalin test than in the tail-flick test. Furthermore, clonidine analgesia in the tail-flick test was completely antagonized by tolazoline and yohimbine, but not by prazosin, whereas clonidine was antagonized by tolazoline and prazosin, but not by yohimbine in the formalin test. The implications of these findings with regard to the contributions of different alpha-receptor subtypes to clonidine-produced analgesia in different pain tests are discussed.

Analgesics↗
PubMed1988

Systemic administration of naloxone produces analgesia in BALB/c mice in the formalin pain test.

Systemic administration of naloxone usually produces either hyperalgesia or no change in nociception depending on the animal species used and/or the pain test employed. This study, however, demonstrates that naloxone produces a dose-dependent analgesia in the formalin pain test using an inbred strain of albino mouse. Female BALB/c, C57BL/6 and CD1 mice were injected subcutaneously with naloxone HCl in saline (0.1 10.0 mg/kg) or saline alone, and tested for analgesia using the formalin test. Naloxone produced a statistically significant dose-dependent analgesia in the BALB/c mice, with an ED50 of 0.24 mg/kg and almost total analgesia at doses of 1 mg/kg or greater. No changes in pain behaviour were observed in the C57BL/6 or CD1 strains of mice. We believe this to be the first report of analgesia following administration of doses of naloxone normally used for opioid antagonism. To determine if this effect was specific to the formalin test, the 3 strains of mice were injected subcutaneously with naloxone HCl and tested in the tail-flick test. Naloxone had no analgesic action in this test in any of the strains.

Analgesia↗
PubMed1986

Metabolism and disposition of 3,6-dibutanoylmorphine in rat brain.

In previous studies from this laboratory it was found that dibutanoylmorphine (DBM) was more potent than morphine as an analgesic in rats and that it was less active than acetyl esters of morphine on behaviour. As DBM is a morphine prodrug, the aim of this work was to determine if rat brain homogenates were capable of deacylating DBM and monobutanoylmorphine (MBM) and to determine relative proportions of parent drug to metabolites in the brain in vivo. In 10% (w/v) brain homogenates, DBM was eliminated with a half-life of about 70 min (corrected for dilution), while MBM was eliminated 10 times as quickly. DBM and its metabolites were found in both blood and brain as early as 1 min after i.v. administration of DBM. After 5 min, the predominant form in blood was MBM and in brain it was DBM. Thus, rat brain possesses the capacity to metabolize DBM by deesterification and the parent drug, MBM, and morphine were found in blood and brain in vivo.

Animals↗
PubMed1984

Evaluation of 3,6-dibutanoylmorphine as an analgesic in vivo: comparison with morphine and 3,6-diacetylmorphine.

Dibutanoylmorphine (DBM), a synthetic diester of morphine, was compared with morphine (M) and diacetylmorphine (DAM) for analgesic efficacy, potency and duration of action following I.V. administration in rats. Analgesia was assessed in groups of eight animals using both tail-flick and hot-plate testing methods following random administration of five different doses of each drug. DBM was found to be substantially more potent than M, but less potent than DAM in both tail-Flick and hot-plate tests of nociception. Similarly, assessment of duration of action at the ED50 for each drug revealed that DBM has a duration of analgesia which is intermediate between the durations of M and DAM. Thus, in rats in vivo, DBM is an effective analgesic and has a reasonable duration of action release to other opioids.

Analgesics↗