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Biomedical subjects

R D Sewell

Publications and source records attributed to R D Sewell.

At least 37 records · Page 2Linked to original sources
PubMed1989

Evaluation of selective actions of dopamine D-1 and D-2 receptor agonists and antagonists on opioid antinociception.

The effect of the selective dopamine receptor agonists SKF 38393 (D-1) and quinpirole (D-2) on nociception was studied in the mouse tail immersion test. The D-1 receptor agonist induced mild hyperalgesia whereas the D-2 agonist produced antinociception. Pretreatment with either the selective D-1 receptor antagonist SCH 23390 or the D-2 receptor antagonist (-)-sulpiride converted the hyperalgesia produced by the D-1 agonist into an antinociceptive response whereas the effect of the D-2 receptor agonist was significantly antagonised. The antinociceptive response of selective opioid agonists was also studied in combination with selective dopamine receptor agonists and antagonists. Sufentanil (mu-opioid) antinociception was enhanced in animals pretreated with (-)-sulpiride but not SCH 23390. In animals co-administered sufentanil with SKF 38393 there was a reduced antinociceptive effect whilst quinpirole enhanced the action of sufentanil. Likewise, antinociception induced by the kappa-opioid agonist U50,488H was unaltered in animals pretreated with SCH 23390, increased by (-)-sulpiride, and reduced by SKF 38393. delta-Opioid antinociception induced by [D-Ala2,D-Leu5]enkephaline remained unmodified following pretreatment with either (-)-sulpiride or SCH 23390 but was potentiated in animals which received both the delta-agonist and the D-2 receptor agonist. It is concluded that D-2 receptor agonists not only have intrinsic antinociceptive activity, but can also potentiate opioid-induced antinociception. Similarly, dopamine D-2 receptor antagonists appear to potentiate opioid-induced antinociception in this nociceptive model.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Novel inhibitors of enkephalin-degrading enzymes. I: Inhibitors of enkephalinase by penicillins.

Several penicillins have been found to have pro-antinociceptive properties and also to be enkephalinase (neutral endopeptidase-24.11) inhibitors, carfecillin being the most potent. Carfecillin i.c.v. (but not i.p.) had significant antinociceptive activity in the mouse tail immersion test and completely suppressed abdominal constrictions (acetic acid) in mice (IC50 = 23 micrograms/animal). In combination with (D-Ala2-D-leu5)-enkephalin (DADL) i.c.v. in the abdominal constriction test the complete protection observed was reversed by the opioid receptor antagonist naltrexone. Carfecillin was a competitive inhibitor of enkephalinase from mouse brain striata (IC50 = 207 + 57 nM, cf thiorphan 10.6 +/- 1.9 nM) but did not inhibit other known enkephalin- degrading enzymes. Carfecillin provides a new lead structure for the development of more potent enkephalinase inhibitors.

Analgesics↗
PubMed1989

Novel inhibitors of enkephalin-degrading enzymes. II: N5'-substituted-4-thioxohydantoic acids as aminopeptidase inhibitors.

Some 2-substituted-(2'-aminophenyl)-4-thioxohydantoic acids (o-amino PTC-amino acids) have antinociceptive activity when administered (icv) alone (IC50 = 0.04-0.87 microM/animal) and show a striking prolongation of the antinociceptive action of (D-Ala-2 D-Leu5)-enkephalin (DADL) in combination. The effects are thought to be mediated via opioid receptors since they are naloxone-reversible. Although inhibitors of the enkephalin degrading puromycin-insensitive, bestatin-sensitive aminopeptidase (possibly aminopeptidase M) their action is weak (IC50 = 32 microM leucine, 536 microM, glycine) and they might be considered to have a direct antinociceptive effect on opioid receptors. The titled compounds constitute novel 'lead' compounds for the development of potent aminopeptidase M inhibitors.

Aminopeptidases↗
PubMed1988

Amelioration of naloxone-precipitated opioid withdrawal symptoms by peripheral administration of the enkephalinase inhibitor acetorphan.

The effects of 60 min pretreatment with the enkephalinase inhibitor acetorphan were assessed on naloxone-precipitated (2.5 mg/kg IP) abstinence in chronically morphinized rats. In addition, the antinociceptive activity of the compound was investigated in mice. Intraperitoneal injection (50 mg/kg) in rats attenuated some aspects of the opioid withdrawal syndrome such as burrowing, wet dog shakes, squeal on touch hostility, tachypnoea, ptosis and rough hair, whereas jumping and escape behaviour were significantly increased in acetorphan-treated animals. No effect was observed on withdrawal hypothermia or acute weight loss. Similarly, chronic dosing with acetorphan after withdrawal produced no significant effect on body weight. Acetorphan (50 mg/kg IP) failed to produce any antinociceptive activity in the mouse tail immersion test, but potentiated the antinociceptive effect of D-Ala2-D-Leu5-enkephalin. These results are discussed in terms of acetorphan crossing the blood-brain barrier before being hydrolysed to thiorphan, thus yielding opioid withdrawal relieving effects.

Amino Acids, Sulfur↗
PubMed1988

Dopamine-mediated behaviour following chronic treatment with B-HT 920.

Following subchronic (5-day) dosing with B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo(4,5-d)azepine (1 mg kg-1 day-1 i.p.) in rats there was a significant increase in both apomorphine-induced motor activity and stereotypy. On continued B-HT 920 treatment, however, the enhancement of apomorphine motor activity faded into insignificance but the increase in stereotypy persisted beyond 15 days. The results are discussed in terms of dopamine autoreceptor tolerance, postsynaptic D2 supersensitivity and possible differential effects in different brain loci on the above two receptor sub-classes.

Adrenergic alpha-Agonists↗
PubMed1988

Effects of beclamide on isolation-induced aggression and locomotor activity in mice.

The anti-aggressive effects of orally administered beclamide (N-Benzyl-beta-chloropropionamide) have been studied in male albino mice which were individually isolated for a 28-day period. Beclamide (50-250 mg kg-1 p.o.) caused an overall dose-dependent increase in the attack onset latency, a reduction in the percentage of animals attacking and the mean number of attacks/animal for this model of aggression. In addition, the highest dose of beclamide (250 mg kg-1 p.o.) did not significantly modify locomotor activity in mice. It was concluded that beclamide induced anti-aggressive effects at non-sedative doses. This anti-aggressive action was thought be at least partially mediated, through a beclamide-induced release of 5-HT from presynaptic sites.

Aggression↗
PubMed1987

Effects of beta-phenylethylamine on locomotor activity, body temperature and ethanol blood concentrations during acute ethanol intoxication.

Beta-phenylethylamine (PEA) is an endogenous amine which is metabolised by MAO B. The function of this enzyme is known to be modified by ethanol so we have studied the interactions of PEA with ethanol. Rectal temperatures of rats were determined and animals pretreated with ethanol (2.5 g kg-1 IP) 90 min before PEA 20, 40, 100 mg kg-1 IP). Spontaneous locomotor activity (SLA) was then recorded, for 30 min, temperatures redetermined and blood ethanol levels evaluated. PEA increased SLA but did not alter rectal temperatures, and at 40 mg kg-1 it not only attenuated ethanol hypothermia and blood levels but also modified ethanol hypomotility. The highest dose of PEA (100 mg kg-1) decreased blood ethanol concentration and sedation but did not counteract the hypothermia. Thus PEA increased ethanol clearance, though the underlying mechanism is not totally clear. This finding is discussed in relation to its catecholaminergic and enzyme inducing characteristics.

Alcoholic Intoxication↗
PubMed1987

Dopamine receptor-mediated spinal antinociception in the normal and haloperidol pretreated rat: effects of sulpiride and SCH 23390.

Nociceptive tail flick latencies (TFL) were recorded in response to noxious thermal stimuli applied to lightly anaesthetized rats. The effects of intrathecally administered dopamine receptor agonists alone and combined with dopamine receptor antagonists were examined upon the TFL. Experiments were repeated on animals made supersensitive to dopamine following withdrawal from 28 day administration of haloperidol. In untreated animals the D2-receptor agonist LY 171555 and apomorphine produced an increase in TFL. In contrast, the Di-receptor agonist SKF 38393 had no significant effect on TFL. TFL. Following haloperidol-induced dopamine-supersensitivity, SKF 38393 produced an increase in TFL. In contrast, LY171555 and apomorphine had minimal effects on TFL in this preparation. In animals not treated with haloperidol, the dopamine receptor antagonists SCH 23390 and (+/-)-sulpiride both blocked the increase in TFL produced by the D2-agonists. SCH23390 and (+/-)-sulpiride also blocked the increase in TFL produced by SKF 38393 in haloperidol-supersensitized animals. The antinociceptive action of intrathecally administered dopamine agonists appears to be mediated via D2-receptors. Whether the antinociception produced by SKF 38393 is exclusively contingent upon the activation of D1-receptors in the dopamine-supersensitive animal is as yet unresolved.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Synthesis and antinociceptive properties of a series of exo- and endo-6-hydroxy-2-aminobenzonorbornenes.

A series of 6-hydroxy endo- and exo-derivatives of 2-aminobenzonorbornene has been synthesized and evaluated for antinociceptive activity in the mouse. The results indicated a stereospecific effect in the antinociceptive responses exhibited by the two isomeric groups of compounds. The exo-amines 10a-10c were inactive in both the tail immersion and tail clip tests. The corresponding endo-isomers exhibited antinociceptive properties; 4a was the most active compound tested but was toxic at the dose administered.

Analgesics↗
PubMed1986

Characterization of the effects of (+/-)-meptazinol, its individual enantiomers and N-methyl meptazinol on food consumption in the rat.

Both (+/-)-meptazinol (2 mg kg-1) and levorphanol (1 mg kg-1) produced hyperphagia over a 4 h period after intraperitoneal injection in free feeding rats during the daylight phase. The individual (+)- and (-)-enantiomers of meptazinol (2 mg kg-1 i.p.) induced comparable increases in cumulative food intake. N-methyl meptazinol (2-10 mg kg-1 i.p.), the quaternary analogue of meptazinol, produced no modification of food intake though it increased food consumption when injected intracerebroventricularly (10-100 micrograms per animal). Meptazinol and levorphanol hyperphagia was abolished by 1 mg kg-1 doses (i.p.) of the opioid antagonists naltrexone, naloxonazine and (-)-Mr 1452 but not by its (+)-enantiomer Mr 1453 which is not effective as an opioid antagonist. Intracerebroventricular administration of the delta-opioid antagonist ICI 154,129 (10 micrograms per animal) suppressed meptazinol but not levorphanol hyperphagia. It was concluded that meptazinol produces centrally mediated stereospecifically reversible hyperphagia through a mu-opioid receptor mechanism common to levorphanol, and also through delta-opioid receptor mechanism(s).

Animals↗
PubMed1985

Involvement of endogenous enkephalins in the feeding response to diazepam.

The effect of the delta-opioid agonist [D-Ala2,D-Leu5]enkephalin (DADLE) and the benzodiazepine diazepam on the food intake of non-deprived rats was investigated. Both compounds produced a significant increase in feeding. The hyperphagic response to DADLE (10 micrograms i.c.v.) and diazepam (1 mg/kg i.p.) was suppressed by concurrent treatment with the selective delta-opioid antagonist ICI 154,129 (10 micrograms i.c.v.). These findings add further support to the concept that endogenous enkephalins may be implicated in the stimulatory effects of benzodiazepines on ingestive behaviour.

Animals↗
PubMed1985

Hyperphagia induced by 2-deoxy-D-glucose in the presence of the delta-opioid antagonist ICI 174,864.

The effect of the selective delta-opioid antagonist ICI 174,864 (N,N-bisallyl-Tyr-Aib-Aib-Phe-Leu-OH: Aib=alpha-aminoisobutyric acid) on the hyperphagia induced by 2-deoxy-D-glucose (2-DG) was investigated in non-deprived rats. The increase in food intake produced by 2-DG (500 mg/kg i.p.) was not reduced by ICI 174,864 at a dose (3 micrograms/rat i.c.v.) which totally abolished the feeding response to the delta-agonist D-Ala2-D-Leu5-enkephalin (10 micrograms/rat i.c.v.). These findings suggest that the appetitive effects of 2-DG are not mediated by an enkephalinergic/delta-receptor system. They do not, however, preclude the possible involvement of endogenous opioids acting at other sub-types of opioid receptor in this glucoprivic ingestional response, which is suppressed by less specific opioid antagonists such as naloxone.

Animals↗
PubMed1985

Are delta-opioid receptors involved in the regulation of food and water intake?

The effect of the delta-opioid antagonists ICI 154,129 (1-100 micrograms, i.c.v.) and ICI 174,864 (1-100 micrograms, i.c.v.) and of the delta-agonist D-Ala2-D-Leu5-enkephalin (DADL; 1-10 micrograms, i.c.v.) on the intake of food and water of non-deprived rats was investigated. Animals treated with either ICI 154,129 or ICI 174,864 ate and drank significantly less than vehicle-treated controls over a 3 hr test period. The suppressant effects of these peptides on appetite were similar to those observed with the more commonly-used opioid antagonists, naltrexone and Mr 2266. In contrast, the delta-agonist DADL produced an increase in both the consumption of food and water in the 3 hr following administration of drug. The findings presented in this study lend further support to the hypothesis that an endogenous enkephalin/delta-receptor system may play a role in the tonic induction of ingestive behaviour.

Animals↗
PubMed1985

Benzodiazepines produce contrasting effects on the active membrane properties of an invertebrate neuron.

A perturbation of excitable membranes mediated by non-receptor (non-specific) mechanisms might be predicted from the hydrophobic nature of 1,4-benzodiazepines. Since correlations between membrane properties and neuronal effects have not been described for benzodiazepines, the effects of flurazepam, oxazepam and the benzodiazepine antagonist flumazepil (Ro 15-1788) were examined on both passive and active electrical properties of the membrane and neuronal discharge frequency. In this study, the isolated sensory neuron of the crayfish has been utilized as a neuronal model system. Flurazepam and flumazepil both enhanced the discharge frequency, in contrast to the depression produced by oxazepam. Discharge frequency was directly correlated with the maximum rate of rise of membrane potential during the threshold phase and was inversely correlated with spike threshold. In addition, the discharge frequency appeared to exhibit little dependence on peak amplitude, duration and the maximum rate of depolarization of the action potential. These findings are discussed in relation to non-specific mechanism(s) of action for benzodiazepines. It is suggested that, in the absence of a specific drug-receptor interaction, benzodiazepines in larger concentrations (greater than or equal to 50 mumol/l) exhibit selective membrane perturbations.

Action Potentials↗
PubMed1984

Synaptic and non-synaptic actions of benzodiazepines on the crayfish sensory neuron.

On the stretch-induced discharge activity of the isolated crayfish sensory neuron flurazepam (less than or equal to 3 X 10(-4) M) and Ro 15-1788 (less than or equal to 10(-3) M) produced reversible concentration-dependent excitation, but oxazepam only produced depression (less than or equal to 5 X 10(-4) M). Similar divergent effects on the membrane properties were observed. Oxazepam increased the threshold to firing without changing resting potential, membrane resistance or the GABA-mediated IPSP. In contrast flurazepam and Ro 15-1788 produced a concentration-dependent decrease in threshold. Flurazepam did not alter membrane resistance or resting potential but facilitated GABA transmission. Ro 15-1788 had the opposite effect on the GABA synapse, and also depolarized the resting potential but did not alter membrane resistance. The change in spike threshold appeared to be an important component in producing discharge excitation or depression. These results not only demonstrate the capability of the sensory neuron to discriminate between structures of benzodiazepines, but also that these agents can produce divergent effects on synaptic and non-synaptic properties of a single neuron.

Action Potentials↗
PubMed1984

Evidence for excitatory and depressant non-receptor-mediated membrane effects of benzodiazepines in the crayfish.

Oxazepam produced a significant reversible monophasic concentration-dependent (50-500 mumol/l) depression of stretch-induced discharge frequency of the isolated crayfish sensory neuron. In total contrast, flurazepam (10-200 mumol/l) evoked reversible excitation of the neuronal firing rate but at concentrations greater than 300 mumol/l it induced transient excitation followed by secondary total depression. The benzodiazepine antagonist flumazepil (less than or equal to 1 mmol/l) also produced an inherent increase in neuronal discharge frequency, though respective concentrations of 50 and 100 mumol/l failed to block flurazepam-excitation or oxazepam-depression. It is suggested that these high concentration qualitatively divergent neuronal effects are not mediated through specific benzodiazepine receptors.

Animals↗