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Biomedical subjects

R G Hill

Publications and source records attributed to R G Hill.

At least 19 recordsLinked to original sources
PubMed1992

Characterisation of NK receptors in guinea-pig urinary bladder smooth muscle: use of selective antagonists.

The aim of the present study was to characterise the neurokinin receptors involved in mediating contractile responses in guinea-pig urinary bladder smooth muscle. The use of selective NK1, NK2, and NK3 receptor agonists indicated that contractile responses in this tissue are mediated via activation of NK1 and NK2, but not NK3 receptors. This was confirmed by the observation that responses to [Sar9,Met(O2)11]substance P were inhibited by (+/-)-CP 96,345 (a NK1 receptor antagonist) and responses to eledoisin (following NK1 receptor desensitization) were inhibited by L-659,877 (a NK2 receptor antagonist).

Animals↗
PubMed1992

Influence of cement layer thickness on the adhesive bond strength of polyalkenoate cements.

The fracture toughness and yield stress values of model zinc polycarboxylate and glass polyalkenoate cements have been used to calculate plastic zone sizes. The size of the plastic zone at the crack tip in these materials has been used to predict whether cement layer thickness is likely to influence the adhesive bond strength. In the model zinc polycarboxylate cement studied, the plastic zone size was comparable to the cement layer thickness and had a pronounced influence on the shear bond strengths obtained. In contrast, the plastic zone sizes obtained for the glass polyalkenoate cements were much smaller and the shear bond strengths were found to be much less dependent on cement layer thickness.

Adhesiveness↗
PubMed1992

Differences in neurokinin receptor pharmacology between rat and guinea-pig superior cervical ganglia.

1. The depolarizations elicited by seven neurokinin receptor agonists were examined in both rat and guinea-pig superior cervical ganglia by use of grease-gap methodology in the presence of tetrodotoxin (0.1 microM). Responses were normalised with respect to 1 microM eledoisin. 2. The rank order of agonist potency in the rat ganglia was senktide greater than substance P greater than substance P methyl ester = eleidosin = Sar-Met-substance P greater than neurokinin B greater than neurokinin A, whereas in guinea-pig superior cervical ganglion (SCG) the rank order was senktide greater than Sar-Met-substance P greater than neurokinin B = eledoisin = substance P methyl ester. The concentration-effect curves for substance P and neurokinin A in guinea-pig ganglia were biphasic which precluded the determination of meaningful potency values. 3. The maximal depolarization achieved by subtype selective ligands was different between these two species. On rat and guinea-pig SCG, the NK3-selective ligand, senktide, produced a maximal depolarization of 27% and 274% respectively, whereas the NK1-selective ligand, substance P methyl ester, produced depolarizations of 77% and 64% respectively. 4. The depolarizations induced by substance P methyl ester and senktide in either species were unaffected by atropine (1 microM), suggesting a lack of involvement of presynaptic neurokinin receptors in the generation of the response. 5. The potency of substance P methyl ester, senktide, and neurokinin A were unaffected by pretreating ganglia with the peptidase inhibitors bacitracin (40 micrograms ml-1), leupeptin (4 micrograms ml-1), and chymostatin (2 micrograms ml-1). Similarly, these peptidase inhibitors had no effect on the maximal depolarizations achieved by any of these agonists.6. It is evident that rat and guinea-pig superior cervical ganglia possess both NK, and NK3 receptors, but that their net contribution to depolarizations are different between the two species. The depolarizations in guinea-pig SCG are mediated predominantly by an NK3 subtype and in rat SCG by an NK, receptor subtype.

Animals↗
PubMed1992

Effects of the delta-opioid receptor antagonist naltrindole on antinociceptive responses to selective delta-agonists in post-weanling rats.

1. Antagonism, by the selective delta-opioid receptor antagonist naltrindole, of the antinociceptive effects of [D-Pen2, D-Pen5] enkephalin (DPDPE), [D-Ser2, Leu5, Thr6] enkephalin (DSLET) and D-Ala2 deltorphin I (DELT I) has been studied in 25 day old rats. 2. Antinociception was measured by the 50 degrees C tail immersion test following i.p. administration of agonists and/or antagonists. 3. Dose-related antinociception was observed with DPDPE, DSLET and DELT I and ED75 doses were computed (0.66 mg kg-1, 0.65 mg kg-1, 0.032 mg kg-1 respectively) and used for antagonism studies. 4. Naltrindole (0.01 mg kg-1) significantly attenuated the antinociceptive effects of DPDPE and DSLET with 0.1 mg kg-1 producing complete reversal of the effects of the ED75 dose. In contrast, naltrindole at 0.01 and 0.1 mg kg-1 did not alter antinociceptive responses to DELT I. Naltrindole at 1 mg kg-1 significantly attenuated DELT I antinociception. 5. Naloxone (1 mg kg-1) produced equivalent degrees of antagonism of the antinociceptive effects of DPDPE, DSLET and DELT I. ICI 174,864 (1 mg kg-1) also antagonized antinociception with a differential degree of attenuation (DSLET > DPDPE > DELT I). 6. Naltrindole (1 mg kg-1) had no effect on the antinociception induced by the selective mu-agonist alfentanil (60 micrograms kg-1). Naltrindole, naloxone or ICI 174,864 had no effect on nociceptive latencies. 7. The differential antagonism by naltrindole of the effects of three selective delta-agonists suggests delta-receptor heterogeneity.Further, the lower sensitivity of response to DELT I suggests that this agent may exert its antinociceptive effects at a different 6 receptor subtype from DPDPE or DSLET.

Analgesics↗
PubMed1992

Creating an agenda for change. Quality assurance in mental health services.

Quality assurance is traditionally viewed in terms of structure, process and outcome, but ignores the fact that they coexist in day-to-day practice. Many quality assurance initiatives are based on the belief that organisational systems can be periodically improved using external experts; this can lead to a disjointed approach and alienate staff. QUARTZ is a quality assurance programme for mental health services, and encourages a collaborative, problem-solving approach among staff. Ongoing evaluation is essential to facilitate long-term change.

Community Mental Health Services↗
PubMed1990

Characterization of kappa-opioid receptors in the guinea-pig ileum.

Equilibrium binding saturation studies with [3H]bremazocine, under mu- and delta-suppressed conditions and [3H]U69593 have demonstrated that both radioligands bind with high affinity to an apparently homogeneous population of binding sites in the guinea-pig ileum longitudinal muscle-myenteric plexus preparation. In competition studies, the absolute affinities and slopes of the inhibition curves for several unlabelled ligands against [3H]bremazocine were not significantly different to those against [3H]U69593 and were consistent with binding to the kappa-opioid binding site. In the intestinal layers underlying the longitudinal muscle-myenteric plexus [3H]bremazocine, under kappa-selective conditions, recognized both a high and low affinity site. In contrast, [3H]U69593 bound to a homogeneous population of binding sites. The [3H]U69593 binding site and the [3H]bremazocine high affinity site demonstrated comparable characteristics to the single, kappa site identified in the longitudinal muscle layer. The nature of the low affinity site was not investigated due to difficulties associated with low specific binding, and its significance therefore remains to be investigated.

Animals↗
PubMed1990

Sensory responses of caudal trigeminal neurons to thermal and mechanical stimuli and their behavioural correlates in the rat.

Behavioural experiments in the freely moving rat were carried out to determine thermal and mechanical nociceptive thresholds to ramp stimuli applied to the face. The mean thermal escape threshold was 43.5 degrees C, and the mean mechanical escape threshold was 179.2 g/mm2. In a parallel set of experiments recordings were made from single neurons in the caudal trigeminal nucleus of the anaesthetized rat. Neurons were classified according to their responses to a range of thermal and mechanical stimuli applied to the face. Three classes of neuron responded exclusively to mechanical stimuli and four classes responded to thermal stimuli (usually in addition to responding to mechanical stimuli). The mean thermal threshold of neurons responsive to warming stimulation was 44.4 degrees C. Neurons responsive to innocuous warming were located in deeper laminae. Many of the neurons responsive to noxious heat appeared to show an exponential relation between temperature and firing rate. An argument is made for a direct role of exponentially responding neurons in thermal nociception. The distribution of all neuronal response thresholds was left-skewed compared with a normal distribution, whereas the behavioural escape thresholds approximated a normal distribution.

Anesthesia↗
PubMed1990

Delta-opioid receptor binding sites in rodent spinal cord.

1. The delta-opioid receptor agonist [D-Pen2,D-Pen5]enkephalin showed an antinociceptive effect in the mouse tail-flick test, following intrathecal administration. This action was reversed by naloxone and by the selective delta-opioid receptor antagonist ICI 174864. 2. High affinity, saturable binding of [3H]-[D-Pen2,D-Pen5]enkephalin has been demonstrated in spinal cord homogenates from guinea-pig, hamster, rat and both adult and young (18-20 g) mice. The binding was shown by autoradiography to be concentrated in the superficial laminae of the dorsal horn. 3. Competition studies confirmed that the binding of [3H]-[D-Pen2,D-Pen5]enkephalin was to the delta-opioid site. However, anomalies were seen with displacement assays using mu-ligands, which may suggest some common high affinity site for delta- and mu-opioid receptor agonists in the spinal cord. 4. The results add further evidence for a role of the delta-opioid receptor in spinally-mediated antinociception.

Analgesics↗
PubMed1989

Correlation of ontogeny with function of [3H]U69593 labelled kappa opioid binding sites in the rat spinal cord.

In this study, we have used a variety of in vitro and in vivo techniques to demonstrate the presence, and examine the function, of [3H]U69593 binding sites in the spinal cord of the 9-16-day-old rat in comparison to the adult. Equilibrium binding of [3H]U69593 to homogenates of adult rat spinal cord revealed a single population of non-interacting sites with a maximum binding capacity of 10.4 +/- 1.4 fmol/mg protein and an apparent equilibrium dissociation constant of 2.31 +/- 0.47 nM while in 9-16-day-old cord these parameters were 57.0 +/- 9.4 fmol/mg protein and 2.28 +/- 0.22 nM, respectively. The total binding capacity per cord was 95.8 +/- 8.3 and 121.8 +/- 7.7 fmol/cord for adult and immature rat, respectively. Competition studies using receptor-selective opioid ligands showed that these sites were kappa opioid in nature. Autoradiographical techniques demonstrated a uniform distribution of these sites over transverse sections of 9-16-day-old rat cord. In vitro electrophysiology was performed on spinal cord slice preparations from the 9-16-day-old rat. U69593 (100 nM-1 microM) had no effect on passive membrane properties but produced a naloxone-reversible depression of both spontaneous and electrically evoked activity in dorsal horn neurones. Direct intrathecal injection of U69593 (0.3-10.0 micrograms/animal) into 9-16-day-old rats produced a dose-dependent, naloxone-reversible, antinociception when measured using the paw-pressure test. In conclusion, we have shown that, in contrast to the adult, the spinal cord of the 9-16-day-old rat has a significantly higher concentration of [3H]U69593 binding sites which have functional in vitro and in vivo correlates.

Action Potentials↗
PubMed1989

Antagonism of central and peripheral anorectic effects of caerulein by L-364,718.

The reduction in food intake induced by i.p. injections of the cholecystokinin (CCK) analogue caerulein was antagonised by a low dose (0.25 mumol/kg s.c.) of the selective CCK antagonist L-364,718. To block the anorectic effect of centrally administered caerulein a dose of 25 mumol/kg of L-364,718 was required, demonstrating that central CCK receptors can be blocked effectively in the rat by choosing appropriate doses of L-364,718.

Animals↗
PubMed1989

Quantitative analysis of autoradiograms.

Quantitative autoradiography of macroscopic specimens using computer-assisted image analysis is now widely used for studying the distribution of peptide receptors in the brain and peripheral tissues and more recently has been used to measure mRNA in tissue sections by in situ hybridisation. The spatial distribution of radiolabelled substances in tissue can be detected by the blackening of the emulsion in sheets of radiation-sensitive film and the resulting pattern of optical densities within the autoradiogram can be quantified by comparison with a calibrated radioactive scale. In this review, the technique of computer-assisted densitometry is described together with guidelines for the selection and preparation of radioactive standards. Strategies are discussed for ensuring that radioactivity can be measured and quantified using film-based emulsions with a precision approaching that of conventional counting techniques.

Animals↗
PubMed1989

L364,718 antagonizes the cholecystokinin-induced suppression of locomotor activity.

To determine the role of CCK-A receptors in the cholecystokinin (CCK)-induced suppression of locomotor activity in the rat, the ability of the selective CCK-A receptor antagonist L364,718 to block these responses was investigated. Cholecystokinin octapeptide (CCK8) (10, 100 micrograms/kg IP) and caerulein (1, 5, 10 micrograms/kg IP) produced marked reductions in locomotor activity whereas cholecystokinin tetrapeptide (CCK4) (100 micrograms/kg IP) was without effect. The reductions in activity produced by CCK8 (10 micrograms/kg) and caerulein (10 micrograms/kg) were antagonized by L364,718 (100 micrograms/kg IP). In an open field test CCK8 (10 micrograms/kg IP) reduced locomotor activity and total number of rears and increased pause duration. These effects of CCK8 on open-field behaviour were also antagonized by L364,718 (100 micrograms/kg IP). It is concluded that L364,718 is a potent antagonist of the actions of CCK8 and caerulein on locomotor activity, suggesting that the effects of these peptides are mediated by a CCK-A receptor.

Animals↗
PubMed1989

Rat hippocampal slices 'in vitro' display spontaneous epileptiform activity following long-term organotypic culture.

Organotypic cultures of rat hippocampal slices were maintained for periods of up to 12 weeks in vitro. Cultures adopted a two-dimensional architecture whilst retaining the subfields characteristic of intact hippocampal slices. Coventional intracellular onset of spontaneous long-lasting epileptiform activity. Epileptiform activity characteristic of both interictal and ictal events (paroxysmal depolarising shifts, tonic/clonic phases and afterdischarges) was observed in the absence of pharmacological manipulation or of orthodromic stimulation. Epileptiform activity was abolished in the presence of high Mg2+ concentration or tetrodotoxin, agents known to block synaptic transmission. In addition, the frequency of epileptiform events was independent of membrane potential and the amplitude of the paroxysmal depolarising shift (PDS) displayed a near linear relationship with membrane potential. The PDS could be reversed at potentials approaching synaptic equilibrium potential. The N-methyl-D-aspartate (NMDA)-receptor antagonist DL-2-amino-5-phosphonovalerate (DL-APV) dose-dependently reduced both the amplitude and duration of the spontaneous paroxysmal shift, having no effect on the initiation of the event or the resting membrane parameters of the neurone. DL-APV also attenuated a late component of the synaptically evoked excitatory postsynaptic potentials (epsp) not observed in non-epileptiform neurones. Application of GABAA receptor antagonists bicuculline or picrotoxin converted interictal events to ictus. In the presence of these agents, ictal events were up to 90 s in duration. These results suggest that long-term culturing of hippocampal explants leads to an alteration in the balance of excitatory and inhibitory synaptic activity. This allows the expression of an excitatory amino acid depolarisation acting through NMDA receptors which contributes to the generation and maintenance of spontaneous epileptiform activity which is synaptic in origin.

2-Amino-5-phosphonovalerate↗
PubMed1989

Highly selective kappa-opioid analgesics. 2. Synthesis and structure-activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide derivatives.

This paper describes the chemical synthesis and the development of structure-activity relationships (SAR) for the kappa opioid receptor affinity and mu/kappa opioid receptor selectivity of novel N-[(2-aminocyclohexyl)aryl]acetamide derivatives. The SAR of this series are investigated by consideration of structural modifications made to the aromatic moiety, the amide linkage, and cyclohexane and the pyrrolidine ring substituents of the prototype kappa selective agonist, PD117302 (trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo[b]thiophene-4- acetamide) (1). The kappa and mu opioid receptor binding affinities of 23 novel compounds are reported. It is observed that optimal mu/kappa receptor selectivity is obtained with a benzo[b]thiophene aromatic system attached via the C-4 position, which is discussed in terms of steric and electronic parameters. The amide linkage has been replaced with the reversed amide, an ester, an aminomethylene, a thioamide, and a secondary amide. The best of these isosteres is the N-methyl amide. Substitution of the pyrrolidine ring of PD117302 in the 3-position with a hydroxymethylene group increases the mu/kappa selectivity compared to the unsubstituted compound, e.g. compound 14, trans-(+/-)-N-methyl-N-[2-[3-(hydroxymethyl)-1-pyrrolidinyl] cyclohexyl]-4-benzo[b]furanacetamide monohydrochloride, mu/kappa receptor selectivity = 244. The cis fused, 4,5 dimethyl ether substituted cyclohexane analogue trans-(+/-)-N-methyl-N-[4,5-dimethoxy-2-(1-pyrrolidinyl) cyclohexyl]-benzo[b]thiophene-4-acetamide monohydrochloride (32) has high in vitro kappa opioid receptor affinity (Ki = 16 nM) and equipotent analgesic activity to morphine after iv administration in rats.

Analgesics, Opioid↗
PubMed1989

A kinetic analysis of kappa-opioid agonist binding using the selective radioligand [3H]U69593.

The interaction of the nonselective opioid ligand [3H]bremazocine and of the kappa-opioid [3H]U69593 with the kappa-receptor was investigated in guinea-pig cortical membranes. Each radioligand bound to a single population of high-affinity sites, although [3H]U69593 apparently recognised only 70% of those sites labelled by [3H]bremazocine. Naloxone and the kappa-selective ligands U69593 and PD117302 exhibited full inhibition of the binding of both radioligands. Kinetic analysis demonstrated biphasic rates of association and dissociation for both [3H]bremazocine and [3H]U69593. Detailed analysis of the binding of [3H]U69593 revealed that the fast rate of association was dependent on radioligand concentration, in contrast to the slow rate, which was independent of ligand concentration. Guanylyl-5'-imidodiphosphate (GppNHp) inhibited binding of [3H]U69593; saturation analysis demonstrated that the inhibitory effects of GppNHp resulted in a decrease in affinity without any significant change in binding capacity. GppNHp attenuated the formation of the slow component of [3H]U69593 binding, while accelerating the fast component. The data are consistent with the formation of a high-affinity complex between the kappa-receptor and a guanine nucleotide binding protein. Guanine nucleotides promote the dissociation of this ternary complex and the stabilisation of a lower-affinity state of the receptor.

Animals↗
PubMed1989

Actions of the GABAB agonist, (-)-baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro.

1. The electrophysiological actions of the GABAB agonist, (-)-baclofen, on deep dorsal horn neurones were studied using an in vitro preparation of the spinal cord of 9-16 day old rat. 2. On all neurones tested, (-)-baclofen (100 nM-30 microM) had a hyperpolarizing action which was associated with a reduction in apparent membrane input resistance. The increase in membrane conductance was dose-dependent and had a Hill coefficient of 1.0. 3. The (-)-baclofen-activated hyperpolarization persisted in the presence of bicuculline (50 microM) and Mg2+ (20 mM). 4. The reversal potential of the hyperpolarizing event was estimated at 102 mV and was made less negative by increasing the external concentration of potassium ions. 5. Over the same concentration range, (-)-baclofen also depressed the polysynaptic composite excitatory postsynaptic potentials (e.p.s.ps) evoked in these neurones by electrical stimulation of the dorsal root entry zone. 6. The potassium channel blockers caesium, applied intracellularly, and barium, applied extracellularly, depressed the postsynaptic response to baclofen but not its effect on e.p.s.ps. 7. We propose that (-)-baclofen has more than one mechanism of action in spinal dorsal horn: a postsynaptic action mediated via an increase in potassium conductance and a presynaptic action that is not associated with potassium channels and may be mediated via calcium channels. Since previous studies have demonstrated little effect of (-)-baclofen on transmitter release in spinal cord, it is possible that the postsynaptic hyperpolarizing action of (-)-baclofen may account for its clinical potency as an anti-spastic agent.

Animals↗
PubMed1989

Reduction of food intake by central administration of cholecystokinin octapeptide in the rat is dependent upon inhibition of brain peptidases.

1. The effects of intracerebroventricular (i.c.v.) injections of cholecystokinin-octapeptide (CCK-8) and caerulein, an amphibian decapeptide structurally related to CCK-8, are inconsistent in the rat. We have therefore investigated the possibility that enzymatic degradation could be responsible for the lack of activity of CCK-8 seen in some studies on food intake. 2. Injections of CCK-8 at doses of 2.5 nmol and 25 nmol into the lateral cerebral ventricle of rats did not reduce the intake of a highly palatable diet whereas injections of the same doses of caerulein reduced food intake potently and dose-dependently. 3. Co-administration of CCK-8 with a combination of the peptidase inhibitors bestatin (70 nmol), captopril (100 nmol) and thiorphan (120 nmol) resulted in an inhibition of feeding similar to that seen after the injection of caerulein alone. The peptidase inhibitors alone did not affect food intake. 4. When caerulein was injected i.c.v. in combination with bestatin, captopril and thiorphan the effect of caerulein was potentiated, suggesting that enzymatic breakdown of caerulein does occur. 5. It is concluded that the effect of centrally administered CCK-8 on food intake is dependent on the activity of cleaving enzymes in the brain. It is emphasized that the action of brain peptidases is a major factor which has to be considered when investigating the role of peptides in the central nervous system.

Animals↗