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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

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

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↗
PubMed1987

Cholecystokinin releases [3H]GABA from the perfused subarachnoid space of the anaesthetized rat spinal cord.

The neuropeptide cholecystokinin(26-33) (CCK) is widely distributed in the mammalian central nervous system, including the spinal cord. We have studied the possible interaction of CCK with GABA release mechanisms. Low doses of CCK-8 (1 nM) have been found to evoke calcium-dependent [3H]GABA release from an in vivo perfused spinal cord preparation in the anaesthetized rat. Tachyphylaxis was seen to the [3H]GABA releasing action of CCK-8. The injection of proglumide (150 mg/kg i.p.) totally blocked the [3H]GABA release produced by CCK-8 or by a medium containing 50 mM potassium. Substance P (10 microM) did not produce release of [3H]GABA, although in the same animals 50 mM potassium containing solutions could be shown to evoke release of [3H]GABA.

Anesthesia, General↗
PubMed1979

The effect of depolarizing potassium concentrations on the efflux of GABA from rat dorsal medulla in vivo and from slices and synaptosomes.

The efflux of [3H]GABA from the dorsal surface of adult rat medulla overlying the dorsal column nuclei (DCN) was found not be influenced by increasing the concentration of potassium in the superfusing solution to 40 mequiv. Similarly, raised potassium was found not to influence the efflux from slices of the dorsal region of the caudal medulla containing the dorsal column nuclei. This lack of effect of raised potassium is not thought to be due to lack of GABAergic terminals in this region because there is good pharmacological evidence for their presence and bacause both electrical stimulation and 100 microM veratridine increased the efflux of [3H]GABA from such slices. Also, 40 mequiv potassium was found to increase the efflux of both endogenous and [3H]GABA from crude synaptosome preparations of this region without influencing the efflux of [14C]sucrose or [3H]leucine. This release of [3H]GABA was calcium-dependent, and was similar whether produced by 20, 40 of 60 mequiv potassium and occurred whether eos or AOAA was used to inhibit GABA metabolism. Release from synaptosomes could also be induced with 100 microM veratridine. Raised potassium was additionally found to prevent the increased efflux from slices produced by electrical stimulation and to increase the efflux from slices prepared from the brains of rats 14 days old. It is suggested that the astrocytic swelling produced by raised potassium concentration restricts the diffusion of GABA away from depolarized terminals.

Aminooxyacetic Acid↗
PubMed1978

GABA-mimetic action of etomidate.

A comparison of antagonism by bicuculline or strychnine of the effects of GABA or etomidate on rat isolated superior cervical ganglia, frog isolated hemisected spinal cords and rat central neurones in vivo indicates that etomidate has GABA-mimetic actions.

Animals↗