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Biomedical subjects

A Neil

Publications and source records attributed to A Neil.

At least 37 records · Page 2Linked to original sources
PubMed1990

Repeated low doses of morphine do not induce tolerance but increase the opioid antinociceptive effect in rats with a peripheral neuropathy.

In rats with a mononeuropathy, repeated low doses of morphine slightly enhanced its own effect in a paw pressure test of the lesioned limb. While the very effectiveness of morphine in neuropathic rats suggests that at least some nociceptive components of neuropathic pain might be sensitive to opioid receptor mechanisms, the absence of a rapid tolerance in this model indicates that tachyphylactic phenomena do not contribute to the reputed clinical ineffectiveness of opioids in neuropathic pain.

Analgesics↗
PubMed1989

Brain and plasma kinetics of the opioid 11C-hydromorphone in two macaque species.

The regional brain kinetics of the opioid receptor agonist, hydromorphone, labelled with 11C, were studied with positron emission tomography in two Macaque species. Rhesus and Cynomolgus monkeys. The plasma kinetics of 11C-hydromorphone was simultaneously determined. Rapid plasma elimination was obvious in both monkey species. Brain radioactivity was generally low in both, but 1.4 times higher in the Rhesus than in the Cynomolgus monkey brain. This observation might explain the more rapid development of tolerance in the Rhesus monkey.

Animals↗
PubMed1989

Differences in efficacies between morphine and methadone demonstrated in the guinea pig ileum: a possible explanation for previous observations on incomplete opioid cross-tolerance.

We have compared the effectiveness of morphine and methadone as agonists in untreated guinea-pig longitudinal muscle preparations and after their treatment with the specific opioid receptor alkylating agent beta-chloronaltrexamine. In untreated ilea, the naloxone pA2 was 8.5 to both morphine and methadone, and their dose-response curves were parallel. After alkylation, the dose-response curve for morphine was shifted to the right with a decreased maximal effect. It was found that about 70% of the receptors were inactivated by the treatment, corresponding to a morphine receptor occupancy at IC50 of about 24%. The maximal effect of methadone was not decreased by the same beta-chloronaltrexamine treatment, indicating a much higher efficacy or receptor reserve for the drug. The possibility that differences in efficacies could account for previously reported heterogeneities in actions of opioids, such as assymmetries in cross-tolerance towards morphine and methadone in experimental animal and man, is discussed.

Alkylation↗
PubMed1989

Estimation of ligand binding parameters by simultaneous fitting of association and dissociation data: a Monte Carlo simulation study.

A new procedure for analysis of ligand binding kinetics was evaluated by Monte Carlo simulations. In this, all association and dissociation data were fitted simultaneously to a set of nonlinear equations. This should have several advantages over more conventional methods; data are better used in a single fitting procedure in which the degrees of freedom are maximized and the error term is spread over more observations; all relevant parameters (Bmax, k1, and k-1) are obtained directly; values obtained from measurements are not treated as errorless; and it yields a single residual term that can be used for statistical comparison among binding models and/or experiments. We have compared this approach with the common practice of analyzing the association and dissociation phases separately, either by nonlinear regression or by linear regression after suitable transformations. With respect to both the precision and accuracy of parameter estimates, the simultaneous procedure was superior to the other two methods. The properties of the simultaneous procedure were further investigated, concerning both parameter estimation and the probability of reliably detecting a second binding site. For the latter, the relative density of receptor subtypes and the dissociation rate constants were found to be of major importance, whereas association rate constants and ligand concentration were of minor importance in this respect. The probability of resolving two sites by kinetic or equilibrium data under similar conditions with the aid of a single labeled ligand was examined. When the selectivity of the ligand was low, the resolution was found to be more probable when based on kinetic, rather than equilibrium, data. This was true at higher selectivities as well, provided kinetic data were obtained at two different ligand concentrations.

Binding Sites↗
PubMed1988

Estimation of binding parameters by kinetic data analysis: differentiation between one and two binding sites.

A method that enables the discrimination between binding models and the estimation of binding parameters, based solely on kinetic data, is described. Experimental data from association and dissociation experiments were fitted simultaneously to models with mono- or biphasic kinetics with the aid of a non-linear maximum likelihood computer program. Discrimination between two models can be performed statistically. The protocol was used to study the binding of the antitussive [3H]noscapine to guinea pig brain homogenate. Two binding processes could be discriminated by their kinetics, despite the fact that [3H]noscapine apparently binds to one homogeneous population of binding sites in equilibrium binding experiments. This method might find general application when two populations of binding sites are suspected from kinetic data, but when selective ligands are lacking. Since parameter estimates are obtained independent of equilibrium binding data, our approach could also serve as an independent control of such experiments, with respect to both Kd and Bmax.

Animals↗
PubMed1988

Characterization of high-affinity binding sites for the antitussive [3H]noscapine in guinea pig brain tissue.

We have characterized the binding of the antitussive alkaloid [3H]L-alpha-noscapine ([3H]noscapine) to guinea pig brain. Binding of [3H]noscapine to brain homogenate is stereospecific, saturable, reversible, heat-sensitive and manifests high affinity (Kd = 7 nM). Binding sites are present in all major brain areas, with the thalamus exhibiting the highest density. Subcellular localization studies showed an enrichment of binding sites in the synaptosomal fraction. Some structurally related compounds with antitussive properties (narceine, hydrastine, narcotoline and papaverine) were potent competitors, while other antitussives did not inhibit [3H]noscapine binding. Various ligands that bind to known neurotransmitter receptors failed to displace [3H]noscapine binding or had IC50 values in the micromolar range. It was concluded that the noscapine binding sites are different from those previously described for antitussives such as codeine and other opiates, or dextromethorphan.

Animals↗
PubMed1988

Behavioural and electrophysiological studies on the paradoxical antinociceptive effects of an extremely low dose of naloxone in an animal model of acute and localized inflammation.

We have previously described the paradoxical antinociceptive effect of low doses of an opiate antagonist, naloxone, in rats suffering from chronic arthritis induced by Freund's adjuvant. In the present work, the appearance of this naloxone sensitivity was studied, using a model of inflammatory hyperalgesia with a more rapid onset, namely carrageenin-induced rat paw edema. In these animals, an extremely low dose of naloxone (3 micrograms/kg i.v.), induced a clear antinociceptive effect (as gauged by the vocalisation threshold to paw pressure), which was observed for both the edematous and the contralateral hind-paw. Small and transient 1 h after carrageenin injection, this effect increased progressively 4 h and 24 h later, reaching a level comparable to that observed with morphine 1 mg/kg i.v. in normal rats, at 24 h. Electrophysiological studies performed in parallel, confirmed the behavioural data so that 24 h after the injection of carrageenin, naloxone (3 micrograms/kg i.v.) reduced the VB thalamic neuronal responses elicited by stimulation of the inflamed paw by 50%. Hypothesis concerning the mechanisms of the paradoxical action of naloxone in models of inflammatory hyperalgesia are discussed.

Action Potentials↗
PubMed1987

Initial nociceptive sensitization in carrageenin-induced rat paw inflammation is dependent on amine autacoid mechanisms: electrophysiological and behavioural evidence obtained with a quaternary antihistamine, thiazinamium.

We have studied the ability of a quaternary antihistamine, thiazinamium, to inhibit the nociceptive sensitization that occurs early, during the first hour, following intraplantar injection of the polysaccharide carrageenin in the rat. Parallel studies were performed with an electrophysiological model (changes in responsiveness of ventro-basal thalamic cells driven by noxious stimulation of the paws), and a behavioural test (changes in threshold stimulus necessary to elicit vocalization by gradually increased pressure to the paws). When thiazinamium was given intravenously 10 min before carrageenin, no sensitization due to inflammation was found in either test. By contrast, when thiazinamium was administered 20 min after carrageenin, there was a clear sensitization in both tests that did not differ from that found in animals not treated with the antagonist. Paw oedema was also slightly decreased by pretreatment with thiazinamium. These results suggests that early inflammatory sensitization of peripheral nociceptors is mainly dependent on an initial release of histamine (and/or serotonin, since thiazinamium could also have some antiserotoninergic activity).

Animals↗
PubMed1987

Neuronal response thresholds to and encoding of thermal stimuli during carrageenin-hyperalgesic-inflammation in the ventro-basal thalamus of the rat.

This study analyzed neuronal encoding and response thresholds to thermal stimuli at the ventro-basal (V.B.) thalamus level during a hyperalgesic inflammation induced by intra-plantar injection of carrageenin in the rat. The threshold and the encoding capacity of the cells were studied during two phases of the inflammatory process, namely the "acute" phase (the first two hours following the injection), and "sub-acute" phase 24 h after). In this second phase the hyperalgesia was verified using a behavioral nociceptive test, just prior to the recording session. Only VB neurones with a receptive field that included the injected paw were considered. In the acute phase, neurones exclusively driven by noxious stimuli were studied before and during the first two hours following the induction of the inflammatory oedema. In the sub-acute phase two groups of neurones which, on the basis of our previous studies, were presumably involved in the transmission of messages giving rise to the hyperalgesia could be separated: a group of neurones which were driven by intense mechanical stimuli and another group driven by moderate mechanical stimulation applied to the inflamed joints and/or the surrounding cutaneous areas. In the "acute" phase there was a dramatic lowering (by about 4 degrees C) of the response threshold of the neurones when the thermal stimulus was applied to the injected paw, although their threshold to the mechanical stimulus was still high. A linear encoding of the bath temperature used as a stimulus was observed for both the injected and the non-injected paws. For a few neurones, a leftward shift of the stimulus-response curve was found for the inflamed limb. In the "sub-acute" phase, neurones with high thresholds to the mechanical indentations still exhibited a low response threshold to the thermal stimulation, not only from the injected but also from the non-injected paw. The other group of neurones responded with relatively low thresholds to the both stimulus modalities. By contrast to the acute phase, the two groups of neurones exhibited only a weak ability to encode the stimulus intensity especially when the stimulus was applied to the inflamed paw. Both peripheral and central mechanisms are likely to be involved in the modifications of response threshold and encoding capacity at the VB thalamus level seen in these conditions of hyperalgesic inflammation. The differential time course of the responses to a liminal or to a supra-liminal temperature during the inflammation, are discussed in reference to some of the mismatches occurring in clinical situations of hyperalgesia.

Action Potentials↗
PubMed1987

Thresholds and encoding of neuronal responses to mechanical stimuli in the ventro-basal thalamus during carrageenin-induced hyperalgesic inflammation in the rat.

Neuronal response thresholds and the encoding of mechanical stimulus intensity in the ventro-basal (VB) thalamus was analyzed in anaesthetized rats before and during the first two hours following induction of hyperalgesic inflammation. This inflammation was induced by the intra-plantar injection of carrageenin in the hindpaw contralateral to the recorded neurones. Only neurones exclusively driven by noxious stimuli and with a receptive field on or including the injected paw were considered. In this early phase of the inflammatory process, there was no significant modification of the response threshold to the mechanical stimulus (indentation of about 300 micron). This suggests the involvement of additional neuronal population(s) to account for the decrease in the vocalisation threshold to pressure observed in the freely moving animal at this time of the inflammation. A liner encoding of the indentation depth was observed before and after the carrageenin injection although the slope of the stimulus response-curve was steeper after the injection. The data emphasize that the carrageenin-sensitization acts differentially on the liminal and supra-liminal responses of the same neurone to a skin indentation, since in the first hour following the initiation of the inflammation the sensitization is essentially observed for responses obtained with stimulus intensity largely above the threshold value. With regard to previous observations using thermal stimulation, the results also illustrate that the carrageenin induced sensitization of responses differs depending on the stimulus intensity and modality used.

Animals↗
PubMed1987

Early oral contraceptive use and breast cancer: results of another case-control study.

We report the results of a case-control study of oral contraceptive use and breast cancer conducted in London, Oxford and Edinburgh between 1980 and 1984. One thousand one hundred and twenty-five women aged 16-64 years with newly diagnosed breast cancer and a like number of matched controls were interviewed and asked about their past due use of oral contraceptives (OCs). Among women aged 45 years or more at diagnosis there was no evidence of an association between OC use and breast cancer. Among the 351 pairs of women aged under 45 years at diagnosis there was a significantly elevated risk associated with increasing duration of use before first full term pregnancy (relative risk for 4+ years use versus never use = 2.6, 95% confidence limits, 1.3-5.4). Since this result is at variance with the findings in some other studies we have investigated the nature of this association with particular emphasis on possible bias, pill type and a latent effect.

Adolescent↗
PubMed1987

Breast self examination and breast cancer stage at diagnosis.

The relationship between breast self examination (BSE) and breast cancer stage at diagnosis was examined in 616 women aged 15-59 years. Differences in tumour characteristics between those not practising BSE and those practising but not taught were small and inconstant. However, women who had both practised and had been taught BSE had more favourable tumours than the non-practising group. The difference was most marked in terms of tumour size and the involvement of axillary nodes. The proportions of women in the non-BSE and taught-BSE groups with each characteristic were respectively: size less than or equal to 2 cm 33% and 45%, T1 clinical stage 27% and 42%, and N0 pathological stage 37% and 50%. This advantage to taught-BSE women persisted after adjustment for the identified confounding factors of age, social class and oral contraceptive use. The likely impact on breast cancer mortality is difficult to assess, although the potential benefit of the lead time gained must not be ignored when assessing the costs and benefits of BSE.

Adolescent↗
PubMed1986

Opioid receptor types and antinociceptive activity in chronic inflammation: both kappa- and mu-opiate agonistic effects are enhanced in arthritic rats.

The antinociceptive effects obtained in arthritic rats with morphine, the opioid mu-agonist DAGO [D-Ala2,MePhe4,Gly-ol5]enkephalin, the delta-selective agonist DTLET [D-Thr2, Leu5]enkephalyl-Thr, and the kappa-agonist U-50,488H were compared to their corresponding effects in normal animals and morphine-pretreated arthritic rats, respectively, using a paw pressure test. The effects of the mu- and kappa-agonists were increased in arthritic rats. While morphine-treated rats were cross-tolerant to the mu- and kappa-agonists, no tolerance to the delta-selective agonist was found. The possibility that the potent action of morphine in this model for chronic inflammatory pain is mediated partly through kappa-mechanisms is discussed.

Analgesics↗
PubMed1986

Repeated low doses of morphine induce a rapid tolerance in arthritic rats but a potentiation of opiate analgesia in normal animals.

The effect of repeated low doses of morphine (0.3-3 mg/kg s.c., twice daily for 4 days) on subsequent sensitivity to the antinociceptive effect of morphine was tested in arthritic and normal rats. Chronic morphine induces tolerance in arthritic rats. This tolerance develops rapidly since it is clearly present after one day of treatment. By contrast, in normal animals similarly treated, a potentiation of morphine analgesia was observed.

Animals↗
PubMed1986

Leukotriene C4 binding sites in the rat central nervous system.

Binding sites for [3H]LTC4 were observed in crude membrane preparations of rat central nervous system tissue. Equilibrium binding studies indicated one high affinity [3H]LTC4 binding site with a KD of 31.4 +/- 3.4 nM for whole brain preparations. The binding was highly specific for [3H]LTC4 and could be inhibited by the SRS-A antagonist FPL 55172. Specific binding was increased with both mono- and di-valent ions. Regional distribution studies revealed a three-fold difference in binding capacity within different regions of the brain with the highest binding capacity in the brainstem (94.1 +/- 6.9 fmol/mg of protein) and the lowest in the hypothalamus (29.6 +/- 12.8 fmol/mg of protein). In addition, weak low capacity binding was observed for [3H]LTB4 and [3H]LTE4, while no saturable binding was observed for [3H]LTD4. The order of selectivity in inhibiting [3H]LTC4 binding was LTC4 much greater than LTD4 = LTE4 greater than LTB4.

Animals↗
PubMed1986

Opiate receptors, neuropeptides in CNS and CSF of two Macaca species with different responsiveness to opiates.

Of two related Macaca species, the rhesus (M. mulatta), acquires opiate tolerance and dependence more readily than the cynomolgus (M. fascicularis). In the cynomolgus, mu-opiate receptors were significantly fewer in the caudate nucleus and globus pallidus; delta-sites were fewer in the thalamus. kappa-Sites showed no species difference. The levels of [Met5]enkephalin, substance P and dynorphin B in various brain areas were comparable. On the other hand, receptor-assayed endorphin activity was higher in CSF of cynomolgus than rhesus monkeys.

Animals↗