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Biomedical subjects

M J Sheehan

Publications and source records attributed to M J Sheehan.

36 records · Page 2Linked to original sources
PubMed1991

Effect of typical and atypical neuroleptics on the behavioural consequences of activation by muscimol of mesolimbic and nigro-striatal dopaminergic pathways in the rat.

Direct injections of muscimol into the ventral tegmental area (VTA) or substantia nigra zona reticulata (SNR) have been used to selectively stimulate the mesolimbic and nigro-striatal dopamine pathways respectively. Such injections induced locomotor activity, rearing, sniffing and in some animals an intermittent grooming response. These responses were rapid in onset, dose-related and relatively short lasting (less than 40 min). Selective increases in dopamine turnover were seen in the nucleus accumbens and in the striatum following VTA and SNR injections of muscimol (100 ng) respectively. Haloperidol inhibited the behavioural consequences of VTA and SNR injections of muscimol with similar potency (ED50S 0.01-0.03 mg/kg IP), and fluphenazine did likewise (ED50S 0.05-0.16 mg/kg IP). However, thioridazine (ED50S VTA: 1.45-2.04 mg/kg IP, SNR 8.50-9.20 mg/kg IP) and in particular clozapine (ED50S VTA: 0.24-0.58 mg/kg IP, SNR: 6.10-9.70 mg/kg IP) were more potent at inhibiting the locomotor activity and sniffing responses due to VTA rather than SNR administered muscimol. Since dopamine D2 antagonists are believed to exert their anti-psychotic effects via an action on mesolimbic dopaminergic systems, and their ability to induce extrapyramidal side effects (EPS) is thought to be due to an action on nigro-striatal dopamine systems, these results suggest that the behavioural models described can be used to predict efficacy and side-effect liability of potential neuroleptic drugs.

Animals↗
PubMed1990

Presynaptic regulation of dopamine release in corpus striatum monitored in vitro in real time by fast cyclic voltammetry.

Dopamine release was evoked by single electrical pulses in slices of rat corpus striatum, and measured by fast cyclic voltammetry in real time. The magnitude of the release varied in the expected way to agents which modify dopamine storage, release and re-uptake. The presence of functional dopamine D2 autoreceptors was demonstrated by showing that the release was potently and completely inhibited by the selective agonists quinpirole and N,N-dipropyl-5,6-ADTN. The selective D1 agonist SKF 38393 was ineffective. The inhibition by quinpirole was competitively antagonised by haloperidol and metoclopramide with potencies which correspond closely to published values at postsynaptic striatal D2 receptors. Thus, the D2 autoreceptors on striatal nerve terminals appear to be indistinguishable from those on the postsynaptic neurons.

Animals↗
PubMed1990

Application of fast cyclic voltammetry to measurement of electrically evoked dopamine overflow from brain slices in vitro.

Fast cyclic voltammetry at a carbon fibre microelectrode was used to monitor the time course of dopamine overflow in slices of rat corpus striatum incubated in a brain slice chamber. Dopamine release occurred in response to electrical stimulation. Electrochemical, physiological and pharmacological evidence indicates that release of endogenous dopamine can be measured reliably for up to 9 h and that fast cyclic voltammetry can be used in brain slices for quantitative studies of dopamine release in the CNS.

Animals↗
PubMed1990

A series of novel, highly potent and selective agonists for the kappa-opioid receptor.

1. This paper describes the opioid receptor pharmacology and in vivo activity of several novel benzene-acetamidopiperidine and benzeneacetamidopiperazine analogues. 2. These compounds all showed potent, naloxone-reversible, full agonist activity in the field-stimulated rabbit vas deferens, indicating that they are kappa-opioid agonists; but showed very little activity in the rat or hamster vas deferens, indicating good selectivity with regard to mu- and delta-opioid receptors. 3. They were all potent antinociceptive agents, the most potent compound, GR 103545, having an ED50 value in the mouse abdominal constriction test of 0.25 micrograms kg-1 s.c. The compounds also produced sedation and diuresis, but had little effect on respiration rate or gastrointestinal motility. 4. It is concluded that the seven novel compounds described are all potent and selective agonists for the kappa-opioid receptor.

Abdomen↗
PubMed1988

Lack of evidence for epsilon-opioid receptors in the rat vas deferens.

Experiments were performed to test the hypothesis that the field-stimulated rat vas deferens preparation contains opioid receptors, other than of mu-type, which mediate part of the inhibitory effect of beta-endorphin. The Piebald Viral Glaxo strain of rats was used. The reported finding that delta-opioid receptors are present in Sprague-Dawley rat vas deferens, the effects of which are greatly enhanced in reduced calcium concentrations, could not be replicated in the rat strain used. Reducing the calcium concentration from 2.5 to 1.25 mM improved the response to opioid drugs: all full agonists were about 10 times more potent, the partial agonist normorphine became able to inhibit the twitch completely, and morphine (which behaves as a competitive antagonist in 2.5 mM Ca2+) appeared to behave as a partial agonist. The pA2 values for antagonism by naloxone in low calcium of the mu-selective peptide [D-Ala2,MePhe4,Gly(ol)5]enkephalin and other mu- or delta-selective agonists were consistent with an action at mu-receptors only. The value for beta-endorphin was slightly but significantly lower. A similar small discrepancy was found with two other competitive antagonists. The discrepancy remained in the presence of the peptidase inhibitors thiorphan, bestatin and bacitracin. Responses to both [D-Ala2,MePhe4,Gly(ol)5]enkephalin and beta-endorphin were attenuated by the irreversible antagonists beta-funaltrexamine and beta-chlornaltrexamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

In-vivo studies with the opioid antagonist, 16-methylcyprenorphine.

The effect of the opioid antagonist, 16-methylcyprenorphine (RX8008M), on the antinociceptive action of the mu-selective agonist, morphine, and the kappa-selective agonist, U50488H, has been investigated in the mouse abdominal constriction test. RX8008M produced a dose-dependent antagonism of the antinociceptive effect of morphine, but did not antagonize the response to U50488H. RX8008M should prove a useful probe for the in-vivo characterization of the receptor selectivity of opioid drugs.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

Norbinaltorphimine: antagonist profile at kappa opioid receptors.

The pharmacological profile of the opioid antagonist norbinaltorphimine has been characterised in vitro and in vivo. In vitro, norbinaltorphimine reversibly antagonised the effects of kappa agonists with pA2 values of 10.2-10.4. Norbinaltorphimine was much less potent as an antagonist at mu and delta receptors, pA2 values were 7.4-7.6 and 7.6-7.8, respectively. In all cases Schild slopes were unity. In vivo, norbinaltorphimine was an effective antagonist only at high dose levels and was not very selective between mu and kappa. The results indicate that in vitro norbinaltorphimine is a potent selective kappa antagonist; however, this antagonist profile is not maintained in vivo.

Animals↗
PubMed1987

Differential sensitivity of models of antinociception in the rat, mouse and guinea-pig to mu- and kappa-opioid receptor agonists.

1 A range of opioid receptor agonists were tested for activity in five antinociceptive models: the acetylcholine-induced abdominal constriction, tail-flick and hot plate tests in the mouse and the paw pressure test in the rat and guinea-pig. 2 Agonists acting preferentially at the kappa-opioid receptor were significantly more potent in the guinea-pig than in the rat paw pressure test, whereas mu-receptor preferring agonists were equipotent in the two tests. The mouse abdominal constriction test was of equal sensitivity to the guinea-pig pressure test for both types of agonist. 3 The mouse tail-flick and hot plate tests were progressively less sensitive than the other three tests, particularly to kappa-receptor preferring agonists. 4 The efficacy of an agonist can also markedly affect its activity in antinociceptive tests. Thus, partial kappa-agonists were weak or inactive in the rat paw pressure test, and partial agonists at both mu- and kappa-opioid receptors were relatively weak in the tests in which heat was the noxious stimulus, particularly the mouse hot plate test. 5 The mouse abdominal constriction test is suggested as the most appropriate antinociceptive model for testing a broad range of opioid agonists, whilst the relative potency of a drug in the rat and guinea-pig paw pressure tests may indicate the degree to which it is selective for kappa-opioid receptors in vivo.

Animals↗
PubMed1986

Pharmacology of delta-opioid receptors in the hamster vas deferens.

Electrically evoked contractions of the hamster isolated vas deferens are inhibited only by opioid drugs which have agonist activity at delta-opioid receptors. Opioids which are mu-, kappa- or sigma-selective were either inactive or were antagonists. The compound beta-funaltrexamine, which irreversibly blocks mu- and delta-opioid receptors, caused a flattening of the dose-response curve and a reduced maximum inhibition available to delta-opioid agonists. Analysis of the curves by the double-reciprocal null method enabled the affinity of these agonists at delta-opioid receptors to be calculated.

Animals↗
PubMed1986

Irreversible selective blockade of kappa-opioid receptors in the guinea-pig ileum.

The irreversible non-selective opioid antagonist beta-chlornaltrexamine (beta-CNA) was used in combination with selective mu receptor protection by [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO) to produce an effective kappa receptor antagonism in the guinea-pig field-stimulated ileum preparation. Using a standard pre-treatment of 10(-7) M beta-CNA incubated for 15 min, DAG (10(-6)-10(-4) M) protected the response to the mu agonist normorphine while reducing the antagonism of the kappa agonist U50488 to a lesser extent. The concentration of DAGO which produced the most selective protection was 10(-5) M. This method was used to find the kappa selectivity of a series of opioid agonists. Of the compounds tested, butorphanol, dynorphin-(1-17), U50488, tifluadom, bremazocine and Mr 2034 were the most kappa-selective. The correlation with kappa agonist selectivity in vitro and effects in vitro on urine output in the rat is demonstrated.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

Cross-protection of mu and delta opioid receptors in the mouse vas deferens.

Opioid receptors in the C57/BL mouse vas deferens can be irreversibly blocked by pre-treatment with beta-chlornaltrexamine. Pre-incubation with the highly selective delta-receptor antagonist ICI 174864 concentration-dependently protected delta-receptors from inactivation, but the same concentrations similarly protected mu receptors. Pre-incubation with selective mu-receptor agonist, [D-Ala2, MePhe4, Gly(ol)5]enkephalin, also protected both mu and delta receptors to the same degree. Neither ligand protected k-opioid receptors. The results suggest that there may be a structural interaction between mu and delta receptors in the mouse vas deferens.

Animals↗
PubMed1985

Determination of the receptor selectivity of opioid agonists in the guinea-pig ileum and mouse vas deferens by use of beta-funaltrexamine.

The irreversible inhibitor of mu-opioid receptor-mediated effects, beta-funaltrexamine (beta-FNA), was used to investigate the selectivity of various opioid agonists at mu-opioid receptors in the electrically stimulated guinea-pig ileum and mouse vas deferens preparations in vitro. In the guinea-pig ileum, pretreatment with beta-FNA (3 X 10(-8) - 3 X 10(-6)M) produced a concentration-dependent antagonism of the inhibitory effect produced by the mu-opioid receptor agonist [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO). High concentrations of beta-FNA (3 X 10(-6) - 1 X 10(-5)M) also antagonized the inhibitory effects of the kappa-opioid agonist U50488. Pretreatment of guinea-pig ileum with beta-FNA at 1 X 10(-6)M resulted in blockade of the effect of some opioid agonists. The compounds which showed the largest rightward shifts in their concentration-response curves, and hence the greatest mu/kappa opioid receptor selectivity, were nalbuphine, [D-Ser2, Leu5]enkephalinyl-Thr6(DSLET), morphine, DAGO and normorphine. Responses to tifluadom, Mr 2034, ethylketocyclazocine, butorphanol, nalorphine, proxorphan and U50488 were not inhibited by beta-FNA. In the mouse vas deferens, pre-treatment with beta-FNA (1 X 10(-6)M) produced a similar shift in the dose-response curves for normorphine as in the guinea-pig ileum. The concentration-response curves for the delta-receptor agonists [D-Ala2, D-Leu5] enkephalin (DADLE) and DSLET were, however, also shifted, indicating that beta-FNA will also block delta-opioid receptors. Since beta-FNA does not block kappa-opioid receptor-mediated effects, it can be used in the guinea-pig ileum preparation as a selective mu-receptor inhibitor. However, its lack of selectivity between mu- and delta-opioid receptors should be taken into account in many other isolated tissues and experiments in vivo.

Animals↗
PubMed1985

A personal construct study of depression.

Twelve out-patients with a 'definite' or 'probable' diagnosis of major depressive disorder were treated by the author using personal construct psychotherapy (Kelly, 1955). Changes in their construct systems were monitored at intervals during the course of therapy using traditional role construct repertory grids and 'multiple perception of the self' grids. The level of depression was measured on each occasion of testing using psychiatric and self-rating depression scales. The most important findings were that high levels of depression were associated with low levels of 'conflict' and a cluster of variables to do with the construing of self, namely negative self-construing, low self-esteem and perceived self-isolation. As the depression lifted during the course of psychotherapy, there was a significant increase in the amount of 'conflict' and in the level of self-esteem, and a significant decrease in the level of self-isolation. The fact that over time the 'multiple perception of self' grids changed significantly more than the grids concerned with the construing of the self and others is interpreted as further evidence of the crucial role that the self-concept plays in depression.

Conflict, Psychological↗
PubMed1984

The cholecystokinin analogue, caerulein, does not modulate dopamine release or dopamine-induced locomotor activity in the nucleus accumbens of rat.

We have investigated the effect of the cholecystokinin (CCK) analogue, caerulein, in the nucleus accumbens on dopamine (DA) release and locomotor activity. Caerulein (10(-9)-10(-4) M) did not affect the resting or K+-evoked release of [14C]DA, although concentrations within this range have been shown to modulate transmitter release in cerebral cortex. When injected bilaterally into the nucleus accumbens, caerulein (30 ng-1 microgram) did not affect spontaneous locomotor activity as compared to vehicle-injected controls. Similarly, bilateral injections of caerulein (1 microgram) into the nucleus accumbens did not modulate locomotor hyperactivity induced by bilateral injections of DA (20 microgram) into the nucleus accumbens. It is concluded that CCK in the nucleus accumbens has no direct effect on dopamine release or dopamine-stimulated locomotor activity.

Animals↗
PubMed1983

Facilitation of GABA release by cholecystokinin and caerulein in rat cerebral cortex.

Cholecystokinin octapeptide and its analogue, caerulein, facilitated the K+-evoked release of 14C-GABA from tissue slices of rat parietal cortex. The effect of caerulein was maximal at 1 nM where an enhancement of 36% was produced. Cholecystokinin octapeptide gave rise to a similar maximal enhancement (29%), but was two orders of magnitude less potent. The enhancement of 14C-GABA release by caerulein was reversed by proglumide, a putative competitive antagonist at the cholecystokinin receptor. The possibility that the cholecystokinin-induced facilitation of GABA release in the cortex is involved in the anticonvulsant properties of cholecystokinin-like peptides is discussed.

Animals↗
PubMed1981

Constructs and 'conflict' in depression.

The relationship between the nature of self-constructs and the level of 'conflict' in depression was discussed. It was hypothesized that depressed patients would have lower self-esteem and a less differentiated self-construct system characterized by a higher level of intensity and a lower percentage of 'conflict' than non-depressed individuals. After drug therapy, it was expected that these differences would diminish - although not entirely - on the grounds that the differences are a more permanent feature of the self-construct system of the depressed-prone individual. A sample of 16 depressed patients (13 in-patients and three out-patients) were given a 'Multiple Perception of the Self' grid at the start of drug therapy. After six/eight weeks of treatment, a further grid was administered and new constructs elicited. A retest grid was administered after a short interval of 12-24 hours. The same procedure was carried out with a group of 16 non-depressed individuals - matched as far as possible for age, sex, intelligence and social class. The results offered strong support for the hypotheses.

Adaptation, Psychological↗
PubMed1979

Relatives and friends group in a psychiatric ward.

To enable relatives and friends of psychiatric patients in a 30-bed acute admission ward to meet the staff team together a relatives and friends group was initiated. The group was intended to provide a forum for questions about the patients' illness and treatment; allow feelings, such as anger and anxiety, about the patient's illness to be expressed; and enable relatives and friends to share their experiences and offer advice and support to each other. A study was designed to assess the feasibility of the group scheme. Relatives and friends were invited to the day room of the admission ward each Wednesday evening for one hour. The visitors chose their own topics for discussion and the staff team tried to answer questions and to facilitate a free exchange of views. An account of each meeting was documented, including details of attenders, the nature of the topics raised, and a simple measurement of some of the emotions expressed by the visitors. Overall, the effect of the meetings seemed positive and productive, for they allowed relatives and friends to ask questions about many topics, to express pent-up emotions, and to gain a better understanding and tolerance of the patient's illness. The relatives and friends group has become an integral part of treatment on the wards. Now that the feasibility of such a group is established, further studies are required to evaluate its efficacy.

Communication↗