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Dive into the research topics where R.M. Hagan is active.

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Featured researches published by R.M. Hagan.


British Journal of Pharmacology | 1991

Investigation into species variants in tachykinin NK1 receptors by use of the non-peptide antagonist, CP-96,345

I.J.M. Beresford; Philip J. Birch; R.M. Hagan; S.J. Ireland

The affinity of the non‐peptide antagonist CP‐96,345 for tachykinin NK1 receptors has been estimated in a range of species by use of both radioligand binding and functional assays. CP‐96,345 was 30–120 fold less active at NK1 receptors in rat and mouse than in the other species examined, including man. These results demonstrate the existence of species variations in NK1 receptors.


Neuropeptides | 1991

Receptor-selective, peptidase-resistant agonists at neurokinin NK-1 and NK-2 receptors: New tools for investigating neurokinin function

R.M. Hagan; S.J. Ireland; Christopher C. Jordan; I.J.M. Beresford; M.J. Deal; P. Ward

The pharmacological profiles of two novel neurokinin agonists have been investigated. delta Ava[L-Pro9,N-MeLeu10]SP(7-11) (GR73632) and [Lys3,Gly8-R-gamma-lactam-Leu9] NKA(3-10) (GR64349) are potent and selective agonists at NK-1 and NK-2 receptors respectively. In the guinea-pig isolated trachea preparation, contractions induced by these agonists were largely unaffected by inclusion of peptidase inhibitors in the bathing medium, indicating that these agonists are resistant to metabolism by peptidases. In the anaesthetised guinea-pig, both agonists were more potent bronchoconstrictor agents than either NKA or the SP analogue, SP methylester. In the anaesthetised rat, the NK-1 agonist, GR73632 was more potent than SP, NKA or NKB at causing the histamine-independent extravasation of plasma proteins into the skin after intradermal administration. The NK-2 agonist, GR64349 and the NK-3 agonist, senktide were without significant effect in this model. These agonists are useful tools for characterizing neurokinin receptor-mediated actions both in vitro and in vivo.


British Journal of Pharmacology | 1990

Effect of 5-HT3 receptor antagonists on responses to selective activation of mesolimbic dopaminergic pathways in the rat

R.M. Hagan; B.J. Jones; Christopher C. Jordan

1 The effects of 5‐hydroxytryptamine3 (5‐HT3) receptor antagonists on the behavioural hyperactivity response which results from injection of the neurokinin receptor agonist [pGlu5, MePhe8, Sar9]‐substance P (5–11) (DiMe‐C7) into the ventral tegmental area (VTA) of the rat midbrain have been determined. 2 Subcutaneous administration of ondansetron (GR38032) (0.001–0.3 mg kg−1), GR65630 (0.01 mg kg−1), ICS 205–930 (0.1 mg kg−1) and MDL 72222 (0.1 mg kg−1), inhibited the DiMe‐C7‐induced hyperactivity response. 3 The effects of ondansetron on DiMe‐C7‐induced changes in dopamine and 5‐HT metabolism in discrete areas of rat forebrain were studied in order to investigate further the possible mechanism of action of 5‐HT3 antagonists in modifying mesolimbic dopaminergic systems. 4 Intra‐VTA administration of DiMe‐C7 increased levels of dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens, olfactory tubercules and right amygdala, indicating increased mesolimbic dopamine metabolism. DOPAC levels were not significantly increased in the frontal cortex, left amygdala or striatum. Dopamine levels were not altered in any of these brain areas. DiMe‐C7 also increased 5‐hydroxyindoleacetic acid (5‐HIAA) levels in the amygdala but this was only statistically significant in the right amygdala. 5‐HT levels were not changed significantly by DiMe‐C7 treatment. 5 In control rats, pretreatment with ondansetron (0.1 mg kg−1) had no effect on the levels of dopamine, 5‐HT or their metabolites, but in rats given DiMe‐C7, ondansetron significantly inhibited the increase in DOPAC levels in the nucleus accumbens. 6 These results are in agreement with the proposed facilitatory role of 5‐HT3 receptor activation on mesolimbic dopaminergic transmission, and suggest that 5‐HT3 antagonists may have important therapeutic indications for the treatment of CNS disorders in which mesolimbic dopamine systems are perturbed.


British Journal of Pharmacology | 1991

Receptors mediating tachykinin‐induced contractile responses in guinea‐pig trachea

S.J. Ireland; F. Bailey; A. Cook; R.M. Hagan; Christopher C. Jordan; M.L. Stephens‐Smith

1 The classification of tachykinin receptors in the guinea‐pig trachea has been investigated. This was of interest because, from previous studies, it was not clear whether the guinea‐pig trachea contains either a mixture of NK1 and NK2 receptors or, alternatively, a single type of novel tachykinin receptor. 2 In the present study, the guinea‐pig trachea was contracted by tachykinin agonists selective for NK1 receptors (substance P methylester (SPOMe) and GR73632) or NK2 receptors (GR64349) but not NK3 receptors (senktide). 3 Against SPOMe and GR73632, the NK1 antagonist, GR71251, behaved as a reversible competitive antagonist having apparent affinity (pKB 7.05 vs SPOMe) consistent with action at NK1 receptors. GR71251 (3 μm) did not antagonize responses to GR64349. 4 The NK2 antagonists L‐659,877 and Ac‐Leu‐Asp‐Gln‐Trp‐Phe‐Gly‐NH2 (R396) antagonized GR64349 although only R396 appeared to behave competitively (pKB 5.73). Neither L‐659,877 (30 μm) nor R396 (30 μm) blocked responses to SPOMe. 5 For L‐659,877 and R396, comparison was made between activity in guinea‐pig trachea and in preparations known to contain tachykinin receptors predominantly of the NK2 type. In the rabbit trachea, both L‐659,877 and R396 had effects similar to those in guinea‐pig trachea. In contrast, in the rat colon muscularis mucosae, both L‐659,877 and R396 appeared to behave competitively with pKB values against GR64349 of 7.83 and 6.90 respectively. 6 It is concluded that in guinea‐pig trachea, contractile responses can be induced by activation of both NK1 and NK2 receptors. The present data are discussed with reference to the proposed existence of subtypes of the NK2 receptor.


European Journal of Pharmacology | 1992

Neurokinin agonists differentially affect A9 and A10 dopamine cells in the rat

Paul G. Overton; Peter J. Elliott; R.M. Hagan; David Clark

The effect of selective neurokinin (NK) receptor agonists on the activity of A9 and A10 dopamine cells was assessed using extracellular recording. A higher proportion of A10 cells which were administered the NK1 receptor agonist GR73632 or the NK3 receptor agonist senktide showed an effect, whereas the NK2 receptor agonist GR64349 did not discriminate as clearly between the two cell groups. The most frequently encountered response in all cases was an increase in firing rate.


Pharmacology, Biochemistry and Behavior | 1997

Development of tolerance in mice to the sedative effects of the neuroactive steroid minaxolone following chronic exposure

Fiona H. Marshall; Sharon C. Stratton; Joanne Mullings; Elaine Ford; Stella P Worton; Nigel R. Oakley; R.M. Hagan

Minaxolone is a potent ligand for the neurosteroid binding site of the GABAA, receptor. In radioligand binding studies to rat brain membranes, minaxolone caused a 69% increase in [3H]muscimol binding and a 25% increase in [3H]flunitrazepam binding and inhibited the binding of [3H]TBOB with an IC50 of 1 microM. In mice, minaxolone (100 mg/kg, orally) had marked sedative effects as indicated by a reduction in locomotor activity. Chronic dosing with minaxolone (100 mg/kg, orally, once daily for 7 days) resulted in a loss of sedative response to an acute dose of the drug, indicating development of tolerance. Chronic dosing with temazepam (10 mg/kg, orally, once daily for 7 days) resulted in the development of tolerance to an acute dose of temazepam; however, the two drugs did not appear to be cross-tolerant, indicating that they may have a different mechanism of action at the level of the GABAA receptor.


European Journal of Pharmacology | 1993

Anxiolytic activity of tachykinin NK2 receptor antagonists in the mouse light-dark box

Sharon C. Stratton; Isabel J. M. Beresford; F.J. Harvey; M.P. Turpin; R.M. Hagan

The tachykinin NK2 receptor antagonists, GR100679 (0.02-200 micrograms/kg s.c.) and (+/-)-SR489698 (0.05-5.0 micrograms/kg s.c.), dose-dependently increased the time which mice spent in the light side of the light-dark box. There was no evidence of sedation or other over behaviours. The amplitudes of these effects were similar to that evoked by diazepam (1.75 mg/kg s.c.). These results indicate a disinhibitory action of NK2 antagonists on suppressed behaviours in a novel aversive environment. This suggests an involvement of NK2 receptors in anxiety-related behaviours.


Trends in Pharmacological Sciences | 1995

Melatonin comes of age

R.M. Hagan; Nigel R. Oakley

Much has been said lately in the lay press about melatonin (Fig. l), the hormone secreted at night from the pineal gland. Science correspondents and even business page reports have highlighted studies indicating the potential benefits of taking melatonin to treat symptoms of jet lag and to promote sleep. Subsequently there has been a large demand for mela- tonin food supplement formulations freely available for sale in health food stores in the USA. This has fuelled the debate about the wisdom of such products remaining unregulated by the Food and Drug Administration, with strong proponents on both sides. Yet, away from this very pub lit debate, a growing body of basic and clinical researchers has con- tinued to examine the actions of this hormone, concentrating in particular on the nature of the cellular targets of melatonin action, its action as an internal zeitgeber (time-giver) for the circadian clock (Fig. 2), and the role that the hormone has to play in the aging process. Recently, significant progress has been made: first, in understanding the receptors at which melatonin acts (for review, seeRef. 1) and second, on the hypothesis that melatonin, or compounds that mimic its action on the human circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus, may be used to treat sleep disorders in the elderly. This could satisfy a largely unmet therapeutic need in what is increasingly recognized as a distressing disorder of the aging population.


Behavioural Brain Research | 1992

Modulation of the rat mesolimbic dopamine pathway by neurokinins

Peter J. Elliott; Glenn S. Mason; Elizabeth A. Graham; Michael P. Turpin; R.M. Hagan

The locomotor activity (LMA) response induced after infusion of selective neurokinin (NK) agonists into the cell body (A10) and a terminal region of the mesolimbic pathway of the rat was investigated. Infusion of the NK1 receptor-selective agonist, GR73632, into the ventral tegmental area (VTA: A10) or the nucleus accumbens (NAS) significantly and dose-dependently increased basal LMA. Agonists selective for the NK2 and NK3 receptors, GR64349 and senktide respectively, had no effect on LMA after intra-NAS infusion. The LMA induced by GR73632 is mediated via dopamine (DA) since the response was abolished by haloperidol. From these studies it would appear that the elevated LMA reported previously after VTA or NAS administration of substance P probably occurs via NK1 receptors. Such data supports the notion that endogenous NKs are likely to be important in modulating the mesolimbic DA pathway and, as a consequence, compounds which antagonise their effects could be useful for the treatment of disorders associated with this system. However, simultaneous infusion of the NK1 agonists, +/- CP-96,345 and its analogue CPQ, into the VTA did not attenuate the LMA induced after intra-VTA infusion of GR73632. Co-infusion of the NK1 antagonist CPQ, but not +/- CP-96,345, attenuated the LMA response induced by GR73632 in the NAS. The apparent poor susceptibility of these responses to blockade by the recently developed non-peptide NK1 antagonists was unexpected but may reflect their poor affinity for the rat variant of the NK1 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)


Neuroscience | 1992

Ontogeny and characterization of [125I]Bolton Hunter-Eledoisin binding sites in rat spinal cord by quantitative autoradiography

I.J.M. Beresford; S.J. Ireland; J. Stables; R.M. Hagan

The distribution and characteristics of [125I]Bolton Hunter-eledoisin binding sites in rat lumbar spinal cord were studied during postnatal development by in vitro receptor autoradiography. At three, six and 10 days of age, specific [125I]eledoisin binding was distributed throughout the dorsal and ventral horns of the spinal cord. In contrast, from day 24 onwards, specific binding of [125I]eledoisin was confined to superficial layers of the dorsal horn, with negligible amounts of specific binding in the ventral horn. [125I]Eledoisin binding to neonatal (three day) and adult (eight to 12 weeks) spinal cord sections was characterized using tachykinin agonists. In both dorsal and ventral horns of neonatal spinal cord, the rank order of potency of agonists indicated that the majority (64%) of specific [125I]eledoisin binding was to neurokinin-3 binding sites. The identity of the non-neurokinin-3 sites labelled by [125I]eledoisin remains to be determined. In adult rat spinal cord, [125I]eledoisin appeared to bind exclusively to neurokinin-3 binding sites. These results suggest that major changes take place in the localization of neurokinin-3 receptors during postnatal ontogeny of the rat spinal cord. These changes may reflect an important role for tachykinins in neuronal plasticity of the developing spinal cord.

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S.J. Ireland

University of Hertfordshire

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Peter J. Elliott

University of Hertfordshire

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