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Biomedical subjects

R D Sewell

Publications and source records attributed to R D Sewell.

At least 19 recordsLinked to original sources
PubMed2000

Do antidepressants affect motivation in conditioned place preference?

The positive motivational effects of a range of antidepressants/neurotransmitter reuptake inhibitor compounds were studied using conditioned place preference. These agents included amitriptyline (2.5-10 mg/kg), venlafaxine (5 and 10 mg/kg), sibutramine (5 and 10 mg/kg), fluoxetine (2.5-10 mg/kg), paroxetine (5-15 mg/kg) and sertraline (2.5-10 mg/kg). Male Wistar rats were place conditioned in a three-compartment box to vehicle or drug alternately for 8 days using a 30-min pretreatment time. Control animals received vehicle only. Cocaine (5 mg/kg) was used as a positive control for the procedure. Significant place preference (P<0.05) was observed with paroxetine (15 mg/kg), fluoxetine (5 and 10 mg/kg), sertraline (2.5-10 mg/kg) and cocaine. Venlafaxine and sibutramine, serotonin/noradrenaline reuptake inhibitors, produced no place conditioning, while the highest dose of the tricyclic antidepressant, amitriptyline (10 mg/kg), produced signs of place aversion. The role of serotonin in reward pathways and differences in serotonin, noradrenaline and dopamine reuptake-inhibiting properties of these compounds may explain why only the serotonin-selective reuptake inhibitors produced place preference in this study.

Adrenergic Uptake Inhibitors↗
PubMed2000

Analgesic doses of the enkephalin degrading enzyme inhibitor RB 120 do not have discriminative stimulus properties.

The systemically active mixed inhibitor of enkephalin metabolism, N-((S)-2-benzyl-3[(S) 2-amino-4-methylthio)butyldithio-]-1-oxopropyl)-L-alanine benzylester (RB 120), alone or in combination with 4-¿[2-[[3-(1H-indol-3-yl))-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1. ]dec-2-yloxy) carbonyl]amino¿propyl]amino]-1-phenylethyl]amino¿-4-oxo-[R-(R*, R*)]-butanoate N-methyl-D-glucamine (CI 988; CCK(1) receptor antagonist) was investigated for discriminative and morphine generalisation effects using an operant drug discrimination paradigm in rats. Animals dosed with RB 120 (10 mg/kg) failed to develop a discriminative response. Combined CI 988 (0.3 mg/kg) and RB 120 (10 mg/kg) also failed to elicit a discriminative response. Morphine-trained animals (3.0 mg/kg) did not generalise to RB 120 (10 and 20 mg/kg). Similarly, subsequent retraining of the same animals with 1.5 mg/kg of morphine did not elicit generalisation to RB 120 (10 or 20 mg/kg). Combined RB 120 (10 or 20 mg/kg) and CI 988 (0.3 or 3.0 mg/kg) treatment produced no notable drug lever selection in rats able to discriminate morphine (1.5 mg/kg) from saline. These results suggest that RB 120 may have low abuse potential at analgesic doses.

Alanine↗
PubMed2000

Potentiation of opioid-induced conditioned place preference by the selective serotonin reuptake inhibitor fluoxetine.

The ability of the selective serotonin reuptake inhibitor, fluoxetine, to modify the effects of morphine, N-((S)-2-benzyl-3[(S) 2-amino-4-methylthio)butyldithio-]-1-oxopropyl)-L-alanine benzylester (RB 120; mixed inhibitor of enkephalin metabolism), and 4-¿[2-[[3-(1H-indol-3-yl))-2-methyl-1-oxo-2-[[(tricyclo[3,3,1,1] dec-2-yloxy) carbonyl] amino¿ propyl] amino]-1-phenylethyl] amino¿-4-oxo-[R-(R*,R*)]-butanoate N-methyl-D-glucamine (CI 988; cholecystokinin receptor subtype [CCK(2)] antagonist), was assessed using conditioned place preference. RB 120 and morphine both induced significant, dose-dependent conditioned place preference, whilst CI 988 failed to elicit conditioned place preference. A subthreshold dose of fluoxetine (2.5 mg/kg) potentiated the morphine submaximal response. Notably, the combination of a subthreshold dose of fluoxetine (2.5 mg/kg) with RB 120 (5 mg/kg) or CI 988 (3 mg/kg) was devoid of any significant conditioned place preference properties. Fluoxetine may act via enhanced serotonergic activity to modulate enkephalinergic tone. Agents that increase enkephalinergic tone more directly such as RB 120 and CI 988, at submaximal doses, did not induce conditioned place preference when co-administered with fluoxetine. These data suggest that fluoxetine, in combination with CI 988 or RB 120, might prove to be a beneficial treatment strategy for opioid drug addiction, though further studies are necessary.

Alanine↗
PubMed2000

Chest compressions in an infant with osteogenesis imperfecta type II: No new rib fractures.

The case report of a newborn female with osteogenesis imperfecta type II who underwent cardiopulmonary resuscitation (CPR) with manual chest compressions for several minutes is presented. Chest radiographs taken before and after the chest compressions were administered were reviewed by several radiologists from 3 different hospitals and demonstrated no new radiographically visible rib fractures. Collagen analysis, the patient's clinical appearance, and clinical course, as well as a consultant's opinion aided in confirmation of the diagnosis of osteogenesis imperfecta type II. A review of 4 previous studies concerning rib fractures and CPR is included. This unique case supports previous articles that have concluded that rib fractures rarely, if ever, result from CPR in pediatrics, even in children with a lethal underlying bone disease, such as osteogenesis imperfecta type II. cardiopulmonary resuscitation, chest compressions, osteogenesis imperfecta, rib fractures, bone disease.

Biomechanical Phenomena↗
PubMed1999

Do alpha2-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds?

Antidepressants are analgesic in the absence or presence of depression. The underlying mechanisms probably involve a complex interplay between several neurotransmitter systems and neuroreceptors. Alpha-adrenoceptors play an important role in pain processing and alpha2-adrenoceptor agonists have been used in clinical pain management so we have investigated whether alpha-adrenoceptor sub-types mediate the antinociceptive activity of antidepressants. Thus, the abdominal constriction assay in mice was used to examine the antinociceptive responses of a diverse range of antidepressants following alpha1- or alpha2-adrenoceptor antagonism. The antidepressants or monoamine reuptake inhibitors included the serotonin selective reuptake inhibitor paroxetine, the serotonin-noradrenaline reuptake inhibitor sibutramine, the resolved (+)- and (-)-enantiomers of the noradrenaline reuptake inhibitor oxaprotiline, plus the tricyclics amitriptyline and dothiepin. All these compounds have been previously shown to be antinociceptive in this paradigm. The respective alpha1- and alpha2-adrenoceptor antagonists prazosin and RX821002 ([2-(2-methoxy-1,-4-benzodioxan-2-yl)-2-imidazoline]) did not produce antinociception though at 1.0 mg kg(-1); s.c., RX821002 but not prazosin blocked clonidine antinociception. The antinociceptive activity produced by sub-maximal doses of amitriptyline, dothiepin, sibutramine, paroxetine, (+)- and (-)-oxaprotiline were all blocked by RX821002 but not by prazosin. Additionally, both morphine and aspirin antinociception was resistant to alpha1- and alpha2-adrenoceptor antagonism. Thus, alpha2- rather than alpha1-adrenoceptors may play an integral role in antidepressant antinociception irrespective of the propensity for inhibiting reuptake of not only noradrenaline but also serotonin. It is probable, however, that other differing pharmacological properties of some antidepressants, such as opioid-like activity, may complicate any empirical correlation between monoamine uptake and analgesia.

Adrenergic Uptake Inhibitors↗
PubMed1999

The involvement of opioidergic and noradrenergic mechanisms in nefopam antinociception.

Nefopam is a clinically effective analgesic agent used to control mild to moderate pain, whose mechanism of action is unknown. We have investigated the antinociceptive activity of nefopam in the mouse abdominal constriction assay and tail immersion test (48 degrees C). Nefopam was found to possess a high degree of potency against acetic acid-induced visceral nociception (ED50 2.5 mg kg(-1)). In the presence of the opioid receptor antagonists, naloxone or naltrindole, the resulting nefopam dose-response relationships were shifted to the right. Naloxone or naltrindole had no effect upon aspirin (ED50 32.1 mg kg(-1)) or clonidine (ED50 0.061 mg kg(-1)) induced antinociception. Acetorphan (10 mg kg(-1); s.c.), an inhibitor of neutral endopeptidase (EC 3.4.24.11) was able to potentiate nefopam's antinociceptive activity (ED50 1.5 mg kg(-1)). The alpha2-adrenoceptor antagonist, 2-[2-(2-methoxy-1,4-benzodioxanyl)]imidazoline hydrochloride (RX821002; 1 mg kg(-1); s.c.), shifted the dose-response curves for clonidine (ED50 7.1 mg kg(-1)) and nefopam (ED50 5.3 mg kg(-1)) to the right in this assay. Additionally, centrally administered RX821002 (1 microg/5 microl/animal; i.c.v.) reduced both clonidine (ED50 7.2 mg kg(-1)) and nefopam's ED50 15.5 mg kg(-1)) efficacy in the abdominal constriction assay. Nefopam (3 and 7.5 mg kg(-1); s.c.) produced significant antinociceptive effect in the thermal assay. Aspirin and RX821002 were devoid of any significant activity in the tail immersion test. Nefopam was shown to possess RX821002-reversible antinociceptive activity in both the tail immersion test and the abdominal constriction assay. These data suggest the involvement of an opioidergic and noradrenergic component to nefopam's antinociceptive activity in the mouse abdominal constriction assay and tail immersion test. However, the present results are unable to determine if the opioidergic component of nefopam antinociception is through a direct and/or indirect activation of opioid receptors.

Abdominal Pain↗
PubMed1999

Detecting drug effects on short-term memory function using a combined delayed matching and non-matching to position task.

Operant delayed non-matching-to-position (DNMTP) and delayed matching-to-position (DMTP) have become standard techniques to investigate drug effects on short-term memory function in rats. However, these two tasks are normally conducted in isolation. Using two standard drugs, the 5HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the muscarinic antagonist scopolamine, this study looked at a two-choice operant task that essentially involved a mixed DNMTP/DMTP paradigm. Thus, DNMTP trials were interspersed with DMTP trials in a random sequence for the duration of a session. 8-OH-DPAT (0.03 mg/kg) slightly but significantly improved response accuracy in a delay-dependent fashion during DMTP but not DNMTP trials. The highest dose of 8-OH-DPAT (0.1 mg/kg) impaired accuracy during DNMTP trials independent of delay and had no significant effect during DMTP trials. Scopolamine (0.1 mg/kg) produced delay-dependent deficits in accuracy during DMTP trials but delay-independent impairments during DNMTP trials. Because both 8-OH-DPAT and scopolamine produced delay-dependent effects with DMTP trials types and either had no effect (8-OH-DPAT) or produced delay-independent impairments (scopolamine) during DNMTP trials types, it is suggested that DMTP trials had a greater dependence on short-term working memory function than DNMTP trials that probably relied more on positional (mediating) strategies for solving the task. Therefore, we believe that this mixed DNMTP/DMTP task offers greater potential for more reliable and discerning interpretation of data regarding short-term memory function in rodents than either of the paradigms performed in isolation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds.

1. Debate exists as to the nature of antidepressant-induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressant-induced antinociception. 2. All the antidepressants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin were also effective antinociceptive agents in this nociceptive assay. 3. Opioid antagonists, naloxone (0.5 mg kg(-1), s.c.) and naltrindole (1 mg kg(-1), s.c.), shifted the dose-response relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)-oxaprotiline and paroxetine). In this context the naloxone dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose-response relationship to the right, by a factor of 2.62, whilst naltrindole had no effect upon morphine antinociception. Aspirin antinociception remained unaffected by both opioid antagonists. 4. The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg(-1) (s.c.). However, at higher doses, acetorphan produced a linear dose-response relationship against acetic acid-induced abdominal constriction. 5. When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant- or morphine-induced antinociception. However, acetorphan had no effect on aspirin antinociception. 6. Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant-induced antinociception is different from that of the non-steroidal anti-inflammatory drugs. 7. These data are consistent with the view that antidepressants may induce endogenous opioid peptide release, as shown by the acetorphan study. In this context, the ability of naltrindole to displace the antidepressant dose-response relationship to the right without affecting morphine antinociception, implicates the delta-opioid receptor and endogenous opioid peptides in antidepressant-induced antinociception.

Abdominal Muscles↗
PubMed1996

Sensitivity differences to 5-HT and carbachol in subsections of the isolated rat stomach fundus strip: an improved preparation.

The rat stomach fundus strip has often been used as a sensitive assay of pharmacological activity at 5-HT receptors. In the present study, we describe an improved preparation based on the finding that the majority of the contractile response to 5-HT and carbachol was present in one particular longitudinal quartile of the tissue. The fundi were dissected into four anatomically consistent sections and labelled accordingly (left ventral = LV; right ventral = RV; left dorsal = LD; right dorsal = RD). A distinct pattern of responsiveness (contraction) to 5-HT and carbachol was observed. For carbachol, the maximum contraction ratios of the sections (LV:LD:RV:RD) were 7.2(+/-0.8):5.8(+/-1.4):4.2(+/-0.46):3.0 (+/-0.22), respectively. For 5-HT, the differences were more pronounced with maximum contraction ratios of 5.6 (+/-0.94): 3.6(+/-0.58):1.4(+/-0.30):1.6(+/-0.22), respectively. When the sections were dissected along the submucosa, the mucosal section responded to carbachol and 5-HT, while the muscularis externa did not respond to these agonists. Selection of the LV section allowed the use of smaller bath volumes, and subsequent bisection facilitated the design of more effective paired experiments.

Animals↗
PubMed1995

Contrasting actions of acute or chronic paroxetine and fluvoxamine on morphine withdrawal-induced place conditioning.

The acute and chronic effects of paroxetine and fluvoxamine on naloxone withdrawal-induced place aversion in morphine dependent rats were investigated. Acutely administered fluvoxamine (25 mg/kg s.c. given 30 min prior to naloxone withdrawal pairing) and chronic daily paroxetine (10 mg/kg s.c.) coadministration with a morphine induction protocol, both attenuated morphine withdrawal place aversion. Conversely, acutely administered paroxetine (up to 25 mg/kg s.c.) or chronic daily fluvoxamine (10 mg/kg s.c.) coadministration with morphine did not modify subsequent withdrawal place aversion. Previous radioligand binding studies indicate that fluvoxamine has opioid-displacing properties. It is suggested therefore that acute fluvoxamine may have decreased withdrawal aversion, probably through serotonin and also, in part, via an opioid-like mechanism whereas chronic paroxetine decreased withdrawal aversion by a serotonergic mechanism, but it is not clear whether opioid systems play any role in the action of paroxetine.

Analysis of Variance↗
PubMed1993

Inhibitors of enkephalin-degrading enzymes as potential therapeutic agents.

A limited number of enzymes such as membrane metalloendopeptidase (enkephalinase) and angiotensin converting enzyme appear to be involved in deactivation and modulation of circulatory regulatory peptides. Peptides such as the enkephalins are also involved in a large number of physiological processes. This multiplicity of physiological roles has made it difficult to establish the therapeutic role of enkephalin-degrading enzyme inhibitors. Other factors such as difficulty in quantification and thus measurement of processes involved in pain and mental illness have also hindered the process of establishing any therapeutic role of enkephalin-degrading enzyme inhibitors in these conditions. However, they have proved to be useful pharmacological 'tools'. The most likely therapeutic role at present appears to be in the treatment of cardiovascular disorders. As a 'profile' of pharmacological actions of enkephalin-degrading enzymes emerges, it is becoming apparent that bioavailability rather than a high degree of specificity or inhibitory potency may be the most important factor. This may be used to an advantage in future developments by the use of less specific or combined inhibitors in the form of prodrugs, designed to be active at specific sites such as the central nervous system.

Aminopeptidases↗
PubMed1992

Novel inhibitors of enkephalin-degrading enzymes. IV: Structure-activity relationships within the penicillins as enkephalinase inhibitors.

A range of penicillins have been examined as competitive reversible inhibitors of enkephalinase (neutral endopeptidase; EC 3.4.24.11). Carfecillin (Ki = 0.18 microM) was the most potent inhibitor in the series, whereas cloxacillin (27.5 microM), ampicillin (41.0 microM), nafcillin (58.7 microM) and carbenicillin (158 microM) had moderate potency and benzyl penicillin (885 microM), mezlocillin (473 microM) and azlocillin (556 microM) were weak inhibitors. Structure-activity relationships within the series have been rationalised from a consideration of molecular graphics analysis of the match between receptor binding groups with thiorphan as well as log P values.

Computer Graphics↗
PubMed1991

Increased dopamine receptor sensitivity in the rat following acute administration of sufentanil, U50,488H and D-Ala2-D-Leu5-enkephalin.

The effects of acutely administered opioid receptor agonists sufentanil, U50,488H and [D-Ala2,D-Leu5]-enkephalin (DADL) were observed upon dopamine D1 and D2 binding site density in the striatum of the rat. In addition, the functional implications of opioid-induced changes in dopamine receptor sensitivity were studied using the behavioural profile elicited by apomorphine in the rat. The mu-agonist sufentanil (1 or 20 micrograms/kg, i.p.), the kappa-agonist U50,488H (10 mg/kg, i.p.) and DADL (1 microgram/animal, i.c.v.) all significantly elevated D2 but not D1 binding site density in rat striatum. Pretreatment with sufentanil (1 microgram/kg, i.p.) induced an elevation in apomorphine-induced stereotyped behaviour, but attenuated locomotor activity. Following administration of U50,488H (10 mg/kg, i.p.), both the degree of stereotypy and the intensity of the locomotor activity were enhanced. Contralateral rotation was observed in animals pretreated with DADL (1 microgram/animal, i.c.v.) following challenge with apomorphine. It is concluded that the opioid agonists studied induce a significant elevation in functional D2 sites to the exclusion of D1 sites. However, the precise mechanism by which this effect is elicited remains to be established.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Acute effects of beclamide on brain regional monoamine concentrations, their metabolites and radioligand binding studies.

The effects of beclamide on regional brain monoamine levels and radioligand binding have been studied in rats. One hour oral pre-treatment with beclamide (400 mg kg-1) increased rat striatal dopamine turnover by increasing the levels of its major metabolites (DOPAC and HVA) three-fold. Simultaneously the drug reduced the concentration of striatal dopamine by a similar factor, and the concentrations of 5-hydroxytryptamine, (5-HT), 5-hydroxyindoleacetic acid, (5-HIAA) and 3-methoxytyramine in the striatum were reduced below the detection limits of the assay. In the frontal cortex, beclamide depleted the dopamine, 5-HT and 5-HIAA content whilst having no significant effect on the noradrenaline level. The concentrations of bioamines and their metabolites in the hypothalamus were unaffected by such acute beclamide treatment. In radioligand binding studies beclamide lacked affinity and failed to displace radioligands from alpha 2, beta, 5-HT, 5-HT2 and dopamine D2 sites in selective loci of the rat brain.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Novel inhibitors of enkephalin-degrading enzymes. III: 4-Carboxymethylamino-4-oxo-3 (phenylamino) butanoic acids as enkephalinase inhibitors.

4-Carboxymethylamino-4-oxo-3-(4'-aminophenylamino) butanoic acid (25), its ethyl ester (26) and the corresponding unsubstituted-aryl analogues (17) and (16) are fairly potent inhibitors of enkephalinase (neutral endopeptidase; EC 3.4.24.11), Ki = 0.14-0.39 microM, with weak inhibitory potency, Ki = 15-75 microM, towards aminopeptidase MII. In the mouse abdominal constriction test, the esters (26) and (16) showed systemic inhibitory (antinociceptive) activity with ED50 values 62 +/- 3.05 and 81 +/- 1.74 mg/kg respectively. In the mouse tail immersion test, both (26) and (16) exhibited antinociceptive activity when administered intracerebroventricularly and (26) also exhibited a systemic effect which was only partially reversed by naltrexone. The antinociceptive effect seen with (26) reflects its ranking in vitro as an inhibitor of enkephalinase (Ki = 0.14 microM) but it is possible that this effect is not totally opioid-mediated. Compounds (26) and (16) represent the first combined inhibitors of enkephalinase and aminopeptidase MII.

Abdomen↗
PubMed1990

Comparison of the inhibitory action of aminobeclamide and beclamide on socially offensive behaviour.

The inhibitory effects of aminobeclamide (N-(p-aminobenzyl)-beta-chloropropionamide) on socially offensive behaviour has been studied and compared with those of the parent drug beclamide (N-benzyl-beta-chloropropionamide). Following oral administration in mice which had been individually housed for a 28 day period then paired with normal group-housed opponents, aminobeclamide and beclamide both produced significant and dose-related inhibition of socially offensive behaviour. Aminobeclamide (20-150 mg kg-1 p.o.) and beclamide (50-250 mg kg-1 p.o.) gave increased offense onset latency whilst at the same time they reduced the incidence of offense encounters/animal and decreased the group percentage of animals displaying offense behaviour. It is likely that both drugs have similar monoamine modifying effects though this animal study suggests that aminobeclamide is 1.5 to 2.7 times more potent than beclamide against socially offensive behaviour.

Animals↗