General Practitioners, Pediatrician, Surgical Specialist
36 years of experience

Accepting new patients
Harris Methodist Southlake Center For Diagnostics
1545 E Southlake Blvd
Ste 140
Southlake, TX 76092
817-748-0200
Locations and availability (1)

Education ?

Medical School Score
The University of Texas at Galveston (1974)
  • Currently 2 of 4 apples

Awards & Distinctions ?

Associations
American College of Surgeons

Affiliations ?

Dr. Sewell is affiliated with 12 hospitals.

Hospital Affilations

Score

Rankings

  • Harris Methodist H E B
    1600 Hospital Pkwy, Bedford, TX 76022
    • Currently 4 of 4 crosses
    Top 25%
  • Texas Health Harris Methodist Hospital Southwest Fort Worth
    6100 Harris Pkwy, Fort Worth, TX 76132
    • Currently 4 of 4 crosses
    Top 25%
  • Texas Health Presbyterian Hospital Of Dallas
    8200 Walnut Hill Ln, Dallas, TX 75231
    • Currently 3 of 4 crosses
    Top 50%
  • Texas Health Harris Methodist Hospital Azle
    108 Denver Trl, Azle, TX 76020
    • Currently 3 of 4 crosses
    Top 50%
  • Harris Methodist Southlake Center For Diagnostics
    1545 E Southlake Blvd, Southlake, TX 76092
  • Texas Health Southlake
  • Harris Continued Care Hospital
    1301 Pennsylvania Ave, Fort Worth, TX 76104
  • Good Shepherd Medical Center
  • Texas Health HEB
  • Harris Methodist Hospital Heb
  • Harris Methodist - Southlake
  • Harris Methodist - Springwood
    1608 Hospital Pkwy, Bedford, TX 76022
  • Publications & Research

    Dr. Sewell has contributed to 84 publications.
    Title Immunoprotection Against Toxic Biomarkers is Retained During Parkinson's Disease Progression.
    Date June 2011
    Journal Journal of Neuroimmunology
    Excerpt

    The aim was to ascertain any possible linkage between humoral immune responses to principal biomarkers (α-synuclein monomers, its toxic oligomers or fibrils, dopamine and S100B) and cellular immunity in Parkinson's disease development. There were elevated autoantibody titers to α-synuclein monomers, oligomers plus fibrils in 72%, 56%, and 17% of Parkinsonian patients respectively with a 5-year disease duration. Additionally, there were increased titers to dopamine and S100B (96% and 89%) in the 5-year patient group. All of these values subsided in 10-year sufferers. Furthermore, CD3+, CD4+, CD8+ T-lymphocyte and B-lymphocyte subsets declined in the patient cohort during Parkinsonism indicating disease associated reductions in these lymphocyte subsets.

    Title Adulterant Profile of Illicit Street Heroin and Reduction of Its Precipitated Physical Dependence Withdrawal Syndrome by Extracts of St John's Wort (hypericum Perforatum).
    Date April 2009
    Journal Phytotherapy Research : Ptr
    Excerpt

    The study evaluated the adulterants in a specimen of illicit street heroin supplied under strict control by the Pakistan Anti-Narcotic Force. It also examined the effects of Hypericum perforatum L. extracts on the naloxone-induced heroin withdrawal syndrome. The GC-MS analysis of the specimen showed that in addition to heroin (37.8%), the sample also contained caffeine (8.4%), phenobarbitone (12.7%), 6-acetyl codeine (5.3%), 6-acetyl morphine (10.9%) and noscapine (15.8%). Administration of the heroin to rats for 8 days induced physical withdrawal signs of abdominal constriction, diarrhoea and vocalization on touch after naloxone treatment. Aqueous Hypericum perforatum extracts (20 mg/kg twice daily chronically or as a single acute dose 90 min before naloxone) given orally to the heroin dependent rats attenuated abdominal constrictions both acutely and chronically while the hydroethanol and ethanol extracts were only effective in acutely treated animals. Diarrhoea was ameliorated by the hydroethanol and ethanol extracts following acute or chronic heroin treatment while the aqueous extract failed to show any effect. Vocalization on touch during withdrawal was reduced by all the extracts either chronically or acutely with the exception of chronic treatment with hydroethanol extracts. The findings suggest that Hypericum perforatum is capable of reducing the physical signs of opiate withdrawal.

    Title The Nootropic and Neuroprotective Proline-containing Dipeptide Noopept Restores Spatial Memory and Increases Immunoreactivity to Amyloid in an Alzheimer's Disease Model.
    Date October 2007
    Journal Journal of Psychopharmacology (oxford, England)
    Excerpt

    The effects of the novel proline-containing nootropic and neuroprotective dipeptide, noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were investigated in NMRI mice following olfactory bulbectomy. We have shown previously that these animals developed Alzheimer's disease (AD)-like behaviour, morphology and biochemistry including impairment of spatial memory, regional neuronal degeneration and elevated Abeta peptide brain levels. In the current investigation, spatial memory was assessed using the Morris water maze and serum antibodies to in vitro morphologically characterized amyloid structures of both Abeta((25-35)) peptide and equine lysozyme, as well as to neurotrophic glial factor S100b, were analyzed by enzyme-linked immunosorbent assay (ELISA). Noopept (administered at a dose of 0.01 mg/kg for a period of 21 days and during a further 5 days training) restored spatial memory and increased serum antibody levels to oligomers of Abeta((25-35)) peptide but not to equine lysozyme amyloid or S100b protein in bulbectomized animals. The positive immunotropic effect of noopept to Abeta((25-35)) peptide prefibrillar aggregates was more marked in sham-operated compared to the bulbectomized subjects which were characterized by an overall suppression of immunoreactivity. Enhancement of the immune response to Abeta((25-35)) peptide prefibrils caused by noopept may attenuate the neurotoxic consequences of amyloid fibrillization and also be associated with an improvement in spatial memory in bulbectomized mice. These actions of noopept, combined with its previously reported neuroprotective and cholinomimetic properties, suggests that this dipeptide may well be useful for improving cognitive deficits induced by neurodegenerative diseases.

    Title Differential Neuroimmune Markers to the Onset of Alzheimer's Disease Neurodegeneration and Dementia: Autoantibodies to Abeta((25-35)) Oligomers, S100b and Neurotransmitters.
    Date August 2007
    Journal Journal of Neuroimmunology
    Excerpt

    Alzheimer's disease (AD) autoimmunity is a focus for dementia prevention. Generated autoantibodies against major etiopathogenic molecular targets as neuroimmune markers of dementia were measured by ELISA in patient sera. Biphasic antibody levels to Abeta((25-35)) oligomers, S100b and DA were detected during distinctly diagnosed dementia stages. Abeta((25-35)) oligomer autoimmune responses reflected mild to moderate AD dementia, while those to S100b, DA and the S100b concentrations, matched moderate to severe dementia progression. 5-HT antibodies increased during mild dementia and plateaued thereafter. This autoimmunity pattern may be used as a differential biomarker profile in designing AD therapeutic strategies involving early vaccination.

    Title Providing Formative Feedback from a Summative Computer-aided Assessment.
    Date July 2007
    Journal American Journal of Pharmaceutical Education
    Excerpt

    OBJECTIVES: To examine the effectiveness of providing formative feedback for summative computer-aided assessment. DESIGN: Two groups of first-year undergraduate life science students in pharmacy and neuroscience who were studying an e-learning package in a common pharmacology module were presented with a computer-based summative assessment. A sheet with individualized feedback derived from each of the 5 results sections of the assessment was provided to each student. Students were asked via a questionnaire to evaluate the form and method of feedback. ASSESSMENT: The students were able to reflect on their performance and use the feedback provided to guide their future study or revision. There was no significant difference between the responses from pharmacy and neuroscience students. Students' responses on the questionnaire indicated a generally positive reaction to this form of feedback. CONCLUSIONS: Findings suggest that additional formative assessment conveyed by this style and method would be appreciated and valued by students.

    Title The Bacterial Profile of Cotton Lint from Worldwide Origins, and Links with Occupational Lung Disease.
    Date February 2007
    Journal American Journal of Industrial Medicine
    Excerpt

    BACKGROUND: Byssinosis, the cotton worker's lung disease persists today in many countries. Several agents have been investigated with respect to causality; among these are Gram-negative bacteria. These organisms are a source of lipopolysaccharide toxins, which are potentially hazardous to the respiratory tract. Despite byssinosis being most prevalent in countries where adequate preventive procedures are lacking, the majority of past studies have been conducted on cotton from the United States. METHODS: The current investigation, involved the identification of Gram-negative bacteria from cotton lint samples originating in 12 world regions. RESULTS: The current investigation, involved the identification of Gram-negative bacteria from cotton lint samples originating in 12 world regions. CONCLUSIONS: Building a bacterial profile of cotton samples with worldwide origins will be useful in isolating sources of these organisms, assessing the risk posed to industry, workers and ultimately assisting the prevention of byssinosis and related conditions.

    Title The Fungal Profile of Cotton Lint from Diverse Sources and Implications for Occupational Health.
    Date December 2006
    Journal Journal of Occupational and Environmental Hygiene
    Excerpt

    There is mounting evidence that inhalation of fungal spores and their fragments and toxins may cause respiratory illness, particularly in indoor environments and industrial settings. However, analysis of these organisms on cotton has not been carried out in detail and, hence, further examination may prove important in identifying sources of these organisms and assessing the risks posed to cotton workers. This study identified fungi from cotton lint samples originating in 12 world regions and revealed six different fungal genera, with the following rank order of sample isolation incidence: Aspergillus > Cladosporium > Fusarium > Rhizopus > Penicillium > Alternaria. Aspergillus was the most common genus and Aspergillus niger in particular was the pecies most frequently identified. Improved understanding of the variety of organisms that contaminate cotton may help to reduce prevalence of organic dust-related lung diseases.

    Title Correlative Measurement of Four Biological Contaminants on Cotton Lint, and Their Implications for Occupational Health.
    Date December 2006
    Journal International Journal of Occupational and Environmental Health
    Excerpt

    Four biological contaminants of cotton fibers (gram-negative bacterial cells, endotoxin, fungal cells, and (1-3)-beta-D-glucan) were measured in 13 cotton lint samples from international origins, using traditional microbiological spread plating and adaptation of the Limulus amoebocyte lysate (LAL) assay. Correlations were evaluated using Spearman's rank correlation analyses. Contamination levels ranged from 713 +/- 212 to 216,830 +/- 30,413 CFU/g gram-negative bacteria; 281 +/- 29 to 9,250 +/- 820 CFU/g fungal cells; 8.30 +/- 0.89 to 137.89 +/- 21.55 ng/g endotoxin; and 15.96 +/- 5.18 to 2,964.42 +/- 313.90 LAL-reactive units/g glucan. Positive correlations existed between all contaminants; however, they were significant only between fungal cells and glucan (p < 0.05) and between endotoxin and glucan (p < 0.01). The highly significant positive correlation between endotoxin and glucan has implications for the health risk posed by the cotton-production environment, as simultaneous inhalation of these agents may cause or exacerbate lung inflammation.

    Title Does the Human Leukaemia Differentiation Factor Fragment Hldf6 Improve Memory Via Brain Dna and Protein Synthesis?
    Date February 2006
    Journal Journal of Psychopharmacology (oxford, England)
    Excerpt

    The novel human differentiating factor peptide fragment HLDF6 (Thr-Gly-Glu-Asn-His-Arg) was synthesized and purified. HLDF6 (0.1mg/kg i.p. but not 1mg/kg i.p.) improved not only long-term (24h) memory in adult rats in the water maze behavioural paradigm but also performance in the delayed matching-to-position (DMTP) task (0.3 and 1.0 but not 0.1mg/kg i.p). Hence, HLDF6 not only enhanced allocentric spatial learning and reference memory (water maze) but also improved temporal, spatial and working memory processes in the DMTP behavioural paradigm. Immunoreactivity blotting analysis of HLDF (the protein precursor of HLDF6) was performed and the following rank order of visual intensities from brain structures was noted: hippocampus cerebral cortex cerebellum hypothalamus striatum. Subsequently, we found that the highest absolute levels of HLDF were expressed in the hippocampus and cerebral cortex as detected by ELISA. We also demonstrated that HLDF6 enhanced [(3)H]-thymidine and [(14)C]-leucine incorporation into whole brain and hippocampal homogenates (maxima occurring within the range 10 (-12)-10 (-6) M) suggesting that this hexapeptide promoted de novo DNA and protein biosynthesis. We discuss this data in terms of their implications for links with other integrative metabolic pathways involving immediate early gene activation which may underpin a potential application for HLDF6 in limiting memory impairments associated with neurodegenerative diseases.

    Title Co-administration of Fluoxetine and Way100635 Improves Short-term Memory Function.
    Date January 2006
    Journal European Journal of Pharmacology
    Excerpt

    The aim of this study was to determine whether the action of the antidepressant fluoxetine or the anxiolytic buspirone could be modified by specific 5-hydroxytriptamine (5-HT(1A)) receptor blockade in a short-term memory paradigm. Male Wistar rats were trained to perform the putative short-term memory task, delayed non-matching to position. WAY100635, a selective 5-HT(1A) receptor antagonist (0.15 mg/kg), was administered 15 min before either the selective serotonin reuptake inhibitor fluoxetine (3 mg/kg), or the partial 5-HT(1A) receptor agonist and dopamine D2 receptor antagonist, buspirone (0.3 mg/kg). 8-Hydroxy-di-n-propylamino tetralin (8-OH-DPAT), a full 5-HT(1A) receptor agonist (0.3 mg/kg), was also included in the study as a positive control. WAY100635 alone had no effect on any behavioural parameter measured (response accuracy, delay lever press activity and trial completion). 8-OH-DPAT impaired response accuracy in a delay-dependent manner, an effect reversed by WAY100635. Fluoxetine also impaired response accuracy delay-dependently. WAY100635 pretreatment not only reversed this deficit but improved response accuracy, in the presence of a significant deficit in trial completion. At the dose used, buspirone showed no significant differences compared to the control group. The data suggest that fluoxetine impairs short-term memory function by the indirect activation of 5-HT(1A) receptors, but that its co-administration with WAY100635 improves short-term memory function.

    Title Effect of 2-(4-aminophenylmethyl)-6-hydroxy-3, 4-dihydronaphthalen-1(2h)-one on All-trans and 13-cis-retinoic Acid Levels in Plasma Quantified by High Perfomance Liquid Chromatography Coupled to Tandem Mass Spectrometry.
    Date December 2005
    Journal Journal of Enzyme Inhibition and Medicinal Chemistry
    Excerpt

    The effect of the titled tetralone as a retinoic acid metabolism blocking agent (RAMBA) in vivo in comparison with ketoconazole, a well known cytochrome P450 inhibitor, was studied. Development of a HPLC/MS/MS method for the quantification of retinoic acid levels extracted from rat plasma was used to demonstrate that ketoconazole and the tetralone (100 mg/kg) enhanced the endogenous plasma concentration of retinoic acid. Levels of retinoid were raised from a control value of 0.11 to 0.15 and 0.17 ng/mL after treatment with tetralone and ketoconazole respectively showing that the tetralone and ketoconazole lead to comparable effects, indicating an inhibitory activity of the tetralone on retinoic acid metabolism.

    Title Autoimmune Responses to Amyloid Structures of Abeta(25-35) Peptide and Human Lysozyme in the Serum of Patients with Progressive Alzheimer's Disease.
    Date February 2005
    Journal Dementia and Geriatric Cognitive Disorders
    Excerpt

    We have found an increased level of serum antibodies to the prefibrillar structures of both Abeta(25-35) peptide and human lysozyme in Alzheimer's disease (AD) patients compared to age-matched controls, indicating that autoimmunity is implicated in AD. In the serum of AD patients with a long-term duration (>15 years) the titer of serum antibodies to aggregates of Abeta(25-35) peptide increased by approximately 5-fold, whilst the antibody titer to lysozyme protofilaments decreased by approximately 8-fold compared to patients with AD duration of <5 years. The content of immunoglobulins of the A, G and M types declined, particularly in AD duration of >15 years. An increase in the concentration of immune complexes and higher lysozyme activity was detected in the serum of all patients and this was suggestive of an inflammatory reaction. We propose that the autoimmune response to different amyloid structures in AD can be viewed as a clearance pathway targeting amyloid development. Autoimmune response can be exploited as a marker of ongoing protein aggregation and hence be used as a diagnostic feature of AD.

    Title Buspirone Differentially Modifies Short-term Memory Function in a Combined Delayed Matching/non-matching to Position Task.
    Date December 2004
    Journal European Journal of Pharmacology
    Excerpt

    This study investigated the action of 5-hydroxytryptamine (5-HT) mimetics on short-term memory function. The objective was to determine whether two closely related tasks could differentiate between partial 5-HT(1A) receptor activation, full 5-HT(1A) receptor activation and generalised enhanced serotonin (5-HT) activity. Male hooded Lister rats were trained to perform an operant-based combined delayed matching/non-matching to position task. Drugs used were: fluoxetine (3 mg/kg, i.p.), a selective 5-HT reuptake inhibitor; the full 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.3 mg/kg, s.c.); and the partial 5-HT(1A) receptor agonist, buspirone (1 mg/kg, i.p.). Buspirone differentially disrupted response accuracy depending on the style of trial. There was no such difference in the case of 8-OH-DPAT, which impaired accuracy in both delayed matching/non-matching to position task, while fluoxetine affected neither. Thus, the findings suggest that partial 5-HT(1A) receptor activation compromises cognitive function to a greater extent than full 5-HT(1A) receptor activation, although a dopaminergic component cannot be excluded since buspirone possesses some dopamine D2 receptor antagonist activity. Furthermore, it suggests that there is a differential role for 5-HT in these two closely related behavioural tasks.

    Title The Measurement and Health Impact of Endotoxin Contamination in Organic Dusts from Multiple Sources: Focus on the Cotton Industry.
    Date July 2004
    Journal Inhalation Toxicology
    Excerpt

    Endotoxin is derived from Gram-negative bacterial membranes, and its inflammatory effects following inhalation are well characterized. The significance of this fact becomes apparent when the wide-ranging environments containing high levels of this microbial product are considered. Endotoxin is present in numerous industrial environments, especially where organic fibers are processed. Microbial contamination of these fibers mainly occurs at the agricultural stage. Materials such as flax and hemp are affected in this way, but the most important product in this context is cotton, from which chronic dust inhalation causes the disease byssinosis. Despite the fact that endotoxin constitutes a significant threat to public health, there are currently no occupational exposure limits for this toxicant. This communication describes the toxicology of endotoxin, and its role in inhalation-induced disease, focusing on measurement of airborne endotoxin in the occupational and domestic environments using the Limulus amebocyte lysate (LAL) enzyme assay. Following the success of the LAL assay for measuring endotoxin in dusts, our laboratory has examined its application to aqueous washes from cotton fibers. Reproducibility of the results was high, and data are presented displaying levels of endotoxin contamination in fibers from different cotton producing countries. Hence, worldwide comparison of industrial endotoxin concentrations can be readily made using this test. It would be highly desirable if the performance of the LAL assay facilitated introduction of industrial endotoxin safety limits, and in spite of minor surmountable shortcomings, the test is accurate, reliable, and well field-tested, so its continued widespread use may achieve this goal.

    Title Morphine, Cocaine and Antidepressant Induced Motivational Activity and Midbrain Dopaminergic Neurotransmission.
    Date July 2003
    Journal European Journal of Pharmacology
    Excerpt

    Positive motivational properties of opioids, stimulants and serotonin selective reuptake inhibitors have been reported following place preference conditioning. The possibility that these effects are associated with changes in dopamine concentration in the nucleus accumbens or striatum was investigated. Male Wistar rats were place conditioned in a three compartment model to vehicle or drug (morphine 2.5 mg/kg, cocaine 5 mg/kg, sertraline 5 mg/kg or paroxetine 15 mg/kg) alternately for 8 days using a 30 min pre-treatment time. Control animals received saline only. Nucleus accumbens and striatal tissue were dissected 72 h after final drug dose, and the concentration of dopamine and its metabolites determined using high performance liquid chromatography (HPLC). Striatal dopamine D1-like receptor density was also determined through radioligand binding. Significant place preference (P<0.05) was observed with morphine, cocaine and sertraline. Morphine treated subjects showed a significant decrease (P<0.05) in striatal dopamine concentration, whilst cocaine and sertraline treatment resulted in a significant increase in striatal dopamine levels. Nucleus accumbens concentrations of dopamine, and striatal dopamine D1-like receptor density remained unchanged. The changes in striatal dopamine concentrations are consistent with withdrawal from opioid and stimulant compounds, and suggest that place preference conditioning may, in part, result from negative motivational or aversive effects.

    Title Drug Dependence: Neuropharmacology and Management.
    Date January 2003
    Journal The Journal of Pharmacy and Pharmacology
    Excerpt

    This overview has attempted to highlight the brain regions associated with reward, and the pathways and neurotransmitters responsible for communication between these regions. Work conducted in this field has shown that stimulants and opioids, despite interactions with different receptor types and different neurotransmitter reuptake transporters, appear to share a common action on brain reward pathways. Their effects on these pathways (the distinct brain regions making up the mesocorticolimbic dopaminergic system) are predominantly mediated through changes in dopamine neurotransmission, and compounds aimed at selectively modulating these effects may form the basis of drugs to treat addiction. Other transmitters such as GABA, acetylcholine and serotonin inevitably have a role to play in reward, although at present the exact nature of their effects remains unclear. Diverging from manipulating the CNS directly as a management strategy for dependence, it might be possible to exploit the immune system to prevent administered psychostimulants penetrating the brain, but antibody saturation and specificity are problematic.

    Title Do Antidepressants Affect Motivation in Conditioned Place Preference?
    Date February 2001
    Journal European Journal of Pharmacology
    Excerpt

    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.

    Title Chest Compressions in an Infant with Osteogenesis Imperfecta Type Ii: No New Rib Fractures.
    Date December 2000
    Journal Pediatrics
    Excerpt

    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.

    Title Analgesic Doses of the Enkephalin Degrading Enzyme Inhibitor Rb 120 Do Not Have Discriminative Stimulus Properties.
    Date October 2000
    Journal European Journal of Pharmacology
    Excerpt

    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.

    Title Potentiation of Opioid-induced Conditioned Place Preference by the Selective Serotonin Reuptake Inhibitor Fluoxetine.
    Date May 2000
    Journal European Journal of Pharmacology
    Excerpt

    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.

    Title Detecting Drug Effects on Short-term Memory Function Using a Combined Delayed Matching and Non-matching to Position Task.
    Date April 2000
    Journal Journal of Pharmacological and Toxicological Methods
    Excerpt

    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.

    Title Do Alpha2-adrenoceptors Play an Integral Role in the Antinociceptive Mechanism of Action of Antidepressant Compounds?
    Date October 1999
    Journal European Journal of Pharmacology
    Excerpt

    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.

    Title The Involvement of Opioidergic and Noradrenergic Mechanisms in Nefopam Antinociception.
    Date April 1999
    Journal European Journal of Pharmacology
    Excerpt

    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.

    Title The Involvement of the Opioidergic System in the Antinociceptive Mechanism of Action of Antidepressant Compounds.
    Date October 1998
    Journal British Journal of Pharmacology
    Excerpt

    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.

    Title Sensitivity Differences to 5-ht and Carbachol in Subsections of the Isolated Rat Stomach Fundus Strip: an Improved Preparation.
    Date December 1996
    Journal Journal of Pharmacological and Toxicological Methods
    Excerpt

    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.

    Title Contrasting Actions of Acute or Chronic Paroxetine and Fluvoxamine on Morphine Withdrawal-induced Place Conditioning.
    Date August 1995
    Journal European Journal of Pharmacology
    Excerpt

    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.

    Title Inhibitors of Enkephalin-degrading Enzymes As Potential Therapeutic Agents.
    Date March 1994
    Journal Progress in Medicinal Chemistry
    Excerpt

    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.

    Title Novel Inhibitors of Enkephalin-degrading Enzymes. Iii: 4-carboxymethylamino-4-oxo-3 (phenylamino) Butanoic Acids As Enkephalinase Inhibitors.
    Date January 1994
    Journal Journal of Enzyme Inhibition
    Excerpt

    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.

    Title Novel Inhibitors of Enkephalin-degrading Enzymes. Iv: Structure-activity Relationships Within the Penicillins As Enkephalinase Inhibitors.
    Date May 1993
    Journal Journal of Enzyme Inhibition
    Excerpt

    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.

    Title Acute Effects of Beclamide on Brain Regional Monoamine Concentrations, Their Metabolites and Radioligand Binding Studies.
    Date November 1991
    Journal The Journal of Pharmacy and Pharmacology
    Excerpt

    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.

    Title Increased Dopamine Receptor Sensitivity in the Rat Following Acute Administration of Sufentanil, U50,488h and D-ala2-d-leu5-enkephalin.
    Date October 1991
    Journal Naunyn-schmiedeberg's Archives of Pharmacology
    Excerpt

    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.

    Title Novel Inhibitors of Enkephalin-degrading Enzymes. Ii: N5'-substituted-4-thioxohydantoic Acids As Aminopeptidase Inhibitors.
    Date May 1991
    Journal Journal of Enzyme Inhibition
    Excerpt

    Some 2-substituted-(2'-aminophenyl)-4-thioxohydantoic acids (o-amino PTC-amino acids) have antinociceptive activity when administered (icv) alone (IC50 = 0.04-0.87 microM/animal) and show a striking prolongation of the antinociceptive action of (D-Ala-2 D-Leu5)-enkephalin (DADL) in combination. The effects are thought to be mediated via opioid receptors since they are naloxone-reversible. Although inhibitors of the enkephalin degrading puromycin-insensitive, bestatin-sensitive aminopeptidase (possibly aminopeptidase M) their action is weak (IC50 = 32 microM leucine, 536 microM, glycine) and they might be considered to have a direct antinociceptive effect on opioid receptors. The titled compounds constitute novel 'lead' compounds for the development of potent aminopeptidase M inhibitors.

    Title Novel Inhibitors of Enkephalin-degrading Enzymes. I: Inhibitors of Enkephalinase by Penicillins.
    Date May 1991
    Journal Journal of Enzyme Inhibition
    Excerpt

    Several penicillins have been found to have pro-antinociceptive properties and also to be enkephalinase (neutral endopeptidase-24.11) inhibitors, carfecillin being the most potent. Carfecillin i.c.v. (but not i.p.) had significant antinociceptive activity in the mouse tail immersion test and completely suppressed abdominal constrictions (acetic acid) in mice (IC50 = 23 micrograms/animal). In combination with (D-Ala2-D-leu5)-enkephalin (DADL) i.c.v. in the abdominal constriction test the complete protection observed was reversed by the opioid receptor antagonist naltrexone. Carfecillin was a competitive inhibitor of enkephalinase from mouse brain striata (IC50 = 207 + 57 nM, cf thiorphan 10.6 +/- 1.9 nM) but did not inhibit other known enkephalin- degrading enzymes. Carfecillin provides a new lead structure for the development of more potent enkephalinase inhibitors.

    Title Comparison of the Inhibitory Action of Aminobeclamide and Beclamide on Socially Offensive Behaviour.
    Date January 1991
    Journal The Journal of Pharmacy and Pharmacology
    Excerpt

    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.

    Title Penicillins Exhibit Enkephalinase Inhibitory Activity in Mice.
    Date March 1990
    Journal Progress in Clinical and Biological Research
    Title 2-substituted-n5-(2'-aminophenyl)-4-thiohydantoic Acids As Aminopeptidase Inhibitors with Pro-antinociceptive Activity.
    Date March 1990
    Journal Progress in Clinical and Biological Research
    Title Possible Role for Endogenous Opiates in the Regulation of Food Intake in the Newborn Rat.
    Date March 1990
    Journal Archives Internationales De Pharmacodynamie Et De Thérapie
    Excerpt

    The possible role of endogenous opiates in the regulation of food intake was investigated by studying their influence on body weight of rat pups. Subcutaneous injection of the opiate antagonist Mr 1452 to non-deprived 1 day old rats (1-4 mg/kg) and 1.5 hr deprived 5 day old rats (2-8 mg/kg) inhibited feeding. Its stereoisomer Mr 1453 increased intake when injected to nondeprived 1 day old rats (1-4 mg/kg), but was ineffective in altering feeding behavior in 1.5 hr deprived 5 day old rats (2-8 mg/kg). Subcutaneous injection of another opiate antagonist, levallorphan (6 and 9 mg/kg), to 3 hr deprived rats also decreased intake, while its stereoisomer dextrallorphan (3-9 mg/kg) was inactive in the same experimental conditions. Subcutaneous injection of the opiate agonist met5enkephalin (16 and 32 mg/kg) to 1.5 hr deprived 5 day old rats increased feeding but leu5enkephalin (8 and 16 mg/kg) did not alter feeding behavior in the same condition. Taken together, these findings suggest a role for endogenous opiates in the facilitation of feeding in the newborn rat.

    Title Evaluation of Selective Actions of Dopamine D-1 and D-2 Receptor Agonists and Antagonists on Opioid Antinociception.
    Date January 1990
    Journal European Journal of Pharmacology
    Excerpt

    The effect of the selective dopamine receptor agonists SKF 38393 (D-1) and quinpirole (D-2) on nociception was studied in the mouse tail immersion test. The D-1 receptor agonist induced mild hyperalgesia whereas the D-2 agonist produced antinociception. Pretreatment with either the selective D-1 receptor antagonist SCH 23390 or the D-2 receptor antagonist (-)-sulpiride converted the hyperalgesia produced by the D-1 agonist into an antinociceptive response whereas the effect of the D-2 receptor agonist was significantly antagonised. The antinociceptive response of selective opioid agonists was also studied in combination with selective dopamine receptor agonists and antagonists. Sufentanil (mu-opioid) antinociception was enhanced in animals pretreated with (-)-sulpiride but not SCH 23390. In animals co-administered sufentanil with SKF 38393 there was a reduced antinociceptive effect whilst quinpirole enhanced the action of sufentanil. Likewise, antinociception induced by the kappa-opioid agonist U50,488H was unaltered in animals pretreated with SCH 23390, increased by (-)-sulpiride, and reduced by SKF 38393. delta-Opioid antinociception induced by [D-Ala2,D-Leu5]enkephaline remained unmodified following pretreatment with either (-)-sulpiride or SCH 23390 but was potentiated in animals which received both the delta-agonist and the D-2 receptor agonist. It is concluded that D-2 receptor agonists not only have intrinsic antinociceptive activity, but can also potentiate opioid-induced antinociception. Similarly, dopamine D-2 receptor antagonists appear to potentiate opioid-induced antinociception in this nociceptive model.

    Title Anaesthetic Influences on Brain Haemodynamics in the Rat and Their Significance to Biochemical, Neuropharmacological and Drug Disposition Studies.
    Date September 1989
    Journal Biochemical Pharmacology
    Title Effects of Beclamide on Isolation-induced Aggression and Locomotor Activity in Mice.
    Date June 1989
    Journal The Journal of Pharmacy and Pharmacology
    Excerpt

    The anti-aggressive effects of orally administered beclamide (N-Benzyl-beta-chloropropionamide) have been studied in male albino mice which were individually isolated for a 28-day period. Beclamide (50-250 mg kg-1 p.o.) caused an overall dose-dependent increase in the attack onset latency, a reduction in the percentage of animals attacking and the mean number of attacks/animal for this model of aggression. In addition, the highest dose of beclamide (250 mg kg-1 p.o.) did not significantly modify locomotor activity in mice. It was concluded that beclamide induced anti-aggressive effects at non-sedative doses. This anti-aggressive action was thought be at least partially mediated, through a beclamide-induced release of 5-HT from presynaptic sites.

    Title Dopamine-mediated Behaviour Following Chronic Treatment with B-ht 920.
    Date February 1989
    Journal The Journal of Pharmacy and Pharmacology
    Excerpt

    Following subchronic (5-day) dosing with B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo(4,5-d)azepine (1 mg kg-1 day-1 i.p.) in rats there was a significant increase in both apomorphine-induced motor activity and stereotypy. On continued B-HT 920 treatment, however, the enhancement of apomorphine motor activity faded into insignificance but the increase in stereotypy persisted beyond 15 days. The results are discussed in terms of dopamine autoreceptor tolerance, postsynaptic D2 supersensitivity and possible differential effects in different brain loci on the above two receptor sub-classes.

    Title Amelioration of Naloxone-precipitated Opioid Withdrawal Symptoms by Peripheral Administration of the Enkephalinase Inhibitor Acetorphan.
    Date July 1988
    Journal Psychopharmacology
    Excerpt

    The effects of 60 min pretreatment with the enkephalinase inhibitor acetorphan were assessed on naloxone-precipitated (2.5 mg/kg IP) abstinence in chronically morphinized rats. In addition, the antinociceptive activity of the compound was investigated in mice. Intraperitoneal injection (50 mg/kg) in rats attenuated some aspects of the opioid withdrawal syndrome such as burrowing, wet dog shakes, squeal on touch hostility, tachypnoea, ptosis and rough hair, whereas jumping and escape behaviour were significantly increased in acetorphan-treated animals. No effect was observed on withdrawal hypothermia or acute weight loss. Similarly, chronic dosing with acetorphan after withdrawal produced no significant effect on body weight. Acetorphan (50 mg/kg IP) failed to produce any antinociceptive activity in the mouse tail immersion test, but potentiated the antinociceptive effect of D-Ala2-D-Leu5-enkephalin. These results are discussed in terms of acetorphan crossing the blood-brain barrier before being hydrolysed to thiorphan, thus yielding opioid withdrawal relieving effects.

    Title Effects of Beta-phenylethylamine on Locomotor Activity, Body Temperature and Ethanol Blood Concentrations During Acute Ethanol Intoxication.
    Date October 1987
    Journal Psychopharmacology
    Excerpt

    Beta-phenylethylamine (PEA) is an endogenous amine which is metabolised by MAO B. The function of this enzyme is known to be modified by ethanol so we have studied the interactions of PEA with ethanol. Rectal temperatures of rats were determined and animals pretreated with ethanol (2.5 g kg-1 IP) 90 min before PEA 20, 40, 100 mg kg-1 IP). Spontaneous locomotor activity (SLA) was then recorded, for 30 min, temperatures redetermined and blood ethanol levels evaluated. PEA increased SLA but did not alter rectal temperatures, and at 40 mg kg-1 it not only attenuated ethanol hypothermia and blood levels but also modified ethanol hypomotility. The highest dose of PEA (100 mg kg-1) decreased blood ethanol concentration and sedation but did not counteract the hypothermia. Thus PEA increased ethanol clearance, though the underlying mechanism is not totally clear. This finding is discussed in relation to its catecholaminergic and enzyme inducing characteristics.

    Title Dopamine Receptor-mediated Spinal Antinociception in the Normal and Haloperidol Pretreated Rat: Effects of Sulpiride and Sch 23390.
    Date April 1987
    Journal British Journal of Pharmacology
    Excerpt

    Nociceptive tail flick latencies (TFL) were recorded in response to noxious thermal stimuli applied to lightly anaesthetized rats. The effects of intrathecally administered dopamine receptor agonists alone and combined with dopamine receptor antagonists were examined upon the TFL. Experiments were repeated on animals made supersensitive to dopamine following withdrawal from 28 day administration of haloperidol. In untreated animals the D2-receptor agonist LY 171555 and apomorphine produced an increase in TFL. In contrast, the Di-receptor agonist SKF 38393 had no significant effect on TFL. TFL. Following haloperidol-induced dopamine-supersensitivity, SKF 38393 produced an increase in TFL. In contrast, LY171555 and apomorphine had minimal effects on TFL in this preparation. In animals not treated with haloperidol, the dopamine receptor antagonists SCH 23390 and (+/-)-sulpiride both blocked the increase in TFL produced by the D2-agonists. SCH23390 and (+/-)-sulpiride also blocked the increase in TFL produced by SKF 38393 in haloperidol-supersensitized animals. The antinociceptive action of intrathecally administered dopamine agonists appears to be mediated via D2-receptors. Whether the antinociception produced by SKF 38393 is exclusively contingent upon the activation of D1-receptors in the dopamine-supersensitive animal is as yet unresolved.

    Title Synthesis and Antinociceptive Properties of a Series of Exo- and Endo-6-hydroxy-2-aminobenzonorbornenes.
    Date February 1987
    Journal Journal of Pharmaceutical Sciences
    Excerpt

    A series of 6-hydroxy endo- and exo-derivatives of 2-aminobenzonorbornene has been synthesized and evaluated for antinociceptive activity in the mouse. The results indicated a stereospecific effect in the antinociceptive responses exhibited by the two isomeric groups of compounds. The exo-amines 10a-10c were inactive in both the tail immersion and tail clip tests. The corresponding endo-isomers exhibited antinociceptive properties; 4a was the most active compound tested but was toxic at the dose administered.

    Title Hyperphagia Induced by 2-deoxy-d-glucose in the Presence of the Delta-opioid Antagonist Ici 174,864.
    Date October 1986
    Journal Neuropharmacology
    Excerpt

    The effect of the selective delta-opioid antagonist ICI 174,864 (N,N-bisallyl-Tyr-Aib-Aib-Phe-Leu-OH: Aib=alpha-aminoisobutyric acid) on the hyperphagia induced by 2-deoxy-D-glucose (2-DG) was investigated in non-deprived rats. The increase in food intake produced by 2-DG (500 mg/kg i.p.) was not reduced by ICI 174,864 at a dose (3 micrograms/rat i.c.v.) which totally abolished the feeding response to the delta-agonist D-Ala2-D-Leu5-enkephalin (10 micrograms/rat i.c.v.). These findings suggest that the appetitive effects of 2-DG are not mediated by an enkephalinergic/delta-receptor system. They do not, however, preclude the possible involvement of endogenous opioids acting at other sub-types of opioid receptor in this glucoprivic ingestional response, which is suppressed by less specific opioid antagonists such as naloxone.

    Title Dopamine D2 Receptors and Sch 23390 Treatment.
    Date October 1986
    Journal Lancet
    Title Characterization of the Effects of (+/-)-meptazinol, Its Individual Enantiomers and N-methyl Meptazinol on Food Consumption in the Rat.
    Date September 1986
    Journal British Journal of Pharmacology
    Excerpt

    Both (+/-)-meptazinol (2 mg kg-1) and levorphanol (1 mg kg-1) produced hyperphagia over a 4 h period after intraperitoneal injection in free feeding rats during the daylight phase. The individual (+)- and (-)-enantiomers of meptazinol (2 mg kg-1 i.p.) induced comparable increases in cumulative food intake. N-methyl meptazinol (2-10 mg kg-1 i.p.), the quaternary analogue of meptazinol, produced no modification of food intake though it increased food consumption when injected intracerebroventricularly (10-100 micrograms per animal). Meptazinol and levorphanol hyperphagia was abolished by 1 mg kg-1 doses (i.p.) of the opioid antagonists naltrexone, naloxonazine and (-)-Mr 1452 but not by its (+)-enantiomer Mr 1453 which is not effective as an opioid antagonist. Intracerebroventricular administration of the delta-opioid antagonist ICI 154,129 (10 micrograms per animal) suppressed meptazinol but not levorphanol hyperphagia. It was concluded that meptazinol produces centrally mediated stereospecifically reversible hyperphagia through a mu-opioid receptor mechanism common to levorphanol, and also through delta-opioid receptor mechanism(s).

    Title Are Delta-opioid Receptors Involved in the Regulation of Food and Water Intake?
    Date November 1985
    Journal Neuropharmacology
    Excerpt

    The effect of the delta-opioid antagonists ICI 154,129 (1-100 micrograms, i.c.v.) and ICI 174,864 (1-100 micrograms, i.c.v.) and of the delta-agonist D-Ala2-D-Leu5-enkephalin (DADL; 1-10 micrograms, i.c.v.) on the intake of food and water of non-deprived rats was investigated. Animals treated with either ICI 154,129 or ICI 174,864 ate and drank significantly less than vehicle-treated controls over a 3 hr test period. The suppressant effects of these peptides on appetite were similar to those observed with the more commonly-used opioid antagonists, naltrexone and Mr 2266. In contrast, the delta-agonist DADL produced an increase in both the consumption of food and water in the 3 hr following administration of drug. The findings presented in this study lend further support to the hypothesis that an endogenous enkephalin/delta-receptor system may play a role in the tonic induction of ingestive behaviour.

    Title Subacute Benzodiazepine Treatment: Observations on Behavioural Tolerance and Withdrawal.
    Date June 1985
    Journal Alcohol and Alcoholism (oxford, Oxfordshire)
    Excerpt

    The acute and subchronic actions of the benzodiazepines triazolam, oxazepam and diazepam have been examined using three behavioural tests. In the accelerating rotarod motor coordination test both diazepam and oxazepam on acute administration produced dose-related discoordination or motor impairment in mice. After chronic administration (50 mg/kg per day i.p. for 14 days) the corresponding dose-response lines were shifted to the right suggesting tolerance development. In a test for conflict behaviour in rats (conditioned suppression of drinking) oxazepam (20 mg/kg i.p.), triazolam (1 mg/kg i.p.) and diazepam (10 mg/kg i.p.) all augmented punished responding rates with no effect on unpunished responses and this has been speculated to reflect anxiolytic activity. These initial elevations in punished responding displayed a gradual decline during repeated daily administration over 20 days, there being little alteration in the unpunished response levels. In separate studies, chronic treatment of mice with triazolam in the drinking water over 30 days showed diminished pentylenetetrazol-induced seizure latencies compared to the level of protection afforded by triazolam at the beginning of the schedule. In additional experiments, mice injected daily with triazolam (1 mg/kg i.p. for 14 days) exhibited a higher seizure susceptibility than their corresponding controls. The results are discussed in relation to tolerance to the anxiolytic, anticonvulsant and neurological impairment properties of benzodiazepines.

    Title Meptazinol Activity on Morphine-naive and Morphine-dependent Guinea-pig Ileum: Correlation with in Vivo Studies.
    Date June 1985
    Journal Alcohol and Alcoholism (oxford, Oxfordshire)
    Excerpt

    The effects of meptazinol and some opioid agonists and antagonists were studied on opioid-naive guinea-pig ileum (GPIN) and ileum taken from morphine-dependent guinea-pigs (GPID). Meptazinol produced a biphasic effect in GPIN and GPID with a depression of the electrically induced twitch response at lower concentrations and contractural potentiation at higher concentrations. The effects of meptazinol in both GPIN and GPID were similar, thus distinguishing it from the other opioid agonists and antagonists which produced differential effects on these tissues. In morphine-pelletted rats, meptazinol (5 mg/kg i.p.) did not produce notable withdrawal as measured by behavioural observation. However, meptazinol (30 mg/kg i.p.) enhanced the signs associated with cholinergic activation. It is suggested that meptazinol possesses a cholinergic component and that the morphine-withdrawal signs observed to the higher meptazinol dose were more probably attributable to cholinergic stimulation rather than any underlying opioid-precipitated withdrawal.

    Title Benzodiazepines Produce Contrasting Effects on the Active Membrane Properties of an Invertebrate Neuron.
    Date June 1985
    Journal Neuropharmacology
    Excerpt

    A perturbation of excitable membranes mediated by non-receptor (non-specific) mechanisms might be predicted from the hydrophobic nature of 1,4-benzodiazepines. Since correlations between membrane properties and neuronal effects have not been described for benzodiazepines, the effects of flurazepam, oxazepam and the benzodiazepine antagonist flumazepil (Ro 15-1788) were examined on both passive and active electrical properties of the membrane and neuronal discharge frequency. In this study, the isolated sensory neuron of the crayfish has been utilized as a neuronal model system. Flurazepam and flumazepil both enhanced the discharge frequency, in contrast to the depression produced by oxazepam. Discharge frequency was directly correlated with the maximum rate of rise of membrane potential during the threshold phase and was inversely correlated with spike threshold. In addition, the discharge frequency appeared to exhibit little dependence on peak amplitude, duration and the maximum rate of depolarization of the action potential. These findings are discussed in relation to non-specific mechanism(s) of action for benzodiazepines. It is suggested that, in the absence of a specific drug-receptor interaction, benzodiazepines in larger concentrations (greater than or equal to 50 mumol/l) exhibit selective membrane perturbations.

    Title Involvement of Endogenous Enkephalins in the Feeding Response to Diazepam.
    Date May 1985
    Journal European Journal of Pharmacology
    Excerpt

    The effect of the delta-opioid agonist [D-Ala2,D-Leu5]enkephalin (DADLE) and the benzodiazepine diazepam on the food intake of non-deprived rats was investigated. Both compounds produced a significant increase in feeding. The hyperphagic response to DADLE (10 micrograms i.c.v.) and diazepam (1 mg/kg i.p.) was suppressed by concurrent treatment with the selective delta-opioid antagonist ICI 154,129 (10 micrograms i.c.v.). These findings add further support to the concept that endogenous enkephalins may be implicated in the stimulatory effects of benzodiazepines on ingestive behaviour.

    Title Meptazinol Cross-tolerance Studies Between Morphine or Oxotremorine.
    Date April 1985
    Journal Neuropeptides
    Excerpt

    The time course of the development of auto-tolerance to meptazinol as determined by combined heat and pressure nociceptive tests has been examined using two dose levels of meptazinol (10 mg and 30 mgkg-1s.c.) corresponding to the partial agonist and cholinergic components respectively. In mice treated twice daily with meptazinol for eight days, there was cross tolerance to morphine in both tests at each dose level of meptazinol. In chronic morphine treated mice challenged with meptazinol (30 mg kg-1 s.c.), there was no cross tolerance with morphine since meptazinol still retained its antinociceptive effects in both tests. Mice treated chronically with meptazinol (30 mgkg-1 s.c.) did not respond to the cholinomimetic agent oxotremorine, implying that there was cross tolerance between these two analgesics. These data suggest the existence of a one-way tolerance between morphine and meptazinol whilst at higher doses of meptazinol a full tolerance occurs with oxotremorine.

    Title The Role of Opioid Receptor Sub-types in Tifluadom-induced Feeding.
    Date January 1985
    Journal The Journal of Pharmacy and Pharmacology
    Excerpt

    There is now considerable evidence that opioid agonists and benzodiazepines increase food and water intake in a variety of animal species. The appetitive effects of the novel opioid-benzodiazepine tifluadom have been investigated. (+/-)-Tifluadom significantly increased food intake in freely-feeding rats. This stimulation of appetite was attributable principally to the activity of the (+)-isomer. Furthermore tifluadom-induced feeding was blocked by the opioid antagonists naloxone, naltrexone, Mr 1452 and Mr 2266 but not by the delta-opioid receptor antagonist ICI 154, 129, or by the benzodiazepine antagonist Ro 15-1788. These results suggest that tifluadom exerts its effect on food intake by interaction with opioid as opposed to benzodiazepine receptors and that this activity is mediated by kappa and/or mu- rather than delta-opioid receptor sub-types.

    Title The Involvement of Mu- and Kappa- but Not Delta-opioid Receptors in the Body Weight Gain of Suckling Rats.
    Date December 1984
    Journal Psychopharmacology
    Excerpt

    The effects of the benzomorphan antagonist Mr 2266 and the selective delta-antagonist ICI 154,129 on the body weight gain of 6-day-old suckling rat pups was observed. Mr 2266 significantly reduced body weight gain in these animals, though ICI 154,129 had no affect on this variable. These findings suggest that mu- and kappa- but probably not delta-opioid receptors are involved in the regulation of ingestive behaviours in infant rats. The results are discussed in relation to the development of opioid-receptor subtypes in the neonatal rat brain.

    Title Synaptic and Non-synaptic Actions of Benzodiazepines on the Crayfish Sensory Neuron.
    Date November 1984
    Journal European Journal of Pharmacology
    Excerpt

    On the stretch-induced discharge activity of the isolated crayfish sensory neuron flurazepam (less than or equal to 3 X 10(-4) M) and Ro 15-1788 (less than or equal to 10(-3) M) produced reversible concentration-dependent excitation, but oxazepam only produced depression (less than or equal to 5 X 10(-4) M). Similar divergent effects on the membrane properties were observed. Oxazepam increased the threshold to firing without changing resting potential, membrane resistance or the GABA-mediated IPSP. In contrast flurazepam and Ro 15-1788 produced a concentration-dependent decrease in threshold. Flurazepam did not alter membrane resistance or resting potential but facilitated GABA transmission. Ro 15-1788 had the opposite effect on the GABA synapse, and also depolarized the resting potential but did not alter membrane resistance. The change in spike threshold appeared to be an important component in producing discharge excitation or depression. These results not only demonstrate the capability of the sensory neuron to discriminate between structures of benzodiazepines, but also that these agents can produce divergent effects on synaptic and non-synaptic properties of a single neuron.

    Title Comparison of the Relative Effects of Aspirin, Mefenamic Acid, Dihydrocodeine, Dextropropoxyphene and Paracetamol on Visceral Pain, Respiratory Rate and Prostaglandin Biosynthesis.
    Date June 1984
    Journal Archives Internationales De Pharmacodynamie Et De Thérapie
    Excerpt

    A comparison was made between the relative effects of aspirin, mefenamic acid, dihydrocodeine , dextropropoxyphene and paracetamol on visceral pain (chemically-inducing writhing), respiratory rate and prostaglandin (PG) biosynthesis (cyclo-oxygenase activity). A close correlation was found to exist between inhibition of PG biosynthesis and inhibition of visceral pain for mefenamic acid, aspirin and paracetamol. Analysis of the complete activity profiles derived from evaluation of the test parameters yielded the following rank order of overall ratios of their beneficial anti-writhing/anti-cyclo-oxygenase to respiratory depressive activities: (1) mefenamic acid, (2) aspirin, (3) dihydrocodeine , (4) dextropropoxyphene and paracetamol.

    Title Evidence for Excitatory and Depressant Non-receptor-mediated Membrane Effects of Benzodiazepines in the Crayfish.
    Date June 1984
    Journal Neuroscience Letters
    Excerpt

    Oxazepam produced a significant reversible monophasic concentration-dependent (50-500 mumol/l) depression of stretch-induced discharge frequency of the isolated crayfish sensory neuron. In total contrast, flurazepam (10-200 mumol/l) evoked reversible excitation of the neuronal firing rate but at concentrations greater than 300 mumol/l it induced transient excitation followed by secondary total depression. The benzodiazepine antagonist flumazepil (less than or equal to 1 mmol/l) also produced an inherent increase in neuronal discharge frequency, though respective concentrations of 50 and 100 mumol/l failed to block flurazepam-excitation or oxazepam-depression. It is suggested that these high concentration qualitatively divergent neuronal effects are not mediated through specific benzodiazepine receptors.

    Title Differential Effects of Skf 38393 and Ly 141865 on Nociception and Morphine Analgesia.
    Date March 1984
    Journal Life Sciences
    Excerpt

    The effects of SKF 38393 and LY 141865 on nociceptive sensitivity and morphine-induced analgesia were compared. SKF 38393 administered to mice either peripherally or centrally was without effect on either base line response latencies or morphine's analgesia. By contrast, s.c. injections of LY 141865 resulted in a dose-related hyperalgesia. A paradoxical analgesia was observed when LY 141865 was given intracerebroventricularly. Both the analgesia and hyperalgesia were antagonized by sulpiride but remained unaffected by the opioid antagonist Mr-1452. Central and peripheral pretreatment with LY 141865 resulted in respective enhancement and attenuation in the analgesic activity of morphine. The present results would indicate that D-2 receptors may be involved in nociception and analgesic mechanisms. In addition it suggests that D-2 receptors may exert both inhibitory and facilitatory influences on nociceptive and analgesic mechanisms.

    Title Characterization of a Kappa-agonist-like Antinociceptive Action of Tifluadom.
    Date January 1984
    Journal Neuropharmacology
    Excerpt

    The novel benzodiazepine tifluadom was compared with a selection of proposed mu- and kappa-opiate agonists using a combined heat/pressure nociceptive paradigm. Calculation of the relative potency ratios to the nociceptive stimuli revealed a distinction between mu- and kappa-agonists. The potency ratio yielded by tifluadom coincided with that displayed by the kappa-agonists and this finding is discussed in relation to morphine withdrawal and radioligand binding studies.

    Title Effects of Elevated Calcium and Calcium Antagonists on 6,7-benzomorphan-induced Analgesia.
    Date October 1983
    Journal European Journal of Pharmacology
    Excerpt

    The hypothesis that the nociceptive state and opiate-induced antinociception are generally regulated by Ca2+ brain levels has been tested. In this context, the effects of intracerebroventricular injections of CaCl2 (0.1-0.5 mumol), D600 (5.0-10.0 micrograms) and EGTA (0.5-1.0 mumol) on ethylketocyclazocine (EKC), ketocyclazocine (KC), Mr-2033, pentazocine (PTC), bremazocine (BMC) and SKF 10,047-induced antinociception were investigated in the mouse tail immersion test. Simultaneous treatment with either D600 or EGTA resulted in a significant and dose-related enhancement in the activities of the kappa-agonists: EKC, KC and Mr-2033, whilst the activities of PTC, BMC and SKF 10,047 remained unchanged. CaCl2 readily blocked the activities of all benzomorphans tested except that of SKF 10,047 against which CaCl2 was less effective. In addition a dose-related hyperalgesia was observed when CaCl2 was given alone. Although the results obtained from the kappa-agonists and CaCl2 per se support the hypothesis in question, data obtained from PTC, BMC and SKF 10,047 tends to oppose it. Additionally the present results taken together indirectly substantiate the notion that benzomorphan-induced analgesia may involve different opiate-sensitive neuronal substrates.

    Title Analgesic Actions of Mu- and Kappa-opiate Agonists in Rats.
    Date August 1983
    Journal Archives Internationales De Pharmacodynamie Et De Thérapie
    Excerpt

    The antinociceptive profiles of mu- and kappa-opiate agonists were determined in a combined tail immersion plus tail pressure nociceptive test in rats. Combined analysis of potencies for pressure against heat noxia enabled differentiation between all mu- and kappa-agonists tested, thus confirming previous studies in other animal species and paralleling observations from studies on isolated tissue preparations. The distinct antinociceptive profiles produced by mu- and kappa-agonists provide further quantitative evidence that these agents are behaviourally different.

    Title Meptazinol in Jarisch-herxheimer Reaction.
    Date July 1983
    Journal Lancet
    Title Inhibition of Alpha-chymotrypsin by 5-substituted -3-phenyl-2-thioxo-4-imidazolidinones and Derivatives.
    Date February 1983
    Journal The Journal of Pharmacy and Pharmacology
    Title Stereospecific Inhibition of Oxotremorine-induced Antinociception by (+)-isomers of Opioid Antagonists: Comparison with Opioid Receptor Agonists.
    Date December 1982
    Journal The Journal of Pharmacy and Pharmacology
    Excerpt

    The antagonistic effects of the two benzomorphan opioid antagonists, Mr-1452 and Mr-2266 and their respective (+)-isomers Mr-1453 and Mr-2267 upon morphine, ethylketocyclazocine (EKC), D-ala2-D-leu5-enkephalinamide (BW 180-C) and oxotremorine (OTMN) antinociceptive activity in mice were investigated. Pretreatment with either Mr-1452 (2.0 mg Kg-1 i.p.) or Mr-2266 (2.0 mg kg-1 i.p.) significantly antagonized the antinociceptive effects of the three opioid agonists in the hot plate test, but were ineffective against OTMN, which in contrast was antagonized by the (+)-isomers. Interaction between the antagonists and submaximal analgesic doses of the opioids or OTMN produced similar results in the tail immersion assay. However, the effect of Mr-2267 on OTMN was biphasic and this contrasted with Mr-1453 which produced consistent and graded antagonism.

    Title Some Observations on the Effects of Enantiomers of Two Benzomorphan Narcotic Antagonists and Atropine on Analgesia, Tremor and Hypothermia Produced by Oxotremorine.
    Date September 1982
    Journal Archives Internationales De Pharmacodynamie Et De Thérapie
    Excerpt

    The action of the benzomorphan narcotic antagonists Mr-1452 and Mr-2266 and their respective (+) isomers Mr-1453 and Mr-2267 as well as the antimuscarinic agent atropine upon oxotremorine (OTMN)-induced analgesia, tremor, and hypothermia were investigated in mice. The (+) isomers Mr-1453 (1.0 mg kg-1 i.p.) and Mr-2267 (2.0 mg kg-1 i.p.), but not the (-) isomers (Mr-1452 and Mr-2266) in doses up to 2.0 mg kg-1 i.p. after 30 min pretreatment produced a significant and parallel shift in OTMN's analgesic dose-response line, assessed by the hot plate test (55 degrees C). None of the isomers tested produced any significant change in OTMN induced tremor or hypothermia. This contrasted with atropine (0.5 mg kg-1 i.p.) which antagonized all three pharmacological parameters. The present data indicate that OTMN-induced analgesia in mice may involve a neuronal substrate which, at least partly, differs from those subserving tremor and hypothermia. In addition it supports the notion that cholinergic analgesia exhibits stereospecific sensitivity to the (+) isomers of narcotic antagonists.

    Title Stereoselective Opiate Antagonist Induced Hyperalgesia: Evidence for a Dopaminergic Involvement.
    Date August 1982
    Journal The Journal of Pharmacy and Pharmacology
    Title Differentiation of Potent Mu and Kappa-opiate Agonists Using Heat and Pressure Antinociceptive Profiles and Combined Potency Analysis.
    Date July 1982
    Journal European Journal of Pharmacology
    Excerpt

    The antinociceptive profiles of strong mu- and kappa-opiate agonists were determined in the tail clip, hot plate (55 degrees C) and tail immersion (48 degrees C and 55 degrees C) tests in mice. All mu- and kappa-agonists produced steep dose-response lines in all the tests. Using a combined analysis of potencies for pressure against heat noxia it was possible to differentiate between mu- and kappa-agonists and this paralleled findings in other laboratories using isolated tissue preparations. It was also concluded that qualitative rather than quantitative differences between noxia were responsible for the observed differentiation since potency differences for mu- and kappa-agonists between tests were maintained even after the intensity of heat and pressure noxia were equated. It was also proposed that use of the combined tail clip and immersion tests may be useful for rapid behavioural classification of novel synthetic mu- and kappa-opiate analgesics.

    Title Evidence for Central Selective Dopamine Receptor Stimulation in the Mediation of Nomifensine-induced Hyperalgesia and the Effects of Opiate Antagonists.
    Date March 1982
    Journal Neuropharmacology
    Title Centrally-mediated Hyperalgesia in Mice Produced by the Antimuscarinic Agents Atropine and Hyoscine.
    Date October 1981
    Journal The Journal of Pharmacy and Pharmacology
    Title Modification of Convulsive Behaviour and Body Temperature in Mice by Intracerebroventricular Administration of Prostaglandins, Arachidonic Acid and the Soluble Acetylsalicylic Acid Salt Lysine Acetylsalicylate.
    Date October 1981
    Journal Archives Internationales De Pharmacodynamie Et De Thérapie
    Excerpt

    The effects of centrally injected prostaglandins (PGE1 and PGF2 alpha), arachidonic acid and lysine acetylsalicylate were examined on the seizure activity and temperature changes produced by pentylentetrazole (PTZ) and also on maximal electroshock (MES) seizures. PGE1 antagonised both PTZ and MES seizures whilst PGF2 alpha had the reverse effect. In addition both PGs alone produced hyperthermia but attenuated PTZ hypothermia. Arachidonic acid protected against PTZ--but potentiated MES--seizures whilst lysine acetylsalicylate augmented the effects of both convulsive stimuli. Lysine acetylsalicylate and arachidonic acid alone were transiently hyperthermic and also antagonised PTZ hypothermia though the total net effect may have been due to a functional antagonism. It is suggested from these findings that PGE1 has anticonvulsant effects whilst PGF2 alpha promotes seizures neither of these properties correlating with thermoregulatory actions.

    Title Dopaminergic Involvement in the Hyperalgesic Effect of Nomifensine.
    Date June 1981
    Journal Life Sciences
    Title Antinociceptive Activity of Opiates in the Presence of the Antidepressant Agent Nomifensine.
    Date October 1980
    Journal Neuropharmacology
    Title Opiate Receptors, Endorphins and Drug Therapy.
    Date September 1980
    Journal Postgraduate Medical Journal
    Excerpt

    A number of opioid peptides isolated from brain and peripheral tissue have been identified, and several types of opiate receptor postulated for these endogenous substances. In this study the effects of pharmacological manipulation of 5-hydroxytryptamine (5-HT) on the antinociceptive activity of morphine and two synthetic enkephalin analogus (D-ala2-leu-enkephalin and D-ala2-met-enkephalin) were investigated in mice and rats. Centrally injected 5-HT and peripheral clomipramine pretreatment potentiated both morphine and synthetic enkephalin analgesia whilst peripheral doses of cyproheptidine, lesions in the dorsal medial raphe (DMR) and reserpine pretreatment attenuated opioid analgesia. In the reserpine-pretreated group, centrally injected 5-HT restored the antinociceptive activity of morphine and D-ala2-leu-enkephalin. These results are discussed with respect to clomipramine therapy.

    Title Antagonism of 2-deoxy-d-glucose-induced Hyperphagia by Naloxone: Possible Involvement of Endorphins.
    Date July 1980
    Journal The Journal of Pharmacy and Pharmacology
    Title Antinociceptive Activity of D-ala2-d-leu5-enkephalin (bw 180c) in the Rat After Modification to Central 5-hydroxytryptamine Function.
    Date December 1979
    Journal Neuropharmacology
    Title The Role of Biogenic Agents in the Actions of Centrally-acting Analgesics.
    Date May 1978
    Journal Progress in Medicinal Chemistry
    Title Importance of 5-hydroxytryptamine in the Antinociceptive Activity of the Leucine-enkephalin Derivative, D-ala2-leu5-enkephalin (bw 180c), in the Rat.
    Date March 1978
    Journal European Journal of Pharmacology
    Title Antinociceptive Activitiy of Narcotic Agonist and Partial Agonist Analgesics and Other Agents in the Tail-immersion Test in Mice and Rats.
    Date February 1977
    Journal Neuropharmacology
    Title Anti-nociceptive Activity of Narcotic Agonists and Partial Agonists in Mice Given Biogenic Amines by Intracerebroventricular Injection.
    Date November 1975
    Journal Psychopharmacologia
    Excerpt

    Using a tail immersion technique in mice, the anti-nociceptive activity of some narcotic agonists (diamorphine, etorphine, morphine and pethidine), partial agonists (cyclazocine, nalorphine and pentazocine) and naloxone have been determined alone, and after the intracerbroventricular (ICV) injection of 5-hydroxytryptamine (5-HT) or noradrenaline (NA). In common with morphine, the anti-nociceptive effects of each agonist and partial agonist studied were significantly increased by ICV 5-HT, and significantly attenuated by ICV NA. The marginal anti-nociceptive activity of naloxone was not significantly affected by the ICV injection of either amine. It is concluded that the anti-nociceptive effects of all narcotic agonist and partial agonist agents are determined by the balance within the brain of the activities of the two amines, 5-HT and NA.

    Title Proceedings: Antinociceptive Activity in Mice After Central Injections of Alpha-and Beta-adrenoceptor Antagonists.
    Date October 1975
    Journal British Journal of Pharmacology
    Title Proceedings: Biogenic Amines and the Anti-nociceptive Activity of Agents with a Non-opiate-structure.
    Date September 1975
    Journal The Journal of Pharmacy and Pharmacology
    Title Proceedings: Modification of the Antinociceptive Activity of Narcotic Agonists and Antagonists by Intraventricular Injection of Biogenic Amines in Mice.
    Date April 1975
    Journal British Journal of Pharmacology

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