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Biomedical subjects

A Cowan

Publications and source records attributed to A Cowan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Aspartic acid conjugates of 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1(3-aminophenyl)-2-(1-pyrrolidi nyl) ethyl]acetamide: kappa opioid receptor agonists with limited access to the central nervous system.

Aspartic acid conjugates of 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-aminophenyl)-2-(1-pyrrol idinyl) ethyl]acetamide (5) were synthesized and evaluated in mice for antinociceptive activity by intravenous and intracerebroventricular routes of administration. The intravenously-administered alpha-conjugate of L-Asp (2), its D-Asp diastereomer (3), and the beta -conjugate of L-Asp (4) were found to be 11-, 31-, and 40-fold, respectively, less effective than the parent ligand 1 (ICI 199,441) in producing central nervous system mediated antinociception in the mouse abdominal stretch assay. In addition, iv-administered 2 and 3 were found to also produce potent antinociception in the tonic phase of the mouse formalin assay, which is a model of tonic rather than acute pain. This study suggests that the attachment of a zwitterionic moiety to a position in the molecule that exhibits bulk tolerance is a viable strategy for the design of peripherally-selective and peripherally-active opioids.

Animals↗
PubMed1996

Pharmacological profiles of two bombesin analogues in cells transfected with human neuromedin B receptors.

We examined the effect of two des-Met-bombesin analogues, [(CH3)2CHCO-His-Trp-Ala-Val-D-Ala-His-Leu-NHCH3] (ICI 216140) and [D-Phe6,des-Met14]bombesin(6-14) ethylamide (DPDM-bombesin ethylamide), on neuromedin B-induced Ca2+ and [3H]arachidonate release in BALB 3T3 cells transfected with human neuromedin B receptors. ICI 216140 and DPDM-bombesin ethylamide both stimulated Ca2+ mobilisation in a concentration-dependent manner but were less potent and efficacious than neuromedin B. BIM 23042 [D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2], a selective neuromedin B antagonist and [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, a broad-spectrum peptide receptor antagonist inhibited neuromedin B-, ICI 216140 and DPDM-bombesin ethylamide-induced Ca2+ release. Pretreatment of cells with either des-Met-bombesin analogue attenuated neuromedin B-induced Ca2+ elevations, suggesting similar agonist-sensitive Ca2+ pools. The pharmacological profiles revealed from the [3H]arachidonate assay were similar, although ICI 216140 was less potent and efficacious than DPDM-bombesin ethylamide. The data suggest that ICI 216140 and DPDM-bombesin ethylamide behave as agonists at the neuromedin B receptor, perhaps as a consequence of neuromedin B receptor overexpression.

3T3 Cells↗
PubMed1996

The effect of acetaminophen, ibuprofen, and misoprostol on prostaglandin E2 synthesis and the degree and rate of orthodontic tooth movement.

The present study compared the effect of acetaminophen, ibuprofen and misoprostol on PGE2 synthesis and orthodontic tooth movement. Guinea pigs were randomly assigned into one of three test groups or a control group. Each group received study treatments every 12 hours as an orthodontic force was applied to the maxillary incisors. Direct linear measurements of tooth separation were recorded at days 2, 4, 6, 10, and 11, and inflammatory exudate from the periodontal ligament (PDL) space was extracted and quantitatively analyzed radioimmunologically for the presence of PGE2 at days 4 and 9. Comparing the concentration of PGE2 in sample extracts, a significant difference (P = 0.001) was found among drug groups. A highly significant difference was found between the mean tooth separation among the various drug groups (P < 0.001). At day 11 the misoprostol group exhibited 4.49 +/- 0.49 mm of separation; ibuprofen 2.56 +/- 0.11 mm, and the control and acetaminophen groups exhibited similar degrees of tooth separation: 3.31 +/- 0.07 mm and 3.31 +/- 0.08 mm, respectively. A highly significant difference occurred between the mean rates of tooth separation among the various drug groups after day 8 (P < 0.001). Results of this study suggest that acetaminophen is the analgesic of choice for the relief of minor discomfort associated with orthodontic treatment.

Acetaminophen↗
PubMed1996

Opioid antagonists and antisera to endogenous opioids increase the nociceptive response to formalin: demonstration of an opioid kappa and delta inhibitory tone.

The present experiments explored the role of endogenous opioids in the behavioral response to a formalin-induced nociceptive stimulus in the rat. Flinching was taken as a measure of the intensity of the nociceptive stimulus after the administration of formalin into the dorsal surface of the paw of control animals, or in animals receiving i.p. administration of receptor-selective doses of opioid antagonists including naloxone, naltrindole (delta opioid antagonist), nor-binaltorphimine (kappa opioid antagonist) or beta-funaltrexamine (mu opioid antagonist). Additionally, antisera to [Leu5]enkephalin, [Met5]enkephalin and dynorphin A (1-13) (dynorphin) were administered intrathecally before formalin to explore the contribution of endogenous opioids in modulation of the flinching response. Formalin-induced flinching was increased significantly by naloxone, and receptor selective doses of naltrindole and nor-binaltorphimine, but not beta-funaltrexamine. Additionally, antisera to [Leu5]enkephalin and dynorphin also resulted in a significant increase in formalin-induced flinching, whereas antisera to [Met5]enkephalin had no effect. On the basis of significant increases in formalin-induced flinching produced by 1) receptor-selective doses of delta and kappa, but not mu, opioid antagonists and 2) antisera to [Leu5]enkephalin and dynorphin A, but not [Met5]enkephalin, these data suggest the presence of an opioid inhibitory tone which acts to limit the intensity of the pain signal. This tone appears to be mediated via activation of delta and kappa receptors, possibly by a [Leu5]enkephalin- and dynorphin-like substance, respectively.

Animals↗
PubMed1994

Pharmacological analysis of receptors for bombesin-related peptides on guinea pig gallbladder smooth muscle.

The aim of this study was to characterize the receptor(s) for bombesin (BN) and its homologues (gastrin releasing peptide, GRP; neuromedin B, NMB; neuromedin C, NMC) in guinea pig gallbladder muscle strips. Dose-dependent contractions were induced by all peptides tested (potency: BN = GRP > NMC > NMB, but with similar efficacy: BN = GRP = NMC = NMB). The contractions were resistant to tetrodotoxin, atropine, phentolamine, and propranolol. BN tachyphylaxis (1 microM) abolished subsequent contractile responses to BN, GRP and NMC; and partially antagonized the response to NMB (66 +/- 7% inhibition). NMB tachyphylaxis (10 microM) markedly inhibited subsequent contractile responses to NMB (78 +/- 5%); and partially antagonized the contractile response to BN (36 +/- 4%), GRP (31 +/- 12%) and NMC (22 +/- 2%). At 1 microM, both [D-Phe6, Des-Met14]-BN(6-14) ethylamide and ICI 216, 140, two BN receptor antagonists, reduced the contractile actions of BN (82 +/- 4% and 59 +/-8% inhibition, respectively), GRP (75 +/- 11% and 45 +/- 5%), and NMC (73 +/- 9% and 51 +/- 6%) while having no marked effect on NMB contractions. Our pharmacological approaches (receptor tachyphylaxis and differential antagonism) provide support for two types of receptors for BN-like peptides on guinea pig gallbladder smooth muscle: a GRP-preferring receptor and a NMB-preferring receptor.

Amino Acid Sequence↗
PubMed1994

Ultrasound localization of screen detected impalpable breast tumours.

Accurate localization of a tumour is imperative before excision biopsy for impalpable breast lesions seen on screening mammography. Ultrasound localization has the advantages of being simple, quick and noninvasive. In a 3-year period from September 1989, 185 women have required localization of a breast tumour prior to biopsy, 159 were performed using a wire localization technique and 26 (14%) were performed using ultrasound alone. Twenty-two out of the 26 were malignant lesions. The mean maximum diameter of tumour diagnosed by ultrasound compared to histological sample was 10.6 mm (8.5-12.7*) to 11.1 mm (8.9-13.3*) with a correlation of r = 0.87. In the malignant cases the mean maximum diameter of tissue excised was 63.0 mm (57.2-65.9*). Complete excision was obtained in 21 out of the 22 patients with malignant disease by one operation. Ultrasound alone has been used successfully as a means of preoperative localization in selected cases prior to excision biopsy of a breast tumour.

Breast Neoplasms↗
PubMed1993

Naloxone causes apparent antinociception and pronociception simultaneously in the rat paw formalin test.

Naloxone is known to decrease, increase or have no effect on nociceptive thresholds. Here, using two commonly accepted pain-related behaviors (licking and flinching) associated with injection of noxious formalin into a hind paw in rats, naloxone (0.1-1 mg/kg s.c.) simultaneously decreases and increases nociceptive responding in the same animal. Licking, which is reduced by naloxone, is enhanced by low doses but attenuated by high doses of morphine. However, although licking initially increases with a rise in formalin concentration, at higher concentrations the time spent licking the injected paw actually declines. By contrast, flinching, which is enhanced by naloxone, is only antagonized by morphine and increases linearly with formalin concentration. Both actions of naloxone can be interpreted in terms of a leftward shift in the formalin concentration-response curves. This study demonstrates that naloxone can increase formalin-induced flinching while simultaneously decreasing licking behavior. These findings suggest that, on its own, an unexpected decrease in a single nociceptive index may be an inadequate criterion for demonstrating antinociception.

Animals↗
PubMed1993

Reserpinization severs the cooperative but not the oppositional interaction between D1 and D2 receptors.

Dopamine D1 and D2 receptors in rat brain interact synergistically to produce stereotypy and antagonistically to induce atypical jerking. This study showed that repeated reserpine treatment (5 daily injections of 1 mg/kg, s.c.), which depleted dopamine stores by 98%, rendered D1 and D2 receptors independent with respect to the production of stereotypy, i.e. either D1- or D2-selective agonists given alone induced stereotypy. In contrast, the atypical jerking induced by the D2 agonist, quinpirole, was still inhibited by the D1 agonist, SKF 82958, indicating that reserpine treatment did not render these two receptors independent with respect to initiation of this behavior.

Animals↗
PubMed1992

Buprenorphine and gastrointestinal transit in rats: effect of naloxone on the biphasic dose-response curve.

1. Buprenorphine (0.01-10 mg/kg, subcutaneous [s.c.]) slowed the passage of a charcoal meal along the gastrointestinal tract in rats. The dose-response relationship was U-shaped. 2. When rats were pretreated with naloxone (0.30 mg/kg, s.c.), both the descending and ascending components of the buprenorphine dose-response curve were displaced to the right. 3. Buprenorphine-induced delay of transit was maximal at a dose of 0.10 mg/kg. In rats pretreated with naloxone, a 30-fold higher dose of buprenorphine was required for a comparable peak effect. 4. Moderate-high doses of buprenorphine may be acting on a functionally related binding site which non-competitively inhibits the usual buprenorphine-mu opioid receptor interaction.

Administration, Cutaneous↗
PubMed1991

Effects of intracerebroventricular beta-funaltrexamine on mu and delta opioid receptors in the rat: dichotomy between binding and antinociception.

The effects of intracerebroventricular (i.c.v.) beta-funaltrexamine (beta-FNA) pretreatment at -24 or -6 h were studied on mu and delta opioid receptor binding and on antinociception produced by i.c.v. morphine in rats. Mu and delta opioid receptor binding in brain membrane preparations was performed with [3H][D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO) and [3H][D-Pen2,D-Pen5]enkephalin (DPDPE) as radiolabeled ligands, respectively. Effects of i.c.v. beta-FNA (24 h) on mu and delta binding depended on dosage. For [3H]DAGO binding, 3 micrograms beta-FNA did not affect either the Kd or Bmax, whereas 10 micrograms increased the Kd without changing the Bmax. beta-FNA pretreatment for 24 h did not alter [3H]DPDPE binding at 3 micrograms; at 10 micrograms, the Kd was increased with no change in the Bmax. Pretreatment with 10 micrograms beta-FNA for 6 h gave similar results to the 24-h treatment in mu binding, but did not change delta binding. When mu binding was performed on various brain regions, pretreatment with 10 micrograms beta-FNA for 24 h increased the Kd in all regions studied (the periaqueductal gray, thalamus, striatum and cortex). However, this pretreatment decreased the Bmax only in the periaqueductal gray (by 22%) and cortex (by 14%). Pretreatment of rats with beta-FNA (3 or 10 micrograms at -24 h), which by itself caused some hyperalgesia, greatly antagonized the antinociceptive effect of morphine (10 micrograms i.c.v.) in the hot-plate test. Our work with beta-FNA has revealed an apparent discrepancy between binding and behavioral results. This dichotomy may, in part, be the result of the limited distribution of beta-FNA to the periventricular area.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Neurogenic and tissue-mediated components of formalin-induced edema: evidence for supraspinal regulation.

Injection of formalin into a hind paw of rats produces localized inflammation and pain. The nociceptive effect of formalin, recorded as flinching/shaking of the injected paw, is biphasic. The present study shows that formalin-induced inflammation and edema (assessed by measurement of paw volume up to 24 h post-injection) is also biphasic, an early neurogenic component being followed by a later tissue-mediated response. Rapid initiation of edema is closely related to early phase nociception and is dependent on activity in primary afferent neurons and axon reflexes, but not on transmission of the noxious stimulus and the perception of pain itself. The major site responsible for down-regulating the inflammatory response, particularly in the later stages when tissue-mediated components are most heavily involved, appears to be located supraspinally. Down-regulation occurs principally by means of descending neuronal pathways but may also involve a secondary humoral component. The perhaps surprising dependence on neuronal mechanisms which this study demonstrates promotes spinal and peripheral sites as potential therapeutic targets in certain inflammatory conditions.

Animals↗
PubMed1991

Standardization of the rat paw formalin test for the evaluation of analgesics.

Administration of 5% formalin into the rat or guinea pig hind paw evokes two spontaneous responses: flinching/shaking and licking/biting of the injected paw. The temporal and behavioral characteristics of these objective endpoints are described. Additionally, several practical suggestions aimed at standardizing this test for the evaluation of analgesics are presented. The early/acute and late/tonic (0-10 and 20-35 min post-formalin, respectively) phases of flinching were used to quantitate antinociception in the rat. PD 117302, the kappa selective agonist, was three times more potent than morphine against tonic flinching after SC administration. Formalin may therefore be a noxious stimulus of choice in the evaluation of kappa agonists. Morphine was only twice as potent against tonic flinching as against acute flinching or the tail-dip reflex to water (50 degrees C). In contrast, PD 117302 was 27 times less potent on early phase and was inactive in the tail-dip test. Thus, while morphine is essentially equipotent across tests, PD 117302 shows a spectrum of activity with impressive potency and efficacy being obtained against tonic pain. Kappa receptors may therefore be prominently involved in tonic pain states. Aspirin given orally was not consistently antinociceptive in either phase of the formalin test. Spinal transection completely abolished late phase responding but only partly attenuated flinching in the early phase. This suggests that the relative involvement of spinal (as opposed to supraspinal) processing of noxious inputs may, at least in part, be a function of stimulus intensity and underlie the differences in antinociceptive potency observed in this work.

Analgesics↗
PubMed1991

Effects of selective opioid agonists on feline colonic transit.

The mu agonist morphine and the non-specific opioid antagonist naloxone both may accelerate feline colonic transit; the effects of morphine are dose dependent. Kappa and delta receptor function was studied in the present work. Colonic transit of a radionuclide marker instilled into the cecum was quantitated for 6 hr in a crossover study. The delta agonist [D-Pen2,D-pen5]enkephalin (1 mg/kg, i.m.) prolonged the cecum and ascending colon half-emptying time by 337% (P less than 0.05), and delayed the progression of the geometric center over time. The kappa agonist U-50,488 (1 mg/kg, i.m.) had no apparent effect on the cecum and ascending colon, but delayed filling of the descending colon. Loperamide, an antidiarrheal agent, also delayed colonic transit. Thus, selective opioid agonists have both site and functional differences in their effect on feline colonic transit.

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

Tonic pain perception in the mouse: differential modulation by three receptor-selective opioid agonists.

The proposition that tonic nociception models are more analogous to clinical pain than traditional acute models prompted our previous development of a modified mouse paw formalin test. To discern possible modulatory roles and site(s) of action of endogenous opioid systems, the receptor-preferring agonists sufentanil (mu), U-50,488H (kappa) and [D-Pen2,5]enkephalin (DPDPE, delta) were evaluated for antinociceptive activity in the formalin paradigm by systemic (except DPDPE), spinal and supraspinal routes. All observations were done under blind conditions. Doses causing overt behaviors that indicated a breach of receptor specificity (during the observation period) were rejected. Higher doses of centrally administered DPDPE (greater than 0.3 micrograms/mouse, intrathecal; greater than 3 micrograms/mouse, intracerebroventricular) induced a behavioral syndrome traditionally associated with mu agonism, and thus were not considered for this study. A50 values from behaviorally acceptable dose ranges for mean percent analgesia (reduction of paw licking compared to controls) were: trans-(+/- )-3,4-dichloro-N-methyl-N-[U-50,488H 2-pyrrolidinyl)cyclohexyl]-benzeneacetamide methanesulfonate,U-50,488H--3200 nmol/kg, subcutaneous, 1100 nmol/kg, intrathecal and 314 nmol/kg, intracerebroventricular; sufentanil--11.1 nmol/kg, subcutaneous, 8.6 nmol/kg, intrathecal; and DPDPE--inactive. On the basis of our dose-response data, we suggest that, in mice, kappa and mu, but not delta, opioid receptors modulate tonic pain perception at both spinal and supraspinal loci. The results also support inclusion of the modified formalin test in preclinical evaluations of potential kappa agonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

A view from inside.

There is sometimes an aspect of a disease that can only be uncovered by surgical exposure in surgical cases and, in spite of all the modern scanning and pathological investigations, by the assembly of the patient's history and symptoms in medical cases. My knowledge of Parkinson's disease is minimal, but I am a trained observer and I have attempted to present a brief study of the condition from 'inside looking out' in the hope that it will assist in expanding clinical rapport.

Accidental Falls↗