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Biomedical subjects

A Cowan

Publications and source records attributed to A Cowan.

At least 19 recordsLinked to original sources
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↗
PubMed1990

Failure of (+)-naloxone to accelerate feline colonic transit.

To determine whether the colonic transit accelerating effect of (-)-naloxone (0.3 mg/kg, i.m.) is due to an action at opioid receptors or a direct pharmacologic effect, its enantiomer, (+)-naloxone (0.3 mg/kg, i.m.), was administered to cats and compared to saline control using colonic transit scintigraphy. Transit was not accelerated by (+)-naloxone. The effects of naloxone on colonic transit are thus stereospecific, and are probably mediated by opioid receptors.

Animals↗
PubMed1990

Formalin nociception in the mouse does not lead to increased spinal serotonin turnover.

The mouse formalin test is a model of tonic (continuous), chemical/inflammatory nociception. To test the hypothesis that bulbospinal serotonergic pathways modulate such nociception, whole spinal cords from mice pretreated with probenecid and sacrificed at 15, 30, 45 and 60 min after injection of 5% formalin or 0.9% saline in the hindpaw were assayed by high performance liquid chromatography with electrochemical detection for the serotonin metabolite, 5-hydroxyindoleacetic acid, as an index of turnover. No difference in serotonin turnover was found between formalin and saline groups, indicating that increased spinal serotonin release is not a normal response to formalin nociception in the mouse.

Animals↗
PubMed1990

[D-Pen2, D-Pen5]enkephalin, the standard delta opioid agonist, induces morphine-like behaviors in mice.

[D-Pen2, D-Pen5]enkephalin (DPDPE; 3-30 micrograms) and morphine (10 micrograms) both caused Straub tails, increased locomotion, and circling after ICV administration to ICR mice. DPDPE-induced tail stiffening was reduced when mice were pretreated with naloxone (0.5 mg/kg SC) or beta-funaltrexamine (10 micrograms ICV), but not with ICI 174864 (2 mg/kg SC), the selective antagonist at delta opioid receptors. These results point to (a) mu receptors mediating the tail stiffening and (b) the loss of delta receptor selectivity after 10 and 30 micrograms DPDPE.

Analgesics↗
PubMed1989

Statistical analysis of drug-drug and site-site interactions with isobolograms.

The use of more than one drug to achieve a desired effect has been a common practice in pharmacologic testing and in clinical practice. For example, combinations of analgesics are frequently prescribed with a view to enhancing pain relief and reducing adverse effects. It is also well established that administration of more than one drug may give effects that are greater than, or less than, the additive effect of each drug given individually. A non-mechanistic method of characterizing the effect resulting from the administration of two compounds is the isobologram. It is relatively simple to draw and interpret isobolograms. However, this graphical technique, which employs equieffective concentrations of individual drugs and combinations of these, obtains the concentrations as random variables from concentration-effect data, usually transformed to a parallel line assay. Thus, statistical confidence limits from such assays, as well as from non-parallel designs, must be expressed on the isobologram if this diagram is to establish superadditive, subadditive, or merely additive effects. We now present a detailed statistical analysis of the isobolographic method illustrated with examples of the statistical procedures, a rational basis for selecting proportions of each drug in the combination, and a relatively novel application of the isobolographic concept, i.e., interactions involving different anatomical sites.

Animals↗