Concurrent Spinal Infusion of MK801 Blocks Spinal Tolerance and Dependence Induced by Chronic Intrathecal Morphine in the Rat

1996 ◽  
Vol 84 (5) ◽  
pp. 1177-1188 ◽  
Author(s):  
Stuart Dunbar ◽  
Tony L. Yaksh
Keyword(s):  
Intrathecal Morphine ◽  
Receptor Activation ◽  
Acute Administration ◽  
Response Curves ◽  
Aspartate Receptor ◽  
Abnormal Posture ◽  
Significant Difference ◽  
Dose Dependent Fashion ◽  
20 Nm ◽  
Dose Dependent

Background MK801, an N-methyl-D-aspartate receptor antagonist, has recently been reported to attenuate tolerance to, and withdrawal from morphine. This study analyzes tolerance and withdrawal in a chronic intrathecal coinfusion model of morphine and MK801. Methods Intrathecal catheters, attached to 7-day miniosmotic infusion pumps, were implanted in rats and infused with saline, 20 nM/h morphine, MK801 (10 and 3 nM/h) + morphine; and 10 nM/h MK801. Analgesia was measured on the hot plate daily. On the day 7, groups received 3 mg/kg intraperitoneal naloxone and six signs of withdrawal were assessed: vocalization to air motion or light touch, abnormal posture, spontaneous vocalization, escape attempts, "wet dog shakes," and ejaculation. Similar groups were tested only on days 1 and 7. Intrathecal morphine dose-response curves were obtained on day 8. A separate morphine-tolerant group received 10 nM MK801 on day 7. Rats from each group received 10 nM intrathecal morphine 1 week later. Results Coinfusion of MK801 with morphine resulted in a dose-dependent preservation of effect, and attenuated three of six signs of withdrawal. Coinfusion of MK801 (10 and 3 nM/h) prevented the reduction of potency observed with morphine alone. ED50 values (maximum percent effect, nM morphine) were: saline (16), morphine (496), MK801 (10 nM/h) + morphine (4), and 10 nM/h MK801 (0.3). Acute administration of MK801 was ineffective in restoring sensitivity to morphine. One week after cessation of infusion, there was no significant difference between groups. Conclusions Chronic spinal MK801 attenuates tolerance to, and withdrawal from spinal morphine in a dose-dependent fashion, supporting the hypothesis that N-methyl-D-aspartate receptor activity plays a role in the reorganization of spinal function produced by chronic opioid receptor activation. Chronic intrathecal MK801 appears to sensitize the spinal cord to intrathecal morphine.

The guinea pig tracheobronchial spiral strip: responses to selected agonists

1978 ◽  
Vol 56 (5) ◽  
pp. 823-827 ◽  
Author(s):  
C. J. Hanna ◽  
S. H. Roth
Keyword(s):  
Regression Analysis ◽  
Guinea Pig ◽  
Dose Response ◽  
Effective Concentration ◽  
Relative Order ◽  
Response Curves ◽  
Response Data ◽  
Significant Difference ◽  
Dose Dependent

The guinea pig tracheal spiral strip is a useful preparation for studying bronchoconstrictor and bronchodilator compounds. Employing a simple and rapid modification of this technique, experiments were performed in vitro to quantitate the effects of selected bronchospastic agents on guinea pig tracheobronchial smooth muscle. Three sections of the main airways were prepared from each animal: an upper tracheal, a lower tracheal, and a bronchial segment. The dose-dependent contractile responses of the three tissue segments were determined for carbachol, acetylcholine, histamine, 5-hydroxytryptamine, and bradykinin, Differences were observed amongst the agonists in magnitudes of contraction, effective concentration ranges, and slopes of dose–response curves. ED25, ED50, and ED75, values were calculated from regression analysis of dose–response data. The relative order for these agents to produce maximum contractions was found to be carbachol [Formula: see text] acetylcholine > histamine > 5-hydroxytryptamine > bradykinin. Furthermore, it was found that there was no significant difference between the three tissue segments in their responses to the various agonists.

Pirenzepine-sensitive muscarinic receptors regulate gastric somatostatin and gastrin

1985 ◽  
Vol 248 (2) ◽  
pp. G184-G187 ◽  
Author(s):  
R. Sue ◽  
M. L. Toomey ◽  
A. Todisco ◽  
A. H. Soll ◽  
T. Yamada
Keyword(s):  
Acid Secretion ◽  
Muscarinic Receptors ◽  
Potent Inhibitor ◽  
Competitive Inhibition ◽  
Hormone Regulation ◽  
Rat Stomach ◽  
Response Curves ◽  
Gastrin Secretion ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Pirenzepine, a newly described antagonist of selective muscarinic receptors (M1), has been shown to be a potent inhibitor of acid secretion. To determine whether this property of pirenzepine can be explained in part by its actions on hormones regulating acid secretion, we examined pirenzepine's effects on gastrin and somatostatinlike immunoreactivity (SLI) secretion from the isolated, perfused rat stomach. Carbachol at a dose of 10(-6) M inhibited SLI and stimulated gastrin secretion. Both atropine and pirenzepine reversed these effects in a dose-dependent fashion with D50 values of 1 X 10(-9) and 1 X 10(-7) M, respectively, against gastrin stimulation and 1 X 10(-8) and 1 X 10(-7) M, respectively, against SLI inhibition. Pirenzepine caused a progressive parallel rightward shift in the dose-response curves for SLI inhibition and gastrin stimulation by carbachol, suggesting competitive inhibition. The apparent inhibitory constant (ki) was calculated to be approximately 2 X 10(-9) M. These results indicate that gastrin and SLI release from the stomach is governed by high-affinity muscarinic receptors that are sensitive to pirenzepine. Pirenzepine's action as an acid secretory inhibitor, and possibly as an ulcer therapy drug, may be explained in part by these effects on gastric hormone regulation.

Prostaglandin fevers in rats: regulated change in body temperature or change in regulated body temperature?

1989 ◽  
Vol 257 (4) ◽  
pp. R695-R699 ◽  
Author(s):  
J. D. Feng ◽  
M. Price ◽  
J. Cohen ◽  
E. Satinoff
Keyword(s):  
Body Temperature ◽  
Dose Response ◽  
Dark Cycle ◽  
Response Curves ◽  
Vehicle Injection ◽  
Dose Dependent Fashion ◽  
Dose Response Curves ◽  
Dose Dependent ◽  
Light Part

Experiments examining the effects of central injections of E-series prostaglandins (PGE) on body temperature have only been done in the light part of a light-dark cycle. The present experiments examined the characteristics of fevers in rats after intraventricular PGE2 injections in both light and dark in a 12:12 h photoperiod. In the light, the change in body temperature (Tb) after 0.5 microgram was not significantly different from the change after vehicle injection. After injection of PGE2 (1, 2, 4, and 8 micrograms), Tb rose in a dose-dependent fashion. Mean initial Tb in the light was 36.4-36.6 degrees C. Tb rose a mean of 1.5 degrees C after 1 microgram, 1.9 degrees C after 2 micrograms, 2.7 degrees C after 4 micrograms, and 3.5 degrees C after 8 micrograms PGE2. A dose of 16 micrograms gave almost identical results as 8 micrograms. In the dark, mean initial Tb was 37.4-37.7 degrees C. Tb rose less than 0.8, 1.1, 1.4, and 2.3 degrees C after 1-8 micrograms PGE2, respectively. Thus there were two distinct dose-response curves for day and night. Nevertheless, peak Tb values attained in the two conditions were not significantly different from each other at any given dose. These results show that a particular dose of PGE2 raises Tb to a particular level, largely independent of either the Tb at the time of the injection or the phase of the light-dark cycle. However, the change in Tb at any dose depends strongly on initial Tb. Therefore, we urge researchers in the pharmacology of thermoregulation to report initial and final Tb values as well as changes in Tb.

Methyl Mercury, Mercuric Chloride, and Silver Lactate Decrease Superoxide Anion Formation and Chemotaxis in Human Polymorphonuclear Leucocytes

1993 ◽  
Vol 12 (5) ◽  
pp. 361-364 ◽  
Author(s):  
Niels Obel ◽  
Birte Hansen ◽  
Margot M. Christensen ◽  
Søren Lyhne Nielsen ◽  
Jørgen Rungby
Keyword(s):  
Mercuric Chloride ◽  
Superoxide Anion ◽  
Methyl Mercury ◽  
Polymorphonuclear Leucocytes ◽  
Response Curves ◽  
Metal Compounds ◽  
Anion Formation ◽  
Functional Deficits ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Cytotoxic effects of mercuric chloride, methyl mercury, and silver lactate on polymorphonuclear leucocytes have been examined by assaying superoxide anion formation capability and chemotaxis of metal-exposed cells. Both superoxide anion formation and chemotaxis were negatively affected by all three metal compounds. Both bacteriotoxic functions were affected in a dose-dependent fashion, the functional deficits were seen at doses not affecting cell viability. Dose-response curves were remarkably similar for all three compounds. The bacteriotoxic capacity of polymorphonuclear leucocytes may be hampered by mercury and silver.

Methacholine dose-response curves in normal and asthmatic man: Effect of starting conductance and pharmacological antagonism

1984 ◽  
Vol 66 (6) ◽  
pp. 665-673 ◽  
Author(s):  
K. F. Chung ◽  
P. D. Snashall
Keyword(s):  
Dose Response ◽  
Normal Subjects ◽  
Small Degree ◽  
Response Curves ◽  
Significant Difference ◽  
Positive Linear Correlation ◽  
Dose Response Curves ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Different Doses

1. The bronchial response of 11 normal and ten stable asthmatic subjects to increasing concentrations of methacholine aerosol was assessed by serial measurements of specific airways conductance (scaw) in a body plethysmograph. 2. Cumulative log dose-response curves were constructed. The threshold provocative dose of methacholine needed to cause a 35% fall in starting sCaw (pD35) and the steepest slope of the response were measured from each curve. 3. On separate days subjects were premedicated with 0.9% NaCl solution (control) in duplicate, chlorpheniramine, salbutamol and atropine, the last-named at two different doses, one twice the other. 4. Asthmatic subjects had a lower mean PD35 and a lower mean slope than normal subjects. 5. Pretreatment with salbutamol resulted in a greater increase in sGaw than after atropine but caused a smaller increase in PD35 in both groups. There was a dose-dependent increase in PD3s after the two doses of atropine, but no significant difference in bronchodilatation between doses. Mean steepest slope approximately doubled in these three sets of challenges. 6. Chlorpheniramine caused a small degree of bronchodilatation and there was a non-significant increase in mean PD3s and in mean steepest slope in both normal and asthmatic groups. 7. There was a positive linear correlation between starting sGaw and steepest slope in each group of premedicated challenges, such that when

Topiramate Inhibits Trigeminovascular Neurons in the Cat

Cephalalgia ◽  
2004 ◽  
Vol 24 (12) ◽  
pp. 1049-1056 ◽  
Author(s):  
RJ Storer ◽  
PJ Goadsby
Keyword(s):  
Cumulative Dose ◽  
Dose Response ◽  
Sensory Input ◽  
Superior Sagittal Sinus ◽  
Maximum Effect ◽  
Response Curves ◽  
Sagittal Sinus ◽  
Dose Dependent Fashion ◽  
Dose Response Curves ◽  
Dose Dependent

To facilitate understanding the action of antimigraine preventives the effect of topiramate on trigeminocervical activation in the cat was examined. Animals ( n = 7) were anaesthetized and physiologically monitored. The superior sagittal sinus (SSS) was stimulated to produce a model of trigeminovascular nociceptive activation. Cumulative dose-response curves were constructed for the effect of topiramate at doses of 3, 5, 10, 30 and 50 mg/kg on SSS-evoked firing of trigeminocervical neurons. Topiramate reduced SSS evoked firing in a dose-dependent fashion. The maximum effect was seen over 30 min for the cohort taken together. At 3 mg/kg firing was reduced by 36 ± 13% (mean ± SEM) after 15 min. At 5 and 50 mg/kg firing was reduced by 59 ± 6% and 65 ± 14%, respectively, after 30 min. Inhibition of the trigeminocervical complex directly, or neurons that modulate sensory input, are plausible mechanisms for the action of preventives in migraine.

Effects of postnatal growth and denervation on characteristics of the saphenous artery in SHR and WKY rats between 3 and 6 weeks of age: an in vitro study

1991 ◽  
Vol 69 (6) ◽  
pp. 731-738 ◽  
Author(s):  
Mary E. Todd ◽  
Rosemary D. Bevan
Keyword(s):  
Muscle Development ◽  
Femoral Nerve ◽  
Receptor Activation ◽  
Response Curves ◽  
Wky Rats ◽  
Significant Difference ◽  
Wistar Kyoto ◽  
Growth Changes ◽  
Saphenous Artery

Thigh vessels of spontaneously hypertensive (SHR) and Wistar–Kyoto (WKY) rats were unilaterally surgically denervated at 10 days of age by femoral nerve section. Denervated and contralateral control segments of saphenous arteries from 3- and 6-week-old rats were mounted in a small vessel myograph for study. Both strains showed growth changes in blood pressure, but there was no significant difference between WKY and SHR. Both strains also had significant growth changes in vessel dimensions and the in vitro measurements suggested that SHR vessels had a thicker wall. Denervation did not affect vessel size. Transmural nerve stimulation indicated loss of innervation due to the surgical procedure. In the denervated vessels, both norepinephrine (NE) and 5-hydroxytryptamine (5-HT) dose response curves were shifted to the left, indicating a postjunctional increase in sensitivity. Maximum tension developed was in the order K+ > 5-HT > NE. In comparing the two strains, vessels from 6-week-old SHR were less sensitive to 5-HT. Relaxation to acetylcholine was significantly decreased in denervated arteries from WKY, whereas in SHR the significant decrease occurred only at 3 weeks. Denervated vessels from both rat strains at 3 weeks showed greater relaxation to β-receptor activation, but not at 6 weeks of age. Therefore, the absence of functional innervation resulted in altered function of the saphenous artery wall.Key words: blood vessel, artery, denervation, smooth muscle, development.

Inhibition of mucin release from airway goblet cells by polycationic peptides

1999 ◽  
Vol 277 (4) ◽  
pp. L811-L815 ◽  
Author(s):  
Kwang Ho Ko ◽  
Choong Jae Lee ◽  
Chan Young Shin ◽  
Mijeong Jo ◽  
K. Chul Kim
Keyword(s):  
Lactate Dehydrogenase ◽  
Epithelial Cells ◽  
Goblet Cells ◽  
Inhibitory Effect ◽  
Treatment Groups ◽  
Lactate Dehydrogenase Release ◽  
Significant Difference ◽  
Dose Dependent Fashion ◽  
Mucin Release ◽  
Dose Dependent

In the present study, we investigated whether polycationic peptides affect mucin release from cultured airway goblet cells. Confluent primary hamster tracheal surface epithelial cells were metabolically radiolabeled with [3H]glucosamine for 24 h and chased for 30 min in the presence of varying concentrations of either poly-l-arginine (PLA) or poly-l-lysine (PLL) to assess the effects on [3H]mucin release. Possible cytotoxicity by the polycations was assessed by measuring lactate dehydrogenase release,51Cr release, and cell exfoliation. The results were as follows: 1) both PLA and PLL inhibited mucin release in a dose-dependent fashion; 2) there was no significant difference in either lactate dehydrogenase release,51Cr release, or the number of floating cells between control and treatment groups; 3) the effects of both PLA and PLL on mucin release were completely blocked by neutralizing the positive charges either by pretreatment with heparin or by N-acetylation of the polycations; and 4) both PLA and PLL completely masked the stimulatory effect of ATP on mucin release. We conclude that these polycationic peptides can inhibit mucin release from airway goblet cells without any apparent cytotoxicity, and the inhibitory effect seems to be attributable to their positive charges. These are the first nonsteroidal agents, to the best of our knowledge, that have been shown to inhibit mucin release from airway goblet cells.

Effects of Intrathecal NMDA and Non-NMDA Antagonists on Acute Thermal Nociception and Their Interaction with Morphine

1998 ◽  
Vol 89 (3) ◽  
pp. 715-722. ◽  
Author(s):  
Tomoki Nishiyama ◽  
Tony L. Yaksh ◽  
Eckard Weber
Keyword(s):  
Ampa Receptor ◽  
Intrathecal Morphine ◽  
Receptor Activation ◽  
Thermal Stimulus ◽  
Nmda Antagonists ◽  
Glycine Site ◽  
Dose Ratio ◽  
Response Curves ◽  
Opioid Agonist ◽  
Thermal Nociception

Background N-methyl-D-aspartate (NDMA) antagonists have minimal effects on acute nociception but block facilitated states of processing. In contrast, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists decrease acute noxious responses. Morphine (a mu-opioid agonist) can also decrease acute nociceptive processing. The authors hypothesized that the interaction between morphine and AMPA receptor antagonists would be synergistic, whereas morphine and NMDA antagonists show no such interaction in acute nociception. Methods Sprague-Dawley rats (weight, 250-300 g) were implanted with chronic lumbar intrathecal catheters and were assigned to receive one of several doses of morphine--ACEA 1021 (NMDA glycine site antagonist), ACEA 2085 (AMPA antagonist), AP-5 (NMDA antagonist), saline or vehicle--and were tested for their effect on the response latency using a 52.5 degrees C hot plate. The combinations of morphine and other agents also were tested. Results Intrathecal morphine (ED50:2 microg/95% confidence interval, 1-4 microg) and ACEA 2085 (6 ng/2-15 ng), but not AP-5 or ACEA 1021, yielded a dose-dependent increase in the thermal escape latency. A systematic isobolographic analysis was carried out between intrathecal morphine and ACEA 2085 using the ED50 dose ratio of 357:1. A potent synergy was observed with decreased side effects. Morphine dose-response curves were carried out for morphine and fixed doses of ACEA 1021 (12 microg) or AP-5 (10 microg). No synergistic interactions were noted. Conclusions Spinal mu-receptor activation and AMPA receptor antagonism showed a synergistic antinociception in response to an acute thermal stimulus. NMDA or NMDA glycine site antagonism had no effect alone nor did they display synergy with morphine. These results suggest an important direction for development of acute pain strategies may focus on the AMPA receptor.

Plasminogen Interactions with Immobilized Fibrinogen

1989 ◽  
Vol 62 (04) ◽  
pp. 1078-1082 ◽  
Author(s):  
Burt Adelman ◽  
Patricia Ouynn
Keyword(s):  
Immunosorbent Assay ◽  
Aminocaproic Acid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Binding Regions ◽  
Dose Dependent Fashion ◽  
Epsilon Aminocaproic Acid ◽  
Dose Dependent

SummaryThis report describes the binding of plasminogen to fibrinogen adsorbed onto polystyrene wells. Binding was determined by enzyme linked immunosorbent assay. Both glu- and lys-plasminogen bound to immobilized fibrinogen in a dose-dependent fashion. However, more lys- than glu-plasminogen bound when equal concentrations of either were added to immobilized fibrinogen. Plasminogen binding was inhibited by epsilon aminocaproic acid indicating that binding was mediated via lysine-binding regions of plasminogen. Soluble fibrinogen added in excess of immobilized fibrinogen did not compete for plasminogen binding but fibrinogen fragments produced by plasmin digestion of fibrinogen did. Treatment of immobilized fibrinogen with thrombin caused a small but significant (p <0.01) increase in plasminogen binding. These studies demonstrate that immobilized fibrinogen binds both glu- and lys-plasminogen and that binding is mediated via lysine-binding regions. These interactions may facilitate plasminogen binding to fibrinogen adsorbed on to surfaces and to cells such as platelets which bind fibrinogen.

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