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Biomedical subjects

W L Dewey

Publications and source records attributed to W L Dewey.

At least 19 recordsLinked to original sources
PubMed2000

Comparison of [(3)H]Glyburide binding with opiate analgesia, tolerance, and dependence in ICR and Swiss-Webster mice.

Our laboratory demonstrated that morphine exhibits a modulatory control over the glyburide-binding site (sulfonylurea receptor) of the ATP-gated K(+) channel. This study evaluated the effect of chronic morphine administration on the sulfonylurea receptor during tolerance and physical dependence. ICR and Swiss-Webster mice were rendered tolerant to morphine by pellet implantation and were withdrawn by pellet removal. Alterations in the B(max) and K(D) were evaluated in mouse spinal cord using the radiolabeled ATP-gated K(+) channel blocker glyburide. The ED(50) for Swiss-Webster mice shifted from 13 to 451 mg/kg and thus they were more tolerant to morphine than ICR mice (ED(50) shift from 12 to 120 mg/kg). Swiss-Webster mice were also dependent to morphine only when the morphine pellet was in place, unlike ICR mice, which were dependent for 48 h after morphine pellet removal. Glyburide binding increased during chronic morphine treatment in Swiss-Webster mice by over 2-fold (from 294 to 635 fmol/mg of protein). This was not observed in ICR mice. In Swiss-Webster mice, chronic morphine treatment also significantly increased the K(D) by 3-fold (from 0.38 to 1.1 nM), whereas there was no change in affinity for ICR mice. Both strains of mice remained tolerant for 2 days after spontaneous withdrawal from morphine. However, the only increases in the B(max) and K(D) of glyburide were observed in Swiss-Webster mice that were highly tolerant to morphine. These results indicate that a high degree of tolerance is needed to alter ATP-gated potassium channels.

ATP-Binding Cassette Transporters↗
PubMed1999

Involvement of intracellular calcium in morphine tolerance in mice.

Opioid analgesic tolerance is associated with a disruption in Ca++ homeostasis. Drugs reducing Ca++ influx can prevent and reverse tolerance. The hypothesis was tested that both Ca++ influx and mobilization from intracellular pools maintains the expression of morphine tolerance. Ca++ modulating drugs were injected ICV at doses not affecting morphine's potency in placebo pellet-implanted mice, in order to determine whether tolerance would be reversed in morphine pellet-implanted mice. The Ca++ chelator EGTA significantly reversed tolerance. The Ca++ channel antagonists nifedipine and omega-conotoxin GVIA also reversed tolerance. The role of intracellular Ca++ was investigated using the membrane permeable intracellular Ca++ chelator EGTA-AM. EGTA-AM reversed tolerance at lower morphine doses, but not at higher morphine doses. Thus, mobilization of intracellular Ca++ contributes to the expression of tolerance. Finally, 1,4-dihydropyridine-sensitive Ca++ channels are known to stimulate Ca++-induced Ca++ release (CICR) from Ca++/caffeine-sensitive microsomal pools possessing ryanodine receptors. We examined whether blocking Ca++ mobilization from these pools with ryanodine would reverse morphine tolerance. Ryanodine's effects were similar to EGTA-AM. Tolerance was reversed at lower morphine doses, but not at higher doses. Thus, morphine tolerance appears to be associated with increases in Ca++ influx and mobilization from Ca++/caffeine-sensitive pools.

Analgesia↗
PubMed1999

Involvement of phospholipid signal transduction pathways in morphine tolerance in mice.

1. Opioid tolerance involves an alteration in the activity of intracellular kinases such as cyclic AMP-dependent protein kinase (PKA). Drugs that inhibit PKA reverse morphine antinociceptive tolerance. The hypothesis was tested that phospholipid pathways are also altered in morphine tolerance. Inhibitors of the phosphatidylinositol and phosphatidylcholine pathways were injected i.c.v. in an attempt to acutely reverse morphine antinociceptive tolerance. 2. Seventy-two hours after implantation of placebo or 75 mg morphine pellets, mice injected i.c.v. with inhibitor drug were challenged with morphine s.c. for generation of dose-response curves in the tail-flick test. Placebo pellet-implanted mice received doses of inhibitor drug having no effect on morphine's potency, in order to test for tolerance reversal in morphine pellet-implanted mice. Injection of the phosphatidylinositol-specific phospholipase C inhibitor ET-18-OCH3 significantly reversed tolerance, indicating a potential role for inositol 1,4,5-trisphosphate (IP3) and protein kinase C (PKC) in tolerance. Alternatively, phosphatidylcholine-specific phospholipase C increases the production of diacylglycerol and activation of PKC, without concomitant production of IP3. D609, an inhibitor of phosphatidylserine-specific phospholipase C, also reversed tolerance. Heparin is an IP3 receptor antagonist. Injection of low molecular weight heparin also reversed tolerance. PKC was also examined with three structurally dissimilar inhibitors. Bisindolylmaleimide I, Go-7874, and sangivamycin significantly reversed tolerance. 3. Chronic opioid exposure leads to changes in phospholipid metabolism that have a direct role in maintaining a state of tolerance. Evidence is accumulating that opioid tolerance disrupts the homeostatic balance of several important signal transduction pathways.

Analgesia↗
PubMed1997

Morphine tolerance-induced modulation of [3H]glyburide binding to mouse brain and spinal cord.

Modulation by opioids of ATP-gated potassium channels, which regulate in part intracellular calcium levels, was measured by the binding of [3H]glyburide. Scatchard analyses generated a KD for whole brain of vehicle-pretreated mice of 288 pM with a Bmax of 694 fmol/mg protein. In the spinal cord the KD was 0.94 nM and the Bmax was 184 fmol/mg protein. Acute morphine decreased the KD in brain and spinal cord with no change in Bmax. Morphine tolerance increased the KD in brain and spinal cord 2.6- and 2.9-fold, respectively, concurrent with 1.6- and 3.4-fold increases in Bmax. Modulation by morphine of glyburide-sensitive binding sites may contribute at least in part to tolerance to morphine via alterations in intracellular calcium levels in neurons.

Adenosine Triphosphate↗
PubMed1994

A comparison of the antinociceptive effects of opioid agonists in neonatal and adult rats in phasic and tonic nociceptive tests.

Changes in the attitudes about neonatal pain and pain management have recently resulted in increases in the administration of opioids to neonates. Little is known, however, about the relative potencies of the various opioid agonists employed, especially in comparison to adult responses. The first objective in the present study was to compare the antinociceptive potency of four clinically relevant opioids in neonatal and adult rats. The second objective was to compare and contrast these agents in two different types of nociceptive tests: tonic (formalin-induced inflammation) and phasic (tail flick and hot plate). Our results indicate that the opioid agonists morphine, meperidine, and fentanyl, and the mixed agonist buprenorphine were all effective antinociceptive agents in both neonates and adults in each of the three tests employed, and that the relative potencies of these agents appeared to be similar in neonates and adults. In general, the pups were more sensitive to the antinociceptive agents when tested in the phasic nociceptive tests, and the drugs were more potent in the tonic test than either of the phasic tests.

Aging↗
PubMed1994

Resistance exercise decreases beta-endorphin immunoreactivity.

Previous research investigating the response of plasma beta-endorphins (beta-EP) to resistance exercise has resulted in equivocal findings. To examine further the effects of resistance exercise on beta-EP immunoreactivity, 10 male and 10 female college-age students participated in a series of controlled isotonic resistance exercises. The session consisted of three sets of eight repetitions at 80% of one repetition maximum (1-RM) for each of the following exercises: (1) bench press; (2) lateral pull-downs; (3) seated arm curls; and (4) military press. Blood plasma was sampled both before and after the lifting routine and beta-endorphin levels were determined by radioimmunoassay. A Students t test for paired samples indicated that mean(s.e.) plasma beta-endorphin levels after exercise (10.5(1.3) pg beta-EP ml-1) were significantly decreased as compared with pre-exercise (control) levels (16.5(1.2), P < 0.05). While the mechanism(s) contributing to the decrease in immunoreactivity is unclear, it may be the result of the synergistic effect of beta-EP clearance during rest intervals and changes in psychological states between sampling.

Adult↗
PubMed1994

Endogenous opioids released by suspending mice by the tail selectively enhance spinal mu opioid analgesia.

In studying the interactions between handling mice and their subsequent analgesic response to an intrathecally (i.t.) administered mu-opioid agonist, DAMGO, it was found that suspending ICR mice by the tail for 1, 5, or 20 sec, 10 min before the tail-flick test, enhanced DAMGO by 5.3-, 7.4- and 23.6-fold, respectively, compared with mice maintained in a level posture. This enhancement was not accompanied by a change in the rostral flow of [3H]-DAMGO (25 ng, i.t.) to the brain (3.7% in 10 min), in its distribution along the neuraxis or in its systemic absorption. However, i.c.v. administration of beta-endorphin (1-27), an antagonist of epsilon opioid receptors, abolished the enhancement of i.t. DAMGO without affecting its basal analgesic potency. Pretreatment with the delta-opioid antagonist naltrindole (5.6 nmol, i.t.,-30 min) also blocked the enhancement of DAMGO without significantly affecting its basal analgesic potency. Alternatively, this same dose of naltrindole injected i.c.v. failed to block the enhancement of DAMGO in suspended mice. A 20-sec suspension failed to enhance i.t. kappa and delta-agonists, but it did enhance i.t. morphine. In mouse strain comparisons, i.t. DAMGO was more potent in C57BL/6J and DBA/2J mice than in C3H/HeJ and ICR mice, but DAMGO was enhanced by a 20-sec suspension in all strains tested. Thus suspending mice by the tail evoked a reflex enhancement of spinal mu agonist-induced analgesia that probably involved both the supraspinal release of beta-endorphin (an endogenous epsilon agonist) and the subsequent spinal release of an endogenous delta-receptor agonist in the reflex pathway.

Analgesics↗
PubMed1993

Effect of intrathecal morphine on the fate of glucose. Comparison with effects of insulin and xanthan gum in mice.

The hypoglycemic effect of morphine (40 micrograms) injected intrathecally (i.t.) was studied with regard to disposition of i.v. [14C]glucose and [3H]2-deoxyglucose and was compared with the effects of two other hypoglycemic agents, insulin (1 IU/kg, s.c.) and xanthan gum (50 mg/kg, i.p.). Mice given i.t. morphine or s.c. insulin exhaled a greater amount of 14CO2 from i.v. [14C]glucose than did control mice given i.t. saline, whereas there was less 14CO2 expiration in xanthan-treated mice. In morphine-treated mice there was less 14C in liver, brain and blood, and more 3H in kidney and hindleg muscle than in control mice. Insulin-treated mice had more 14C in muscle, less 14C in liver, brain, kidney and blood, and less 3H in liver and blood. In xanthan-treated mice, levels of both radiolabels were higher in liver, brain and kidney. Much lower glycogen content in muscle and depletion of liver glycogen occurred in morphine-treated mice, compared with control mice. Spinal transection completely inhibited the hypoglycemic effect of morphine, whereas adrenalectomy caused no inhibition. Morphine, insulin and xanthan appear to be acting by different mechanisms, although the hypoglycemic effects of both morphine and insulin appear to be due largely to an increased glucose uptake by muscle.

Animals↗
PubMed1993

The mouse paw withdrawal assay: a method for determining the effect of calcitonin gene-related peptide on cutaneous heat nociceptive latency time.

Previously we have shown that calcitonin gene-related peptide (CGRP) modulates nociception and the effect of opioid analgesics in the central nervous system of mice. Cutaneous primary afferent nerve terminals also contain a high concentration of CGRP, however the lack of a suitable method for assessing cutaneous nociceptive latency changes in the hindpaw skin of the mouse hindered our investigations. We report here on the development of an assay to investigate the effect of CGRP on nociception in the dorsal hindpaw skin. Subcutaneous injection of CGRP produced a modest elevation of withdrawal latency time at doses that were two orders of magnitude greater than the physiologic levels determined in naive animals by radioimmunoassay. This elevation of threshold was minimal when compared to the elevation produced by mepivacaine. These results indicate that subcutaneous injection of CGRP into the dorsal hindpaw skin of the mouse produces a modest increase in paw withdrawal latency times at high, non-physiologic doses.

Animals↗
PubMed1993

Endogenous dynorphin modulates calcium-mediated antinociception in mice.

We previously reported that calcium administered IT produces antinociception by stimulating spinal Met-enkephalin release. However, at times the antinociceptive effects of calcium in the tail-flick test are greatly diminished. The results of this study indicates that during these periods calcium also stimulates endogenous dynorphin release. Dynorphin has been reported to block opiate-induced antinociception. Calcium-injected mice (150-600 nmol, IT) pretreated with vehicle IP displayed a poor degree of antinociception. Alternatively, pretreating mice with pentobarbital (45 mg/kg, IP) restored the antinociceptive effects of calcium. Low doses of naloxone and norbinaltorphimine (BNI) did not produce antinociception but restored the antinociceptive effects of calcium. Dynorphin (1-17) (Dyn 1-17), and Dyn (1-13), but not Dyn (1-8), blocked the antinociceptive effects of calcium restored with pentobarbital. These results indicate that calcium-mediated antinociception was sensitive to injected dynorphins. In additional experiments, antiserum to Dyn (1-13) was found to restore the antinociceptive effects of calcium, presumably by binding dynorphin released by calcium.

Animals↗
PubMed1993

Neonatal pain: a comprehensive survey of attitudes and practices.

We surveyed 352 physicians board certified in neonatal-perinatal medicine on their attitudes and practices in the area of pain and pain management in neonates and infants. In contrast to earlier surveys of this type, almost all respondents indicated that even the youngest and most premature infants are able to perceive pain, and most reported that they always advocated anesthesia during the intraoperative period. The use of analgesic agents in the postoperative period, however, was more variable. Respondents who indicated that neonates perceived less pain than adults reported seeing fewer signs of pain and using less analgesia in the postoperative period. They were also more likely to believe that analgesics are too dangerous to use in neonates and that physiologic factors such as incomplete myelination of the pain pathways and neural/physical immaturity (factors now known not to play a role) contribute to diminished pain sensitivity. Conversely, respondents who indicated that neonates do not perceive less pain than adults, the majority of respondents, reported seeing more signs of pain and using more medication in the postoperative period. These physicians also believed that the physiologic stress associated with pain can be more dangerous than the analgesics. We conclude that attitudes and reported practices have changed in the area of neonatal pain and pain management. Furthermore, our data indicate that these attitudes significantly predict reported postoperative medicating practices.

Attitude of Health Personnel↗
PubMed1993

Plasma beta-endorphin immunoreactivity: response to resistance exercise.

Previous research investigating the response of plasma beta-endorphins (beta-EP) to resistance exercise has resulted in equivocal findings. To further examine the effects of resistance exercise on beta-endorphin immunoreactivity, six resistance-trained athletes participated in a three-set series of eight repetitions of isotonic exercise. All exercises were performed at 80% maximal effort. Blood was sampled from the group by venepuncture, both prior to and following the exercise bout, and beta-endorphin concentration was determined by radioimmunoassay. The results indicated that mean (+/- S.E.) plasma levels of beta-endorphins following exercise (18.04 +/- 3.4 pg beta-EP ml-1) were not significantly changed from pre-exercise (control) levels (19.59 +/- 2.4 pg beta-EP ml-1), although there was considerable inter-individual variability. Our results support previous research which has reported no significant changes in beta-endorphin immunoreactivity following resistance exercise, as well as reported findings of considerable variability in the beta-endorphin response to exercise.

Adult↗
PubMed1993

Beta-endorphin response to endurance exercise: relationship to exercise dependence.

Considerable research has shown significant increases in beta-endorphin levels after aerobic activity. These increases and their accompanying euphoric effect have been suggested as a possible psychophysiological mechanism underlying the exercise-dependence syndrome. The relationship between plasma beta-endorphin levels and a tendency towards exercise dependence, however, has not been established. To examine this relationship, 8 women trained in aerobic dance completed an exercise-dependence assessment prior to participation in a 45-min. session of continuous aerobic dance. Plasma beta-endorphin concentration was measured both prior to and following the aerobics routine. A Student t test for paired observations indicated that mean plasma beta-endorphin levels (+/- SE) were significantly higher after the aerobics routine (11.96 +/- 1.3 pg beta-EP.ml-1) than preexercise levels (8.62 +/- 1.4). However, beta-endorphin difference values (% change) were not significantly correlated with scores on the exercise-dependence survey. Those data suggest that scores on exercise dependence are not related to changes in plasma beta-endorphin levels after aerobic exercise.

Adult↗
PubMed1993

Changes in the levels of several endogenous opioid peptides in dog cerebrospinal fluid following morphine administration.

The cisterna magna of dogs anesthetized with sodium Surital was fitted with a cannula, and cerebrospinal fluid (CSF) was withdrawn before (control) and one hour after the s.c. injection of 10 mg/kg of morphine sulfate (morphine). The CSF from control and morphine-treated dogs was purified initially by gel filtration. Each fraction was submitted to opiate bioassay procedures, followed by high performance liquid chromatography (HPLC) purification on a mu-Bondapak C18 column. Two of the CSF fractions from HPLC purification showed greater opiate-like activity after morphine treatment than that in controls. One fraction contained morphine, the other an unknown peptide. This latter fraction produced a dose-dependent effect in the mouse tail-flick test. This fraction did not show radioimmunoreactivity to methionine (met)- or leucine (leu)-enkephalins, but showed a small amount of reactivity to beta-endorphin and dynorphin (1-13). Further purification of this fraction by HPLC yielded a fraction with five peaks, which upon amino acid analysis were found to contain small peptides. Met- and Leu-enkephalins, beta-endorphin and dynorphin (1-13)-like immunoreactivity in the fraction in which the respective standard was eluted by HPLC was significantly increased after a single administration of morphine. Based on these results, it is suggested that morphine at an antinociceptive dose causes the release of endogenous opioid peptides and may also stimulate the biosynthesis of their precursor molecules, pre-pro-opiomelanocortin, pre-pro-enkephalin A and pre-pro-enkephalin B.

Amino Acids↗
PubMed1993

The role of endogenous opioids as mediators of the hypothermic effects of intrathecally administered calcium and calcitonin gene-related peptide in mice.

To the authors' knowledge, the effect of i.t. administered calcium on thermoregulation in mice has not been investigated. Calcium administration (i.t.) induced hypothermia in mice. It was found that calcitonin gene-related peptide (CGRP) (i.t.) also produced hypothermia. Because opioids have well documented thermoregulatory effects, the authors evaluated whether the hypothermia induced by calcium and CGRP was the result of the release of opioids. Calcium induced hypothermia at different ambient temperatures (4 degrees C, 22 degrees C and 30 degrees C) in intact mice. Similarly treated spinalized mice maintained body temperature. Using laser Doppler flowmetry, there was a significant increase in blood flow in the tails of calcium-injected mice vs. those of vehicle-injected mice. Both naloxone and naltrindole failed to block the hypothermic effects of calcium (i.t.). Nor-binaltorphimine (i.t.) significantly blocked calcium (i.t.)-induced changes in body temperature. CGRP (i.t.) produced hypothermia for 15 hr postinjection, with the maximum decrease at 3 hr. CGRP induced hypothermia in intact and sham-lesioned mice but not in spinalized mice. CGRP (i.c.v.) also produced hypothermia (onset, 15-min postinjection) followed by the peak effect at 1 hr with recovery to baseline temperature by 2 hr. Subthreshold doses of calcium and CGRP given in combination produced greater than additive hypothermia. The hypothermic effects of CGRP were reversed by naloxone, naltrindole and nor-binaltorphimine. CGRP produced significant hypothermia in both morphine-tolerant and nontolerant mice. Chronic administration of CGRP in nontolerant and morphine-tolerant mice did not alter hypothermia after pretreatment with CGRP (i.t.).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Elevated CSF beta-endorphin immunoreactivity in Rett's syndrome: report of 158 cases and comparison with leukemic children.

Because some symptoms of Rett's syndrome are suggestive of excessive endogenous opioid activity, we measured the levels of beta-endorphin-like immunoreactivity in lumbar CSF from 158 affected female patients and from 13 female controls. The mean (+/- SE) control level of beta-endorphin immunoreactivity in CSF was 35.3 +/- 2.8 pg/ml (range, 23 to 48 pg/ml), whereas those with Rett's syndrome had a mean level of 95.3 +/- 3.6 pg/ml (range, 31 to 293 pg/ml). The levels of beta-endorphin immunoreactivity in initial CSF samples exceeded the control range in 90% of the patients with Rett's syndrome. The mean beta-endorphin immunoreactivity was also elevated in CSF from leukemic children (119.2 +/- 16.9 pg/ml; range, 40 to 159 pg/ml), relative to the control group. These results are consistent with the hypothesis that some symptoms of Rett's syndrome may be associated with excessive endogenous opioid levels in the CNS.

Adolescent↗
PubMed1992

Evidence that endogenous opioids mediate the antinociceptive effects of intrathecally administered calcium in mice.

Mice injected with calcium in the intrathecal (i.t.) space display dose-dependent antinociception in the tail-flick test. The aims of this study were to evaluate whether endogenous opioids mediate the antinociceptive effects of calcium (i.t.) and to determine if antinociception resulted from calcium acting directly in segmental spinal sites. Mice spinalized at T6 to T8 were more sensitive to the antinociceptive effects of calcium (150-600 nmol i.t.) than sham-lesioned mice. In intact mice, naloxone (138-275 pmol i.t.) and naltrindole (2.8-22 nmol i.t.) dose-dependently blocked the antinociceptive effects of calcium (600 nmol i.t.), with inhibitory dose-50 (ID50) values of 235 picomol and 11.4 nanomol, respectively. nor-Binaltorphimine (nor-BNI) (14-54 nmol i.t.) did not antagonize the antinociceptive effects of calcium (i.t.). Furthermore, the calcium (i.t.) dose-response curve was shifted right-ward by naloxone (206 pmol i.t.) and naltrindole (5.5 nmol i.t.). nor-BNI (54 nmol i.t.) was ineffective in shifting the dose-response curve. In spinalized mice, naloxone (206-687 pmol i.t.) and naltrindole (11-44 nmol i.t.) blocked the antinociceptive effects of calcium (i.t.), with ID50 values of 342 and 19.2 nmol, respectively. nor-BNI did not antagonize antinociception. In addition, the calcium (i.t.) dose-response curve was shifted right-ward by naloxone (275 pmol i.t.) and naltrindole (11 nmol i.t.). The dose-response curve was not shifted by nor-BNI (54 nmol i.t.). A 4-hr pretreatment with the irreversible mu receptor antagonist beta-funaltrexamine (0.01-0.4 nmol i.t.) blocked [D-Ala2, N-Me-Phe4, Gly5-ol]enkephalin but not [D-Pen2,5]enkephalin or calcium (i.t.)-mediated antinociception.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗