Biomedical subjects

R Spangler

Publications and source records attributed to R Spangler.

At least 19 recordsLinked to original sources

PubMed2001

Hypothalamic CRH mRNA levels are differentially modulated by repeated 'binge' cocaine with or without D(1) dopamine receptor blockade.

We previously found that there was a rapid stimulatory effect of acute (1 day) 'binge' cocaine on CRH mRNA levels in the rat hypothalamus. In contrast, after 3 days of 'binge' cocaine, there was a modest decrease (12%) in hypothalamic CRH mRNA levels, which after 14 days of 'binge' cocaine was greater (32%) and significantly lower than control values. Also, our previous studies found an elevation of CRH mRNA in the frontal cortex after 3 days of 'binge' cocaine. The present study was designed to investigate the possible role of dopamine receptors in modulating these effects. Administration of 3 days of 'binge' cocaine (3 x 15 mg/kg, i.p.) was preceded by daily injections of either D(1) (SCH23390, 2 mg/kg) or D(2) (sulpiride, 50 mg/kg) dopamine receptor antagonist. Neither SCH23390 nor sulpiride had an effect on basal CRH mRNA levels in the hypothalamus, frontal cortex or amygdala. Small decreases (10-13%) in hypothalamic CRH mRNA levels were found again to be induced by 3 days of repeated 'binge' cocaine. However, this modest decrease was not found in the rats that received D(1) antagonist SCH23390 pretreatment. Pretreatment with D(2) antagonist sulpiride had no effect on this decrease. These findings suggest that the inhibitory effect of repeated 'binge' cocaine on the hypothalamic CRH mRNA expression is absent when there is D(1), but not D(2), dopamine receptor blockade. In the frontal cortex, pretreatment with either SCH23390 or sulpiride did not alter the increases in the CRH mRNA levels induced by repeated 'binge' cocaine. The results suggest that the cocaine-induced modulation of hypothalamic CRH mRNA expression is secondary to changes in the activity of specific components of dopaminergic systems.

Amygdala↗

PubMed2001

Elevation of guinea pig brain preprodynorphin mRNA expression and hypothalamic-pituitary-adrenal axis activity by "binge" pattern cocaine administration.

The endogenous opioid system and the hypothalamic-pituitary-adrenal (HPA) axis have been implicated in many of the neurobiological effects of cocaine. Previous studies in our laboratory showed that "binge" pattern cocaine administration increases preprodynorphin (ppDyn) mRNA levels in the caudate putamen and circulating levels of corticosterone in the rat. The present study extended these findings to guinea pigs, a species known to have a kappa opioid receptor profile similar to that of humans. Male guinea pigs were treated with: (a) "binge" pattern cocaine for 7 days (subchronic) (3 x 15 mg/kg/day, hourly, intraperitoneal); (b) "binge" pattern saline for 5 days followed by "binge" pattern cocaine for 2 days (subacute); or (c) "binge" pattern saline for 7 days. Thirty minutes after the final injection, levels of ppDyn mRNA were quantitated in the nucleus accumbens, caudate putamen, frontal cortex, amygdala, hippocampus, and hypothalamus using a solution hybridization RNase protection assay. Regional distribution of ppDyn mRNA levels in the guinea pig brain was similar to that found in rat, with highest levels in the nucleus accumbens and caudate putamen. In the caudate putamen, ppDyn mRNA was significantly increased following either 2 days (38% increase) or 7 days (32% increase) of "binge" pattern cocaine administration as compared to saline-treated controls. No significant changes in ppDyn mRNA levels were found in any other brain region. Both subacute and subchronic "binge" cocaine administration significantly elevated plasma levels of adrenocorticotropin hormone (ACTH) and cortisol. However, the ACTH and cortisol increases were significantly blunted following 7 days of "binge" cocaine administration as compared to 2 days of drug treatment, reflecting the development of HPA tolerance or adaptation to repeated cocaine administration. Thus, the ppDyn mRNA and HPA responses to cocaine in guinea pigs are similar to those observed in rats.

Animals↗

PubMed2000

Detection of single nucleotide polymorphisms of the human mu opioid receptor gene by hybridization or single nucleotide extension on custom oligonucleotide gelpad microchips: potential in studies of addiction.

The human mu opioid receptor (MOR) plays a central role in mediating the effects of opioids, both endogenous and exogenous. Epidemiological studies have shown that addiction in general, and especially opiate addiction, has a heritable component. Clinical and laboratory studies suggest that the MOR gene may contribute to the heritable component of vulnerability to develop opiate addiction. Naturally occurring single nucleotide polymorphisms (SNPs) have been identified in the MOR gene by conventional methods. Two coding region SNPs, the A118G and C17T substitutions, occur at high allelic frequencies (10.5% and 6.6%, respectively, in our previous studies). These common SNPs cause amino acid changes in the receptor, and may have implications for differences in individual responses to opioids, as well as decreased or increased vulnerability to opiate addiction. The A118G substitution encodes a variant receptor with binding and signal transduction differences in response to beta-endorphin in cellular assays. Recent innovations in microchip technology offer new potential methods for SNP detection. We report here on the development of two separate approaches using custom oligonucleotide gelpad microarrays for detection of these two common SNPs of the MOR gene in human DNA samples. First, PCR-amplified genomic DNA samples were used to produce target sequences, which were labeled with fluorescent dye and hybridized to custom microchips. Oligonucleotides on these reusable microchips were designed to query nucleotide substitutions at positions 17 and 118 of the MOR gene. Thirty-six human DNA samples were assayed both on these custom microchips and by conventional automated gel sequencing, with highly concordant identification of both heterozygous and homozygous substitutions. A second approach was developed for the C17T SNP utilizing single nucleotide extension on custom microchips. These custom gelpad microchips have potential for the rapid and inexpensive detection of specific SNPs for genetic and genomic studies.

DNA↗

PubMed2000

Reduced hypothalamic POMC and anterior pituitary CRF1 receptor mRNA levels after acute, but not chronic, daily "binge" intragastric alcohol administration.

BACKGROUND: Endogenous corticotropin-releasing factor (CRF), its pituitary CRF1 receptor, and proopiomelanocortin (POMC) may be involved in the hypothalamic-pituitary-adrenal (HPA) responses to alcohol. METHODS: Alcohol (1.5 g/kg) or water was administered intragastrically to male Fischer rats after the "binge" pattern regimen, that is, three times daily at 1 hr intervals at the beginning of the light cycle. The levels of CRF, CRF1 receptor, and POMC mRNAs in the hypothalamic-pituitary axis were measured after acute (1 day) or chronic (14 days) binge pattern alcohol administration. Plasma levels of ACTH and corticosterone were measured to examine time-dependent alterations of HPA responses. RESULTS: Plasma ACTH and corticosterone levels were elevated dramatically after 1 day of acute binge pattern alcohol administration. After 14 days of chronic alcohol, however, no elevation in plasma ACTH levels and an attenuated elevation in plasma corticosterone levels were found. CRF mRNA levels in the hypothalamus were not altered after either acute or chronic alcohol administration. CRF1 receptor mRNA levels in the anterior pituitary were decreased significantly after acute administration, with no change after chronic alcohol administration. POMC mRNA levels in the anterior pituitary were not altered by either acute or chronic alcohol administration. In the hypothalamus, POMC mRNA levels were decreased significantly after acute but not chronic binge alcohol administration. CONCLUSIONS: These results suggest that (1) rats exposed to chronic binge alcohol develop tolerance in HPA activity, as shown by no elevation of ACTH and an attenuated corticosterone response to chronic alcohol after initial dramatic elevations by acute alcohol administration; (2) a concurrent acute decrease in CRF1 receptor mRNA levels in the anterior pituitary is associated with increased HPA activity, and (3) alterations of POMC gene expression in the hypothalamic region may have implications for a molecular understanding of the neuroendocrine response to alcohol.

Administration, Oral↗

PubMed1999

Acute intermittent morphine increases preprodynorphin and kappa opioid receptor mRNA levels in the rat brain.

We determined the effects of morphine on mRNA levels for the opioid ligands preprodynorphin (PPD) and preproenkephalin (PPE) and the kappa opioid receptor (KOR). Rats received six injections of morphine (6.25 mg/kg/injection) every 2 h, and were sacrificed 30 min later. mRNA levels were measured in brain tissue after removal of the cortex, cerebellum and brainstem. There were increases in PPD and KOR mRNA levels (P<0.05 and P<0.005, respectively), with no alteration of PPE. These alterations in the kappa/dynorphin system may counter morphine-induced effects on the brain.

Animals↗

PubMed1999

Acute "binge" cocaine increases mu-opioid receptor mRNA levels in areas of the rat mesolimbic mesocortical dopamine system.

Autoradiography studies demonstrated that chronic "binge" cocaine administration increased mu-opioid receptor density in dopaminergically innervated rat brain regions, including the cingulate cortex, the nucleus accumbens, and the basolateral amygdala. The present study investigated the effects of a single day of binge-pattern cocaine administration (3 x 15 mg/kg, intraperitoneally [i.p.] at hourly intervals) on mu-opioid receptor mRNA levels in selected brain regions. Rats were sacrificed 30 min after the third injection and mRNA levels were measured by a quantitative solution hybridization RNase protection assay. Acute binge cocaine administration significantly increased mu-opioid receptor mRNA levels in the frontal cortex, nucleus accumbens, and amygdala, but not in the caudate-putamen, thalamus, hippocampus, and hypothalamus. As has been suggested for other G-protein coupled receptors, the rapid increase of MOR mRNA reported in this study might represent an adaptive response to compensate for a decrease in number of receptors following cocaine-induced opioid peptide release.

Animals↗

PubMed1999

Effects of chronic 'Binge' cocaine administration on plasma ACTH and corticosterone levels in mice deficient in DARPP-32.

The product of the DARPP-32 gene mediates intracellular signals initiated by the binding of dopamine to its receptors. Cocaine administration leads to increased activation of dopamine receptors, and causes activation of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis. We determined the effects of chronic 'binge' pattern cocaine on HPA activity in mice containing a targeted disruption of the DARPP-32 gene. Mice received three daily injections of cocaine (15 mg/kg/injection) for 14 days, and were sacrificed 30 min after the last injection. We measured the levels of plasma adrenocorticotropin (ACTH) and corticosterone which reflect HPA activity. In wild-type controls, 'binge' cocaine administration significantly increased plasma ACTH and corticosterone levels. In contrast, DARPP-32-deficient mice failed to show a significant elevation of either plasma ACTH or corticosterone levels following 'binge' cocaine. The results indicate that DARPP-32 plays a role in mediating the stimulatory effects of cocaine on the HPA axis.

Adrenocorticotropic Hormone↗

PubMed1999

Hypothalamic-pituitary-adrenal activity and pro-opiomelanocortin mRNA levels in the hypothalamus and pituitary of the rat are differentially modulated by acute intermittent morphine with or without water restriction stress.

Acute administration of morphine stimulates the secretion of hypothalamic-pituitary-adrenal (HPA) hormones, ACTH, beta-endorphin and corticosterone in the rat. In this study we investigated the effects of repeated multiple-dose morphine on HPA activity under two different conditions: without or with water restriction stress. Rats received six intermittent injections of morphine (6.25 mg/kg per injection, s.c.) every 2 h and were killed 30 min after the last injection. The results were as follows. (1) Morphine significantly elevated plasma ACTH and corticosterone levels; water restriction also significantly increased ACTH secretion, but with no significant increase of plasma corticosterone levels. In contrast, rats treated with morphine under the water restriction condition failed to show any increases of either ACTH or corticosterone levels. (2) Morphine did not change pro-opiomelanocortin (POMC) mRNA levels in the anterior pituitary; whereas water restriction significantly increased the POMC mRNA levels. The water restriction-induced increases of POMC mRNA in the anterior pituitary were absent in the rats which received morphine. (3) Morphine significantly increased POMC mRNA levels in the hypothalamus; water restriction had no effect. The morphine-induced increases in POMC mRNA in the hypothalamus were absent in the rat under the water restriction condition. These findings, that the effects of morphine on HPA activation or POMC mRNA expression depend on the presence of stress, suggest a counter-regulatory role of opiates on a stress response and opioid gene expression.

Adrenocorticotropic Hormone↗

PubMed1998

Effects of memantine alone and with acute 'binge' cocaine on hypothalamic-pituitary-adrenal activity in the rat.

The effects of memantine, a non-competitive NMDA-receptor antagonist used in the management of dementia, and its coadministration with acute 'binge' pattern cocaine on hypothalamic-pituitary-adrenal axis activity were investigated in the rat. Measurements 3 h after injections showed that memantine alone at 20 mg kg(-1) (i.p.), but not 10 mg kg(-1), increased corticotropin-releasing factor (CRF) mRNA levels in the hypothalamus and both adrenocorticotropic hormone and corticosterone levels in the blood, and decreased type I CRF receptor mRNA in the anterior pituitary. Our previous studies have shown that acute 'binge' cocaine increases CRF mRNA levels in the hypothalamus. In this study, pretreatment with memantine (10 and 20 mg kg(-1), i.p.) did not alter the up-regulation of hypothalamic CRF mRNA induced by acute 'binge' cocaine (3 x 15 mg kg(-1), i.p.). Of interest, pretreatment with memantine at 10 mg kg(-1), which alone had no effect on corticosterone levels, caused a greater elevation of corticosterone levels in combination with 'binge' cocaine than acute 'binge' cocaine alone, indicating that memantine does not attenuate 'binge' cocaine-stimulated hypothalamic-pituitary-adrenal activity. These results indicate that both memantine and acute 'binge' cocaine stimulate hypothalamic-pituitary-adrenal activity by activating CRF neurons in the hypothalamus.

Adrenal Glands↗

PubMed1997

Quantitation of dopamine transporter mRNA in the rat brain: mapping, effects of "binge" cocaine administration and withdrawal.

Dopamine transporter (DAT) mRNA from selected brain regions of individual male Fischer rats was quantitated utilizing a sensitive solution hybridization assay in which the levels of RNase-protected 32P-labeled mRNA:cRNA hybrids were measured. DAT mRNA was detected in whole brain regions known to contain abundant DAT mRNA (mean picogram of DAT mRNA/microgram of total RNA +/- SEM): substantia nigra, 7.17 +/- 0.47; ventral tegmentum, 4.71 +/- 0.38. In regions known to contain low levels of DAT mRNA, these levels were detected: central grey, 0.39 +/- 0.06; hypothalamus, 0.14 +/- 0.03. In addition, DAT mRNA was detected in areas where it had not previously been identified: amygdala, 0.19 +/- 0.03; caudate-putamen, 0.15 +/- 0.03; nucleus accumbens, 0.13 +/- 0.01; pons/medulla, 0.12 +/- 0.02; globus pallidus, 0.09 +/- 0.04; pituitary 0.07 +/- 0.01; frontal cortex, 0.05 +/- 0.01. No DAT mRNA was detected in 150 micrograms of rat liver RNA. As cocaine binds to and inhibits the activity of the dopamine transporter, we sought to determine if there were differences in dopamine transporter mRNA levels between saline- and cocaine-injected rats or rats withdrawn from a chronic "binge" pattern (15 mg/kg per dose i.p.; three doses at 1 h intervals each day) cocaine injection. Using trichloroacetic acid precipitation of mRNA:cRNA hybrids from RNA extracted from whole brain regions, we found no significant differences in the substantia nigra or the ventral tegmentum following subacute (3 days) binge, chronic (14 days) binge or 10 days withdrawal from a chronic binge pattern cocaine or saline administration.

Animals↗

PubMed1997

Behavioral stereotypies induced by "binge' cocaine administration are independent of drug-induced increases in corticosterone levels.

Cocaine administration causes dramatic stereotypic behavior and elevation of circulating corticosterone levels in rodents. The present study tested the possible role of increased corticosterone in mediating stereotypic behavior caused by "binge' pattern cocaine administration. Animals were administered saline or cocaine intraperitoneally for 3 days, with or without pretreatment with a D1 (SCH 23390, 2 mg/kg) or D2 (sulpiride, 50 mg/kg) dopamine receptor antagonist. Three days of cocaine "binges' significantly increased corticosterone levels in vehicle pretreated rats (P < 0.01). Both SCH 23390 and sulpiride pretreatment daily significantly attenuated this increase (P < 0.01). Cocaine administration caused stereotypic behaviors in vehicle pretreatment rats (P < 0.01). These behavioral responses were blocked by the D1 dopamine receptor antagonist SCH 23390, but not by the D2 antagonist sulpiride. These findings reaffirm the dominant role of the D1 receptor in mediating behavioral stereotypy caused by elevations of extracellular dopamine in the synaptic cleft. The fact that the dose of sulpiride used in these studies prevented the elevation of plasma corticosterone caused by cocaine, without blocking the stereotypy caused by cocaine, indicates that this stereotypic behavior does not require drug-induced elevation in circulating levels of corticosterone.

Animals↗

PubMed1997

Chronic food restriction and streptozotocin-induced diabetes differentially alter prodynorphin mRNA levels in rat brain regions.

It was previously reported that chronic food restriction and streptozotocin-induced diabetes lead to brain region-specific changes in levels of Prodyn-derived peptides. These changes parallel behavioral adaptations that are reversed by opioid antagonists. In the present study, effects of food restriction and diabetes on Prodyn gene expression were measured in rat brain regions using a quantitative solution hybridization mRNA assay. Picogram amounts of Prodyn mRNA were determined in extracts of five brain regions. The highest density of Prodyn mRNA was observed in extracts of nucleus accumbens (4.68 pg/microg total RNA), bed nucleus of the stria terminalis (4.18 pg/microg), and in caudate nucleus (3.51 pg/microg). Lower levels were observed in the lateral hypothalamus (1.87 pg/microg) and central nucleus of the amygdala (1.22 pg/microg). Food restriction and diabetes both markedly increased the levels of Prodyn mRNA in the central amygdala (163% and 93%, respectively). Levels in the lateral hypothalamus were also increased (35% and 29%, respectively), though only the food-restriction effect was statistically significant. Neither treatment altered prodynorphin mRNA levels in the caudate nucleus, nucleus accumbens or bed nucleus of the stria terminalis. These results suggest that dynorphin neurons in central amygdala and lateral hypothalamus may be involved in behavioral or physiological adaptations to sustained metabolic need.

Animals↗

PubMed1997

Prodynorphin, proenkephalin and kappa opioid receptor mRNA responses to acute "binge" cocaine.

Previous studies showed that preprodynorphin (ppDyn) mRNA increases in caudate-putamen while kappa opioid receptor (KOR) mRNA decreases in substantia nigra after 3 and 14 days "binge" cocaine. To further characterize opioid mRNA responses, rats were administered: saline; 1 day cocaine followed by 1 day saline; 1 day cocaine; or 2 days cocaine. ppDyn mRNA in caudate-putamen increased in both groups receiving cocaine on the final day compared to groups receiving saline. Preproenkephalin (ppEnk) mRNA in caudate-putamen increased, and KOR mRNA in substantia nigra decreased, after 2 days of cocaine. Thus ppDyn mRNA is elevated acutely by cocaine, while ppEnk and KOR mRNAs show a significant response only on the second day of "binge" cocaine.

Animals↗

PubMed1996

Steady-state methadone in rats does not change mRNA levels of corticotropin-releasing factor, its pituitary receptor or proopiomelanocortin.

Male Fischer rats received either methadone (a long-acting opioid agonist, 10 mg/kg/day) or saline (24 microliters/day) subcutaneously by osmotic minipumps for 7 days. Chronic steady-state methadone administration did not alter (a) corticotropin-releasing factor (CRF) mRNA in the hypothalamus, (b) proopiomelanocortin (POMC) and CRF type 1 receptor (CRF-R1) mRNAs in the anterior lobe and neurointermediate/posterior lobe of the pituitary, or (c) circulating levels of corticosterone. No change was found in levels of either POMC mRNA in the hypothalamus and amygdala, or CRF mRNA in the frontal cortex, olfactory bulb and amygdala. These results demonstrate that neither the activity of the hypothalamic-pituitary-adrenal axis, nor the beta-endorphin and CRF systems in the brain, are altered by steady-state occupancy of opioid receptors with the long-acting opioid agonist methadone.

Animals↗

PubMed1996

Dopamine antagonist and "binge' cocaine effects on rat opioid and dopamine transporter mRNAs.

The modulation by selective dopamine receptor antagonists of the effects of "binge' cocaine (3 x 15 mg kg-1 day-1, i.p., for 3 days after 11 days of adaptation to saline injections) on preproenkephalin, preprodynorphin, kappa opioid receptor and dopamine transporter mRNAs was determined. Administration of cocaine was preceded by daily single injections of a D1 (SCH 23390; 2 mg kg-1) or the D2 (sulpiride; 50 mg kg-1) dopamine receptor antagonist. The D1, and not the D2, antagonist blocked cocaine-induced preprodynorphine and preproenkephalin increases in the caudate-putamen. Sulpiride alone, and sulpiride plus cocaine, increased preproenkephalin mRNA. Dopamine transporter mRNA levels showed a cocaine treatment-antagonist interaction. These data indicate that this administration paradigm elevates both preprodynorphin and preproenkephalin mRNAs by a D1-dependent mechanism not requiring D2 activation.

Analysis of Variance↗

PubMed1996

Regulation of kappa opioid receptor mRNA in the rat brain by "binge' pattern cocaine administration and correlation with preprodynorphin mRNA.

We previously reported that 'binge' pattern administration of cocaine elevates preprodynorphin (ppDyn) mRNA in the caudate-putamen of rats. The present study confirms this finding. In addition, we report here that "binge' pattern administration of cocaine leads to a significant decrease in the mean level of kappa opioid receptor (KOR) mRNA in the substantia nigra, with no significant change in the mean level of KOR mRNA in the caudate-putamen. The decrease in KOR mRNA in the substantia nigra after 3 day or 14 day 'binge' administration of cocaine was comparable to the increase in ppDyn mRNA in the caudate-putamen. While there was no significant change in the mean levels of KOR mRNA in the caudate-putamen following cocaine administration, there was a positive within animal correlation between the levels of ppDyn mRNA and KOR mRNA in the caudate-putamen, both in animals administered saline and in animals receiving 'binge' cocaine for 14 days. Finally, mean levels of ppDyn or KOR mRNA in cocaine treated rats were not different from saline treated controls following a 10 day withdrawal from 14 days of 'binge' cocaine administration. The results provide evidence of regulation of KOR mRNA by cocaine in the substantia nigra.

Animals↗

PubMed1996

Modulation of CRF-R1 mRNA in rat anterior pituitary by dexamethasone: correlation with POMC mRNA.

Glucocorticoids have been shown to decrease CRF receptor binding in the anterior pituitary. To determine whether glucocorticoids or CRF peptide modulate CRF-R1 gene expression, CRF-R1 mRNA levels in rat pituitary and brain were measured after administration of a synthetic glucocorticoid, dexamethasone (DEX) or rat/human CRF (r/hCRF), using a sensitive solution hybridization RNase protection assay. DEX (400 micrograms/day) or r/hCRF (100 micrograms/kg/day) was administered twice daily for 5 days to male rats. DEX treatment caused a significant decrease in CRF-R1 mRNA levels in the anterior pituitary. Also, a significant positive correlation was found between CRF-R1 and POMC mRNA levels in the anterior pituitary of the individual animals: levels of both mRNAs were reduced by DEX. However, r/hCRF treatment had no significant effect on CRF-R1 mRNA levels in the anterior pituitary. In extrahypothalamic brain regions, mRNA levels of CRF-R1 did not change following either DEX or r/hCRF administration. Our data suggest that in addition to POMC and CRF genes, CRF-R1 gene may also be subject to negative feedback control by glucocorticoids.

Amygdala↗

PubMed1996

The in vitro effects of 6-methoxy-2-naphthylacetic acid, the active metabolite of nabumetone, on rat gastric mucosal eicosanoid synthesis and metabolism.

Nabumetone is a neutral non-steroidal anti-inflammatory drug with a low propensity to cause gastrointestinal (GI) damage. Previous studies, in vivo, have shown that the drug has weak effects on gastric mucosal cyclooxygenase activity, which may help to explain its favourable GI profile. The present study set out to determine whether the observed effects of nabumetone on cyclooxygenase, in vivo, parallel those of its active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA), in vitro. We have also studied nabumetone and 6MNA on two other systems, namely 15-prostaglandin dehydrogenase (15-PGDH) and 5-lipoxy-genase (5-LO), which when inhibited may confer mucosal protection. The results showed that 6MNA had variable effects on cyclooxygenase activity, depending on the concentration and was less potent and less effective than indomethacin. Cyclooxygenase activity was not inhibited by the reversible inhibitor, aminopyrine, but at low concentrations stimulation was observed. Sulphasalazine inhibited 15-PGDH in a concentration-dependent manner whereas 6MNA inhibited it only at high concentrations. Nabumetone was devoid of activity. Basal 5-LO activity was attenuated by phenidone and unaltered by 6MNA but increased by nabumetone at the highest concentration. In the presence of arachidonic acid, to raise 5-LO activity, nabumetone, 6MNA, BW755C and phenidone apparently inhibited this activity. However, it was possible that both nabumetone and 6MNA inhibited a prostanoid-mediated stimulatory effect on 5-LO rather than effecting enzyme inhibition per se. Nabumetone's favourable GI profile may, therefore, relate to 6MNA having weak effects on mucosal cyclooxygenase and is unlikely to involve inhibition of prostanoid metabolism or 5-LO.

Animals↗