Biomedical subjects

G K Yim

Publications and source records attributed to G K Yim.

At least 37 records · Page 2Linked to original sources

PubMed1989

MDMA transiently alters biogenic amines and metabolites in mouse brain and heart.

(+-)-3,4-Methylenedioxymethamphetamine (MDMA) (10, 20, and 40 mg/kg) was administered to male CF-1 mice which were sacrificed 3, 6, or 24 hours posttreatment for analysis of brain and cardiac biogenic amines and metabolites. In contrast to reported effects of MDMA in the rat, the highest dose of MDMA transiently elevated mouse brain 5-hydroxytryptamine (5-HT) 3 hours following drug treatment. Levels of dopamine were not significantly affected. 5-Hydroxyindoleacetic acid and dihydroxyphenylacetic acid were significantly lowered by MDMA at the two early time points. The highest dose of MDMA produced a transient depletion of norepinephrine in mouse brain and heart tissue. Only the effects of MDMA on cardiac norepinephrine were prevented by pretreatment of animals with desipramine. A regimen consisting of four daily doses of 40 mg/kg MDMA only produced significant declines in 5-HIAA, dopamine and homovanillic acid levels one week following the last dose. These data confirm previous reports that mice are resistant to the neurotoxic effects of MDMA suggesting that a species variation in response to MDMA exists.

3,4-Methylenedioxyamphetamine↗

PubMed1989

Induction of interleukin-1 and tumor necrosis factor by 12-O-tetradecanoylphorbol-13-acetate in phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice.

12-O-tetradecanoylphorbol-13-acetate (TPA), the most potent skin tumor promoter known, evokes significant inflammatory responses in mouse skin after topical application. Infiltrating inflammatory cells have been hypothesized to contribute to genetic damage in epidermal cells through the generation of reactive oxygen intermediates (ROIs), thus facilitating the development of tumors. Interleukin-1 (IL-1) and tumor necrosis factor (TNF), small mol. wt cytokines produced by macrophages (MPs), are known to have important roles in the inflammatory process. Lipopolysaccharide (LPS)-triggered release of IL-1 and TNF was determined in culture supernatants of splenic MPs from phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice following topical application of 8 micrograms of TPA twice in one week. The findings reported herein indicated that topical application of TPA primed splenic MPs from both SENCAR and B6C3F1 mice in a quantitatively similar manner for the production of IL-1 and TNF; in addition, the release of IL-1 and TNF by splenic MPs from control (naive or acetone-dosed) SENCAR and B6C3F1 mice in response to LPS-triggering in vitro was not significantly different. Therefore, the production and release of these cytokines by activated MPs does not correlate with the reported strain-dependent susceptibilities to TPA-induced inflammation and/or tumor promotion.

Administration, Topical↗

PubMed1989

Induction of suppressor macrophages by 12-O-tetradecanoylphorbol-13-acetate in phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice.

Following topical application of 8 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) twice in one week, the ability of splenic macrophages (M phi s) isolated from phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice to suppress the phytohemagglutinin (PHA)-induced lymphocyte blastogenesis and NK activity mediated by spleen cells from naive animals was determined. In B6C3F1 mice, suppression of lectin-induced lymphocyte blastogenesis was mediated by M phi s from TPA-dosed animals. Alternatively, in TPA-dosed SENCAR mice, induction of M phi s suppressive to lectin responses was not apparent. In addition, suppressor M phi s did not mediate the decreased splenic natural killer (NK) activity that is characteristically observed in TPA-dosed SENCAR mice. Therefore, it is proposed that the decreased PHA responsiveness and NK activity observed in vivo in TPA-dosed SENCAR mice may be the result of a decreased proportion of lectin-responding T cells and NK cells in the spleen as a result of proliferation of inflammatory cell precursors.

Animals↗

PubMed1988

Anthralin, a non-phorbol tumor promoter, fails to inhibit metabolic cooperation in mutant human fibroblasts, but inhibits phytohemagglutinin-induced lymphocyte blastogenesis in vitro.

Two (among many) of the hypotheses put forward to explain mechanisms of action of tumor promoters are: (1) immunosuppression of the host; and (2) inhibition of intercellular junctional communication. Murine spleen cells were exposed for 30 min to various concentrations of anthralin (1,8-dihydroxy-9-anthrone), a polyphenolic non-phorbol promoter, and 1,8-dihydroxyanthraquinone (1,8-DHAQ), an inactive congener. Phytohemagglutinin (PHA)-induced T cell blastogenesis, an indicator of lymphocyte function, was then assessed in vitro. Exposure to anthralin resulted in a concentration-dependent suppression of lymphocyte proliferation with complete suppression occurring at 1 microM. The inactive congener, 1,8-DHAQ, failed to suppress lectin-induced blastogenesis at concentrations up to 10 microM. Dithiothreitol (DTT), a sulfhydryl (SH) compound, failed to protect against the suppression of lymphocyte function by anthralin. In addition, anthralin failed to inhibit in vitro microtubule assembly, a SH-dependent process, in a crude rat brain extract. Finally, unlike 12-O-tetradecanoylphorbol-13-acetate (TPA), the most potent skin tumor promoter known, anthralin failed to inhibit metabolic cooperation between mutant human fibroblasts as assayed by [14C]citrulline incorporation. In summary, the data suggest that anthralin may act as a tumor promoter by suppressing immune parameters, a property which is shared by the phorbol esters.

Animals↗

PubMed1988

Stress- and morphine-induced elevations of plasma and tissue cholesterol in mice: reversal by naltrexone.

Our earlier studies indicated that stress-induced facilitation of gallstone formation could be prevented by the opiate antagonist naltrexone. In view of the possible link between gallstone formation and atherosclerosis, the present study examined the possibility that endogenous opioids might also mediate stress-induced hypercholesterolemia. A 28-day immobilization stress schedule was used to induce increases in plasma, aortic and liver cholesterol of mice maintained on a high cholesterol diet. These stress-induced increases in plasma, hepatic and aortic cholesterol were reversed by pretreatment with the opiate antagonist, naltrexone (1 mg/kg). Exposure of mice to morphine (0.1% in the drinking water for 28 days) resulted in elevations of plasma, liver, and aortic cholesterol levels, similar to those observed following immobilization. In contrast, chronic exposure to the peripherally restricted opiate agonist, loperamide (0.1% in the drinking water for 28 days), was ineffective. The antagonism by naltrexone and duplication by morphine but not loperamide suggest that stress-induced hypercholesterolemia may require the activation of central endogenous opioid systems.

Animals↗

PubMed1988

Nocturnal depletion of hypothalamic dynorphin in anorexic Walker-256 tumor-bearing rats.

Rats implanted with the Walker-256 (W-256) tumor exhibit marked anorexia that is most apparent at night. In this model, the hypothalamic kappa opioid system was examined for deficits that might contribute to this tumor-induced anorexia. In anorexic tumor-bearing rats (TBR), nocturnal levels of ir-DYN-8 were significantly reduced in the hypothalamus, but ir-DYN-17 levels were not. Accumulation of 3H-etorphine or 3H-ethylketocyclazocine, a putative ligand for the kappa receptor subtype, was not increased in the hypothalamus of the TBR, as might have been expected if there were less endogenous dynorphin to occupy the opioid receptors in this region. In vitro binding assays with 3H-ethylketocyclazocine indicated that dynorphin depletion in the TBR was not sufficient to increase the numbers of kappa opioid receptors in the hypothalamus. Also, the sensitivity of kappa opioid receptors involved in feeding was not altered in the TBR as indicated by an intact feeding response to ketocyclazocine. In summary, the marginal deficits of hypothalamic dynorphin in W-256 tumor-bearing rats that coincide with the phase of tumor-induced anorexia may contribute to the reduction in food intake.

Animals↗

PubMed1988

Modulation of natural killer activity by 12-O-tetradecanoylphorbol-13-acetate and benzoyl peroxide in phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice.

Following two weeks of topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) at 2, 4 and 8 micrograms/mouse on alternate days (7X total) or benzoyl peroxide (BZP) at 10, 20 and 40 mg/mouse, natural killer (NK) activity was determined in local (lymph nodes draining the lower dorsal region) and systemic (spleen) lymphoid tissue in phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice. SENCAR mice, sensitive to tumor induction by TPA in two-stage chemical-induced carcinogenesis protocols, demonstrated suppression of NK activity in the spleen (no significant change in lymph nodes) and substantial dose-dependent increases in cell numbers in these organs after topical exposure to TPA. B6C3F1 (C57BL/6 X C3H F1) mice, reported to be resistant to TPA-induced promotion, demonstrated significant increases in NK activity in lymph nodes/spleen with an increase in cell numbers in the draining nodes only. Unlike the C57BL/6 parental strain, B6C3F1 mice are also reported to be resistant to promotion with BZP. Significantly, studies in this laboratory indicated that B6C3F1 mice dosed with BZP demonstrated increased NK activity in the spleen as was observed after dosing with TPA. These data suggest that alterations in NK activity as a result of exposure to tumor promoters may, in part, account for the resistance of particular strains of mice to tumor development. In both SENCAR and B6C3F1 mice, the blastogenic response of spleen cell suspensions isolated from TPA-dosed animals to phytohemagglutinin (PHA), a T cell lectin, was suppressed in a dose-dependent manner; BZP had no effect on spleen cell responses in either strain. Blastogenic responses of lymph node cells to PHA were enhanced in both strains of mice after topical application of TPA and BZP. Therefore, alterations in lymphoid cell responsiveness to PHA appeared unrelated to the reported sensitivities of SENCAR and B6C3F1 mice to tumor promotion.

Administration, Topical↗

PubMed1987

Morphine-induced alterations in plasma and tissue cholesterol levels.

In rats fed a cholesterol-cholic acid supplemented diet, implantation of a 75 mg morphine pellet elevated total plasma cholesterol, raised low density lipoprotein (LDL) plus very low density lipoprotein (VLDL) cholesterol, and lowered high density lipoprotein (HDL) cholesterol levels. The resultant increase of the atherogenic index was accompanied by enhanced aortic cholesterol deposition. These alterations were prevented by daily administration of naltrexone (1.0 mg/kg, sc), and were not associated with hyperphagic or hepatotoxic actions of morphine. An increase in total plasma cholesterol and in LDL plus VLDL cholesterol was also observed in morphine pelleted rats maintained on a normal diet. The possible implications of opiate-induced hypercholesterolemia are discussed.

Animals↗

PubMed1987

Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]monoamines into synaptosomes from different regions of rat brain.

3,4-Methylenedioxymethamphetamine (MDMA) is a recently popularized recreational drug, although some have advocated its psychotherapeutic potential. Since the pharmacology of MDMA is largely uncharacterized, the stereochemical profiles of MDMA and some of its homologs were derived on inhibition of synaptosomal uptake of [3H]monoamines and compared to those of amphetamine and the hallucinogenic phenylisopropylamine 2,5-dimethoxy-4-methylamphetamine (DOM). In contrast to the 5-fold stereoselectivity observed with amphetamine, only the S-(+) enantiomer of MDMA and 3,4-methylenedioxyamphetamine (MDA) inhibited [3H]dopamine uptake into striatal synaptosomes. Neither stereoisomer of the alpha-ethyl homolog of MDMA, N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), inhibited [3H]dopamine uptake. The two stereoisomers of amphetamine and the MDMA-related compounds were equipotent in inhibiting [3H]norepinephrine uptake into hypothalamic synaptosomes. Both stereoisomers of MDMA, MDA and MBDB were potent inhibitors of [3H]serotonin uptake into hippocampal synaptosomes, but only S-(+)-amphetamine produced an appreciable inhibition of [3H]serotonin uptake. Neither stereoisomer of DOM inhibited synaptosomal uptake of any [3H]monoamine. These results suggest that MDMA and its homologs may be more closely related to amphetamine rather than to DOM in their biochemical mode of action. The pronounced effects of the methylenedioxy-substituted compounds on [3H]serotonin and [3H]norepinephrine uptake implicate these neurotransmitters in the pharmacological effects of these drugs.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1987

Iodoacetic acid and related sulfhydryl reagents fail to inhibit cell-cell communication: mechanisms of immunotoxicity in vitro.

The present study was undertaken to examine the effects of iodoacetic acid, a non-phorbol tumor promoter, on metabolic cooperation between mutant human fibroblasts as measured by [14C]citrulline incorporation. Other thiol-reactive polyphenolic compounds such as hydroquinone and 2-hydroxyestrone were also examined. 12-O-Tetradecanoyl phorbol-13-acetate (TPA), a potent skin tumor promoter, inhibited the cell-cell communication by more than 60% at 20 ng/ml. However, iodoacetic acid, hydroquinone, and 2-hydroxyestrone, had no effect on the process even at cytotoxic concentrations. Induction of intercellular contact (agglutination) among lymphocytes during the course of phytohemagglutinin (PHA)-induced blastogenesis was monitored turbidometrically at 620 nm. Hydroquinone and 2-hydroxyestrone suppressed the PHA-induced lymphocyte agglutination at 1-2 microM in vitro concentrations while iodoacetic acid was devoid of any effects at concentrations up to 100 microM. Hydroquinone and 2-hydroxyestrone concomitantly suppressed PHA-induced lymphocyte blastogenesis at 1-2 microM in vitro concentrations while the suppression by iodoacetic acid was significant at 10 microM. All 3 compounds failed to disrupt microtubule assembly, a sulfhydryl-dependent process, in a rat brain crude extract. However, p-benzoquinone, an oxidation product of hydroquinone, did inhibit the process at 1 mM. In summary, these studies suggest that, unlike TPA, thiol-reactive non-phorbol tumor promoters and polyphenolic compounds do not inhibit cell-cell communication between mutant human fibroblasts. Although the compounds demonstrate diverse molecular mechanisms of action, they all inhibit in vitro immune functions suggesting that immunosuppression may play a role in tumor promotion.

Agglutination↗

PubMed1986

Opioid and non-opioid components of insulin-induced feeding.

The present study was initiated to clarify the involvement of endogenous opioids in insulin-induced feeding. Naloxone (3 mg/kg) was injected in male Sprague Dawley rats every hour for 2 hours after insulin injection (10 U/kg). Only the first hour food intake was depressed (68% reduction). When naloxone was given only 1 hour after insulin administration, depression of food intake was not noted. When food was withheld for 2 hours after insulin injection, both naloxone and its long acting congener, naltrexone (3 mg/kg) were able to depress only the first hour feeding subsequent to food presentation. These data suggest that insulin-induced feeding can be divided into two pharmacologically distinct phases: the early phase being naloxone-sensitive while the late phase is naloxone-insensitive. Furthermore, the early phase begins with the presentation of food and not with the administration of insulin.

Animals↗

PubMed1986

Lack of tolerance of morphine-induced spasm of guinea pig sphincter of Oddi.

To determine whether guinea pigs chronically exposed to morphine would develop tolerance to the morphine-induced contraction of the sphincter of Oddi (SO), adult male guinea pigs were implanted with morphine pellets (100 mg morphine). The effect of increasing IV doses of morphine on the SO was assessed by determining the duration of which saline perfusate stopped flowing into the duodenum of morphine-treated guinea pigs (MTGP) vs nonimplanted animals (non-MTGP). Isolated bovine and guinea pigs SO were also challenged with morphine. In the in vivo experiments the spasmogenic response of the SO from MTGP to morphine was greater than that of SO from non-MTGP. However, morphine had no effect on isolated SO. These results indicate that chronic morphine exposure does not result in tolerance of the SO to the spasmogenic effects of morphine. On the contrary, chronic morphine even sensitized the SO to morphine, in addition, the in vitro data indicated that morphine does not act directly on the smooth muscle of SO to cause its spasmogenic effect.

Ampulla of Vater↗

PubMed1985

Presence of dynorphin-like immunoreactivity but not opiate binding in Walker-256 tumors.

Walker-256 tumor tissue was removed from rats on day 8 of tumor growth. An acidified methanol extract of the tumor tissue was assayed for immunoreactive (ir) dynorphin-A 1-17 (DYN-17) and ir-dynorphin-A (DYN-8). Levels of ir-DYN-17 and ir-DYN-8 were nearly 4-and 8-fold higher, respectively, in tumors versus normal muscle. However, tumor homogenates did not exhibit specific 3H-naloxone binding. These results indicate that although the Walker-256 carcinosarcoma may produce opioids, it is unlikely that these ectopic substances have direct opioid actions on the tumor itself.

Animals↗

PubMed1985

Brain catecholamine alterations accompanying development of anorexia in rats bearing the Walker 256 carcinoma.

In the present study, the relationship between central catecholamine levels and the anorexia induced by Walker 256 carcinoma was investigated. Results indicate that the anorexia is not due to depletion of central catecholamines. Tumor bearing rats sacrificed at night, when spontaneous food intake is selectively depressed, showed increased norepinephrine levels in the hypothalamus, cortex and hippocampus and increased dopamine levels in the striatum, midbrain, and cortex. Increased nighttime hypothalamic norepinephrine levels were positively correlated with the magnitude of spontaneous food intake in tumor rats.

Animals↗

PubMed1985

Assessment of dynorphin-A depletion in the anorexia of Walker-256 tumor bearing rats.

Rats bearing the Walker-256 (W-256) tumor display an anorexic profile which resembles that of normal animals forced to drink 2% NaCl [2,24], a regimen which depletes neurohypophyseal dynorphin-A (DYN) [3,9]. As expected, the naloxone reversible feeding induced by 2-deoxy-D-glucose (2-DG) was attenuated (36%) in the W-256 tumor bearing rats (TBR). Interestingly, immunoreactive (ir) levels of dynorphin-A 1-17 (DYN-17) and its postulated breakdown product, dynorphin-A 1-18 (DYN-8), were also reduced in the neurohypophysis of W-256 TBR by 42 and 50%, respectively. However, ir-DYN levels were not reduced in TBR in those brain regions which are probably involved in the regulation of appetite (e.g., hypothalamus). 2-DG itself did not consistently affect ir-DYN levels in any tissue for either controls or TBR. The ratio of DYN-8 to DYN-17 did not change in response to any treatment, including the depletion of both peptides from the NIL of TBR. In summary, the present data do not support DYN depletion as being a factor which contributes to the anorexia of the W-256 TBR.

Animals↗

PubMed1985

Effects of 2% sodium chloride imbibition on various opiate related hyperphagic conditions.

Dynorphin is one of the most potent appetite stimulants among the endogenous opioids. In this study, we describe the anorexic effects of 5 days of forced 2% NaCl drinking in rats, a regimen which depletes vasopressin as well as dynorphin in the neurohypophysis. Feeding induced by direct activation of kappa-opioid receptors with ketocyclazocine was unaffected by the NaCl regimen. However, 2% NaCl imbibition reduced 2-deoxy-D-glucose (2-DG) induced feeding by 65% and spontaneous nocturnal feeding by 38%. Feeding subsequent to 24 hour food deprivation was not decreased. Naloxone-resistant hyperphagia induced by insulin and spontaneous daytime feeding were also not reduced. The combination of naloxone (3.0 mg/kg) and the NaCl regimen produced an additional 50% reduction in 2-DG induced feeding and an extra 40% decrease in nocturnal feeding. Naloxone, given with 2% NaCl to food deprived animals, retained its appetite suppressing activity, indicating that the NaCl regimen did not deplete the endogenous opioid which mediates food deprivation hyperphagia. These results demonstrate that 2% NaCl imbibition suppresses certain opioid mediated hyperphagias. However, the failure of 2% NaCl to affect all of the naloxone-sensitive types of feeding and the independence of naloxone-sensitive and NaCl-sensitive components suggests that NaCl drinking does not deplete dynorphin in the brain areas which mediate opiate-sensitive hyperphagias.

Animals↗

PubMed1985

Naltrexone fails to suppress spontaneous locomotor activity in hamsters.

The increased spontaneous locomotor activity (SLMA) of rats exposed to a novel environment is decreased by opiate antagonists. In the present study, naltrexone (1.0-40 mg/kg) failed to reduce the SLMA of hamsters exposed to the novel environment of activity cages. The SLMA of another group of untreated hamsters declined following 4 consecutive exposures to the activity cages. Thus, the novelty-induced increase in hamster SLMA is not sensitive to opiate antagonism. The differential sensitivity of rats and hamsters to opiate effects on activity and feeding may be due to the presence of an opiate-sensitive hibernation system in hamsters.

Animals↗

PubMed1985

Opioid modulation of feeding behavior following forced swimming exercise in male rats.

Adult male rats were subjected to an acute bout of swimming exercise for 50 min during the early morning or late afternoon. Compared to nonexercised controls, all exercised groups showed an initial approximately 2-hr period of increased feeding (period I hyperphagia). A 50-min period of sham swimming (wading in water) was followed by period I hyperphagia but not period II hypophagia. Opioid modulation of period I hyperphagia was indicated by the ability of naltrexone to antagonize, in a dose-dependent manner, the postexercise hyperphagia. Furthermore, plasma concentrations of immunoreactive B-endorphin (Ir-B-ep) were increased during period I following exercise. Opioid modulation of the period II hypophagia was equivocal. Plasma Ir-B-ep was not altered in period II, and naltrexone did not modify period II hypophagia. The ability of 2-deoxy-D-glucose to induce feeding was slightly depressed (p less than 0.05) during period II after exercise, and the ability of exogenous insulin to induce feeding was not changed. These differential feeding responses to 2-deoxy-D-glucose (opioid-mediated) and insulin (relatively opioid-independent) suggest that an opioid deficiency may exist during period II and contribute to the hypophagia.

Animals↗