Biomedical subjects

E R Meyer

Publications and source records attributed to E R Meyer.

At least 19 recordsLinked to original sources

PubMed2000

Gender differences in the reinforcing properties of morphine.

The purpose of the present studies was to examine whether gender differences could be observed in an important aspect of morphine's pharmacology: its reinforcing properties. Our results showed that morphine served as a positive reinforcing agent in both male and female rats in a place conditioning paradigm, but that the dose-response curves displayed marked sex-related differences. At doses from 0.2 up to 10.0 mg/kg, morphine induced an equally strong preference for the drug-associated chamber in males and females. However, as the dose was increased from 10-17.5 mg/kg, morphine ceased to act as a positive reinforcer in males. In contrast, a very strong preference for the morphine-associated chamber was still observed in females at doses up to 30 mg/kg. No gender differences in the blood and brain levels of morphine were observed subsequent to morphine administration during the conditioning phase, suggesting that pharmacokinetic factors were not involved in the sex-related differences observed. Consequently, these results suggest that there are intrinsic sex-linked differences in the doses of morphine that can induce a preference for the drug-associated chamber in a place-conditioning paradigm that are most likely related to differences in the sensitivity of the central nervous system to morphine's reinforcing properties in males and females.

Animals↗

PubMed1998

Imidazoles suppress rat testosterone secretion and testicular interstitial fluid formation In vivo.

The aim of these studies was to examine the effects of imidazoles on testosterone secretion and testicular interstitial fluid (TIF) formation through measurement of serum LH, serum testosterone, TIF testosterone, and TIF volumes. Imidazole, 1-methylimidazole, 4-methylimidazole (4-MI), and ketoconazole, an oral imidazole antifungal agent, caused dose-dependent decreases in testosterone secretion and TIF formation. Imidazole, 2-methylimidazole, and 4-MI decreased LH secretion. 4-MI decreased testosterone secretion 1-6 h after injection, increased testosterone at 8-16 h, decreased LH secretion at 4 h, decreased TIF volumes at 1-8 h, and slightly increased TIF volumes at 24 h. 4-MI blocked the stimulatory effects of hCG on testosterone secretion and prevented an expected increase in LH secretion after the 4-MI-induced decrease in testosterone secretion. 4-MI also reversed the effects of three other stimulants of testosterone secretion that presumably act through three different testicular regulatory systems: N-methyl-D,L-aspartate, an excitatory amino acid; NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor; and naltrexone, an opioid antagonist. These results support the hypothesis that imidazoles inhibit testicular function and male reproductive function through inhibition of testosterone secretion, TIF formation, and LH secretion regulatory systems.

Animals↗

PubMed1997

Interactions between alcohol- and opioid-induced suppression of rat testicular steroidogenesis in vivo.

To examine interactions between alcohol and endogenous opioids in their suppressive effects on rat testicular function, the opioid antagonist naltrexone or the opioid agonist morphine was administered to adult male rats alone or in combination with alcohol. Serum testosterone, testicular interstitial fluid (TIF) testosterone, and TIF volumes were measured to assess testicular function. Naltrexone induced dose-dependent increases in serum and TIF testosterone levels without changes in TIF volume. Alcohol (0.5 g/kg) inhibited naltrexone-induced stimulation of testosterone secretion and shifted the naltrexone dose-response curve to the right. Conversely, naltrexone (0.05 mg/kg) inhibited alcohol-induced suppression of testosterone secretion and shifted the alcohol dose-response curve to the right. Relatively high doses of naltrexone (5 to 30 mg/kg) were needed to stimulate testosterone secretion maximally in rats treated with a low dose of alcohol (0.5 g/kg) and to stimulate normal levels of testosterone secretion in rats treated with a high dose of alcohol (2 g/kg). In addition, combined treatment with 1 and 30 mg/kg of naltrexone and 0.5 to 2 g/kg of alcohol did not alter blood alcohol concentrations significantly, suggesting that the interactions between alcohol and naltrexone were unrelated to gross changes in alcohol metabolism or bioavailability factors. Simultaneous treatments with a low dose of alcohol (0.3 g/kg), near the threshold of efficacy, and low-moderate doses of morphine (0.3 to 3 mg/kg) were not additive in suppressing testosterone secretion, compared with either agent alone. These results support the hypothesis that opioid antagonists can reverse the suppressive effect of alcohol on testicular steroidogenesis, but the results also suggest that endogenous opioids do not exclusively mediate alcohol's effects on testosterone secretion.

Alcoholism↗

PubMed1997

Sex-related differences in morphine's antinociceptive activity: relationship to serum and brain morphine concentrations.

In earlier studies, it was shown that male rats were considerably more sensitive to the antinociceptive properties of morphine than females in several antinociceptive assays. The purpose of our studies was to examine whether these male-female differences might be due to differences in the blood and brain levels of morphine attained after its s.c. injection rather than to intrinsic differences in the central nervous system sensitivity to the drug. Our results confirmed that males were considerably more sensitive than females to the antinociceptive properties of morphine on the hot-plate test; the ED50 in males was approximately half that found in females. These sex differences were not unique to morphine because males were also more sensitive to the antinociceptive properties of the potent mu agonist, alfentanil. With respect to the pharmacokinetics of morphine, we found that there was a linear relationship in both males and females between the dose of morphine injected and the blood and brain levels achieved 60 min after the injection when the sex-linked differences in morphine-induced antinociception was greatest; no sex differences were found in the peak levels of morphine attained in blood or brain at any dose of morphine. Furthermore, there were no sex-linked differences in the elimination half-life of morphine from blood and, similarly, there were no differences in the disappearance of morphine from brain. On the basis of these data, it appears that the sex-related differences we have observed between males and females in the response to morphine's antinociceptive activity cannot be explained by differences in the pharmacokinetics of morphine. Rather, it appears that sex differences in morphine-induced antinociception are related to inherent differences in the sensitivity of the brain to morphine.

Alfentanil↗

PubMed1996

Effects of nitric oxide-related agents on opioid regulation of rat testicular steroidogenesis.

These studies examined whether nitric oxide (NO) mediates opioid suppression of testicular steroidogenesis. Adult male rats were treated with various combinations of a NO synthase (NOS) inhibitor (NG-nitro-L-arginine methyl ester; NAME), a NO donor (isosorbide dinitrate; ISDN), an opioid agonist (morphine, and an opioid antagonist (naltrexone). Serum LH and testosterone and testicular interstitial fluid (TIF) testosterone concentrations were then measured. Inhibition of NO production by NAME reversed morphine-suppressed testosterone secretion; treatment with the NO donor, ISDN, reversed naltrexone-stimulated testosterone secretion. NAME did not alter morphine's effects on LH secretion and attenuated morphine's suppression of hCG-stimulated testosterone secretion, indicating that these effects occur directly in the testes and are not dependent on LH secretion. Even though these effects suggested possible interactions between NO and opioid systems, no additive or synergistic effects were found with suppressive combinations of morphine and ISDN, or with stimulatory combinations of naltrexone and NAME at does that had little effect on testosterone secretion when given alone. These results indicate that opioid and NO exert independent effects on testicular steroidogenesis through separate pathways or mechanisms and that NO does not mediate opioid-induced testicular suppression.

Animals↗

PubMed1996

Gender-related differences in the antinociceptive properties of morphine.

As part of an effort to examine gender-related differences in the abuse liability of morphine, the present parametric study was undertaken to systematically establish whether there are gender-related differences in the antinociceptive activity of morphine in rats. Our results showed that male rats were uniformly more sensitive to the antinociceptive properties of morphine than were females in three different assays, i.e., the hot-plate, tail-flick and abdominal-constriction tests. This enhanced sensitivity to morphine was reflected in the peak antinociceptive effect, the magnitude of antinociception (i.e., area under the time-action curve), the duration of the antinociceptive response and the 50% effective dose. These differences appear to reflect markedly enhanced central nervous system sensitivity to morphine in males, compared with females, because we observed no gender-linked differences in serum levels of morphine after its injection, at the time when peak antinociceptive effects were observed. Furthermore, these gender-related differences appear to be reflected in antinociception thought to be mediated by both spinal and supraspinal mechanisms. Finally, our results suggest that the acute effects of steroids play little role in the gender-related differences observed, because short-term castration did not alter the gender-related differences we observed. Rather, it appears more probable that the organizational effects of steroids during critical periods in development, which determine gender-related distinctions, may be significant in the male-female differences we have observed. In view of a great deal of largely anecdotal data for humans that suggest that there may be gender-related differences in the abuse liability of psychoactive substances, the model described in this paper may provide a means to examine this important issue.

Analgesics, Opioid↗

PubMed1995

Nitric oxide-related agents alter alcohol withdrawal in male rats.

Evidence has been reported supporting the hypothesis that nitric oxide (NO) partially mediates the expression of morphine dependence. To examine whether NO-related agents also affect the expression of alcohol dependence, adult male rats were treated chronically with alcohol. Upon withdrawal of alcohol administration, abstinence signs were observed after treatment with a NO synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (NAME), or a NO donor, isosorbide dinitrate (ISDN). Withdrawal severity was based primarily on the presence and intensity of tremors, rigidity, hyperactivity, and spontaneous and audiogenic convulsions. The NOS inhibitor, NAME (10-100 mg/kg), injected during alcohol withdrawal significantly inhibited withdrawal severity decreasing the intensity of signs of hyperactivity, tremors, and rigidity, but not affecting the occurrence of convulsions. The NO donor, ISDN (30 mg/kg), administered during alcohol withdrawal significantly increased the severity of most withdrawal signs. These results suggest that NO mediates some aspects of the expression of alcohol dependence.

Alcohol Withdrawal Delirium↗

PubMed1995

Adverse effects of paternal opiate exposure on offspring development and sensitivity to morphine-induced analgesia.

We have shown previously that chronic morphine administration to adolescent male rats produced a number of gender specific deficits in their offspring. The purpose of the present studies was to extend our earlier observations by examining the acute, direct effects of morphine exposure to male rats on their fertility and the development of viable offspring. Sexually mature male rats were injected with a single dose of morphine (25 mg/kg) and 24 hr later were bred with drug-naive females. Fertility rates (vaginal plugs and pregnancies) were monitored throughout the breeding period as was the development of the offspring. Our results showed that a large, acute dose of morphine given to drug-naive male rats 24 hr before the initiation of breeding had no effect on fertility rates, but produced several adverse effects on fetal outcome. Litter sizes in morphine-derived offspring were considerably smaller than in controls and mortality rates were more than 6 times higher. Moreover, morphine-derived male, but not female, offspring had a significantly enhanced sensitivity to the antinociceptive effects of morphine. Collectively, these data suggest that acute paternal morphine exposure just before breeding with drug-naive females had no effect on fertility, but exerted negative effects on the viability and development of their offspring. These results represent the most compelling evidence to date that paternal opiate exposure can adversely affect fetal outcome and are particularly striking in that they were produced by a single injection of morphine. We are aware of no animal studies, clinical cases or anecdotal reports in humans in which such a phenomenon has been described.

Analgesia↗

PubMed1994

Acute alcohol exposure markedly influences male fertility and fetal outcome in the male rat.

Although it is recognized that drugs ingested by pregnant females produce marked cognitive and physiological deficits in their offspring, the possibility that paternal exposure to drugs prior to mating may have adverse effects on fertility and fetal outcome has not received much attention. The purpose of the present studies was to examine whether a single, acute exposure to alcohol influences the subsequent ability of adult male rats to mate and produce healthy and viable litters. Our results showed that a relatively large dose of alcohol 24 hours prior to breeding had little effect on the mating behavior of male rats, but there were markedly fewer pregnancies in females mated with alcohol-exposed male rats than in controls. Of equal importance, we found that, even when conception occurred and live births were produced, there were striking differences in fetal outcome. Alcohol-treated males sired many fewer pups than control males and there was a markedly enhanced mortality rate in their offspring. Collectively, these data suggest that acute paternal alcohol administration 24 hours prior to breeding does not affect mating behavior, but results in a greatly diminished fertility rate and fewer and less viable offspring. These studies suggest that paternal alcohol use may be as important as maternal alcohol abuse as a negative variable in pregnancy and fetal outcome.

Animals↗

PubMed1994

Acute paternal alcohol exposure impairs fertility and fetal outcome.

An acute injection of an intoxicating dose of alcohol to male rats 24 hours prior to breeding with drug-naive females produced no discernible effect on copulatory activity, as reflected in vaginal plugs, but resulted in markedly (> 50%) reduced pregnancy rates. Fetal outcome was also markedly affected in offspring sired by alcohol-treated males: litter sizes were appreciably smaller (30%) and fetal mortality was more than 2 times higher than in controls. These results suggest that paternal alcohol use, like maternal alcohol abuse, may adversely affect fertility and fetal outcome.

Alcoholic Intoxication↗

PubMed1994

Effects of nitric oxide-related agents on alcohol narcosis.

To examine whether nitric oxide (NO) affects alcohol (ethanol) narcosis, adult male rats were pretreated with a NO synthase (NOS) inhibitor, NG-nitro-l-arginine methyl ester (NAME); a NOS substrate, l-arginine methyl ester (AME); or a NO donor, isosorbide dinitrate (ISDN); then treated with anesthetic doses (3-5 g/kg, ip) of alcohol. Pretreatment with NAME (30-100 mg/kg, sc) 40 min before alcohol treatment delayed the onset of alcohol-induced loss of the righting reflex (LORR) and increased the duration of the LORR. NAME (100 mg/kg) pretreatment combined with high doses of alcohol (4-5 g/kg) exerted significant lethal effects, even though treatment with either agent alone or NAME combined with lower doses of alcohol (3-3.5 g/kg) was not lethal. Simultaneous treatment with the NOS substrate AME (100 mg/kg, subcutaneous) blocked the effects of NAME on LORR duration times, but did not alter LORR onset times. The NO donor ISDN (30 mg/kg) given by oral gavage 2 hr before alcohol decreased LORR duration times without affecting the onset of LORR. In addition, ISDN dose-dependently inhibited NAME-induced LORR duration increases during alcohol narcosis without significantly altering LORR onset times. Neither ISDN nor NAME significantly altered blood alcohol concentrations. These results suggest that NOS inhibition and subsequent decreases in NO production enhance alcohol-induced narcosis and that increases in NO concentrations inhibit alcohol narcosis, supporting the hypothesis that inhibition of arginine-NOS-NO systems mediates part of the sedative-hypnotic effect of alcohol.

Amino Acid Oxidoreductases↗

PubMed1994

Effects of nitric oxide-related agents on rat testicular function.

The effects of nitric oxide (NO)-related agents on testicular function were examined in male rats with measurements of serum luteinizing hormone, serum testosterone, testicular interstitial fluid (TIF) testosterone, and TIF volumes. Serum and TIF testosterone levels and luteinizing hormone secretion were significantly decreased by the NO donor, isosorbide dinitrate (ISDN), and the NO synthase (NOS) substrate, L-arginine methyl ester, a source for the endogenous production of NO. The effects of ISDN on TIF volumes were inconsistent, but L-arginine methyl ester decreased TIF formation in a dose-dependent manner. In addition, ISDN dose dependently suppressed testosterone secretion stimulated by human chorionic gonadotropin treatment, suggesting that the effects on testosterone secretion were independent of changes in secretion of the endogenous gonadotropin luteinizing hormone. ISDN, L-arginine methyl ester, and the endogenous NOS substrate L-arginine completely blocked testosterone secretion stimulated by the NOS inhibitor NG-nitro-L-arginine methyl ester (NAME), whereas the relatively inactive NOS substrate, D-arginine, only partially blocked NAME-stimulated testosterone secretion. Hydralazine and nicardipine, two vasodilators that do not exhibit prominent NO-related effects, also blocked basal testosterone secretion and testosterone secretion stimulated by the vasoconstrictor NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗

PubMed1993

Inhibition of the morphine withdrawal syndrome by a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester.

The hypothesis that an arginine-nitric oxide (NO) synthase-NO system mediates the morphine abstinence syndrome was tested in adult male rats implanted subcutaneously for 3 days with one morphine (75 mg) pellet followed by naloxone-precipitated withdrawal (0.5 mg/kg). Injection with a NO synthase inhibitor, NG-nitro-L-arginine methyl ester (NAME, 100 mg/kg subcutaneous), shortly before naloxone-induced withdrawal significantly inhibited abstinence signs by 25-80%. Continuous infusion of NAME via subcutaneous osmotic pumps during the development of morphine physical dependence and during naloxone-precipitated withdrawal also inhibited morphine abstinence signs. In addition, treatment with isosorbide dinitrate, a NO donor, induced a quasi morphine-abstinence syndrome (QMAS) that was significantly suppressed by implantation of a morphine pellet 3 days before isosorbide dinitrate treatment. These results indicate that NO mediates part of the expression of the morphine abstinence syndrome.

Amino Acid Oxidoreductases↗

PubMed1993

Antagonism of alcohol-induced suppression of rat testosterone secretion by an inhibitor of nitric oxide synthase.

To examine whether nitric oxide (NO) mediates the suppression of testosterone secretion by alcohol (ethanol), adult male rats were pretreated with a NO synthase inhibitor, NG-nitro-L-arginine methyl ester (NAME), then treated with alcohol. Serum and testicular interstitial fluid (TIF) testosterone concentrations, serum luteinizing hormone (LH) concentrations, blood alcohol concentrations (BAC), and TIF volumes were measured 2 hr after alcohol treatment at a time of peak effects of alcohol and NAME on testosterone secretion. Pretreatment with NAME (30 or 100 mg/kg, subcutaneous) 30 min before alcohol treatment (0.5-3 g/kg, intraperitoneal) completely blocked the alcohol-induced suppression of testosterone secretion into the general circulation and into TIF without significantly altering blood alcohol concentrations (BAC) or TIF volumes. These results support the hypotheses that NO synthase inhibitors can antagonize alcohol-induced suppression of testicular steroidogenesis, that alcohol interacts with arginine-NO synthase systems that regulate testicular steroidogenesis, and that NO is involved in mediating alcohol's testicular and reproductive effects.

Amino Acid Oxidoreductases↗

PubMed1993

Opioid-induced suppression of rat testicular function.

The effects of opioids on testicular function were assessed in the rat through measurements of serum testosterone levels, testicular interstitial fluid (TIF) formation and TIF testosterone levels after morphine and opioid antagonist (naloxone, naltrexone) treatment. Serum and TIF levels of testosterone were significantly decreased 1 to 6 h after morphine (10 mg/kg) injection, and TIF volumes were decreased 2-3 h after injection morphine. Each of these decreases was dose-related. In contrast to the effects of morphine, the opioid antagonist naloxone increased TIF testosterone but did not alter TIF volumes. Moreover, the opioid antagonist naltrexone totally blocked morphine's effects on both testosterone secretion and TIF volume, suggesting that morphine's testicular effects were mediated by naltrexone-sensitive opioid receptors in the testes. The possible role of morphine-induced reductions in gonadotropin secretion in morphine's testicular effects was also examined. Morphine suppressed testosterone secretion and TIF volumes after pretreatment with human chorionic gonadotropin, which reverses morphine's suppression of luteinizing hormone (LH). Our results, therefore, indicate that morphine exerts effects on testicular function that are independent of its effects on LH. They furthermore support the hypothesis that both endogenous and exogenous opioids disrupt two major aspects of testicular function: Testosterone secretion and TIF formation. Because of the role of TIF in maintaining testicular function, our results suggest that opioid-induced changes in testosterone secretion into TIF and TIF formation may, at least in part, explain the well-established effects of opioids on reproductive endocrinology and function in the male.

Animals↗

PubMed1991

Paternal alcohol consumption in the rat impairs spatial learning performance in male offspring.

Pubescent (30 day old) male rats were maintained on an alcohol liquid diet containing 35% ethanol-derived calories (ALC) for 39 days or were pairfed an isocaloric control diet (PF). The concentration of alcohol in the diet was gradually increased to permit adaptation, then stabilized and then gradually tapered to prevent an alcohol withdrawal syndrome. Following a drug-free period (2 weeks), the males were mated with nontreated females. Offspring were evaluated on several developmental indices and on various learning/memory tasks to assess functional deficits in adulthood. Offspring sired by ALC-treated males did not differ from the offspring of PF males on several developmental parameters including body weights, when developmental landmarks appeared, or on tests of sensorimotor development. As adults, male offspring groups did not differ on tests of activity or on an object exploration/recognition task. However, male offspring of ALC-treated males demonstrated impaired acquisition performance (days and errors to criterion) on a win-shift spatial discrimination in an eight-arm radial maze and on a win-stay discrimination (days to criterion) conducted in a T-maze at a later age. The radial maze results were replicated in a subsequent experiment using different groups of rats.

Alcohol Drinking↗

PubMed1990

Influence of chronic alcohol administration on representative indices of puberty and sexual maturation in male rats and the development of their progeny.

The effects of chronic alcohol administration on reproductive endocrinology in the developing male rat were examined. Prepubescent male rats (25 days of age) were maintained on an alcohol liquid diet or were pair-fed a control diet until early adulthood and selected indices of sexual maturation were examined at weekly intervals. To determine whether sexually immature animals were more sensitive to the effects of alcohol than adults, fully mature male animals were exposed to an identical period of alcohol exposure and comparisons were made between the two groups. The results demonstrated that alcohol significantly affected many of the primary indices of puberty and sexual maturation. The normal pubertal increases in serum testosterone levels, the weights of the testes and secondary sex organs and beta-endorphin levels in the hypothalamus were substantially reduced in alcohol-exposed animals compared with controls. In contrast to these results, the effects of alcohol on reproductive endocrinology in the fully mature animal were transitory and of considerably less magnitude. After a 2-week alcohol-free period, male rats exposed to alcohol during development were bred with drug-naive primiparous females. Although the same number of pregnancies resulted from matings between alcohol-exposed males and drug-naive females compared with controls, litter sizes were significantly smaller in alcohol-derived offspring than in controls. In all other respects, such as body weights, sex ratios, mortality rates and gross developmental features (eye opening, incisor eruption and testes descent), alcohol-derived offspring were identical with controls. Upon closer examination, however, significant disturbances were detected in alcohol-derived male offspring.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Age-related differences in the sensitivity to opiate-induced perturbations in reproductive endocrinology in the developing and adult male rat.

The effects of a single morphine pellet (75 mg) implanted in developing male rats at 27 days of age on reproductive endocrine parameters were compared to those found in adult (65-day-old) animals after the same treatment. The pellets were left in place to provide the release of morphine during critical phases of puberty and sexual maturation and to prevent an abrupt withdrawal syndrome upon pellet removal which would confound our results. Developing rats were sacrificed at representative intervals after pellet insertion to assess the development of key indices of reproductive endocrinology; adult rats were sacrificed at the same time intervals to permit an evaluation of age-related differences in the sensitivity to opiate-induced endocrine disturbances. Our results showed that morphine markedly influenced a number of endocrine parameters associated with the maturation of the hypothalamic-pituitary-gonadal axis in developing rats for prolonged periods of time, whereas the effects of the opiate in the adult rat were relatively modest and transient. In the developing rat, serum luteinizing hormone (LH), testosterone, the wet tissue weights of the seminal vesicles and testes and hypothalamic LH-releasing hormone (LHRH) levels were substantially depressed immediately after pellet implantation and these effects persisted for up to 4 weeks when compared to placebo-implanted, age-matched controls. In contrast to these results, adult rats showed only transient effects (less than 1 week) of morphine on certain reproductive endocrine parameters (e.g., serum LH, testosterone and the weights of the seminal vesicles) and no effects on others (e.g., testes weights and hypothalamic LHRH).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗