Biomedical subjects

T J Cicero

Publications and source records attributed to T J Cicero.

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↗

PubMed2000

Testosterone is required for corticosteroid-binding globulin upregulation by morphine to be fully manifested.

We previously reported that morphine increases the concentration of corticosteroid-binding globulin (CBG) in blood of male, but not female, rats. This pronounced sexual dimorphism suggested that CBG upregulation by morphine might be androgen-dependent. In the current studies, we found that castration, whether performed just before or just after puberty or in adulthood, increased the concentration of CBG in adult male rats. Naltrexone did not prevent this increase and, therefore, it does not appear to be attributable to the release of endogenous opioids. Exposure to morphine for 1 week in adulthood increased ( approximately 100%) the concentration of CBG in intact, i.e., sham-castrated, males. The CBG levels of castrated rats treated with morphine did not differ from those of intact rats treated with morphine. However, because castration increased the concentration of CBG, the difference between the placebo and morphine groups decreased with time after castration. At 4 weeks after castration, the difference between the morphine and placebo groups (19%) was no longer statistically significant. Testosterone replacement prevented the rise in CBG levels following castration and maintained the magnitude of the difference between placebo and morphine-treated rats within the normal range. Thus, testosterone appears necessary for morphine effects on CBG to be fully manifested.

Animals↗

PubMed1999

A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States.

Tramadol HCl, marketed as Ultram in the USA, was introduced as a non-scheduled drug in April 1995 based on the assumption that the risk of abuse was sufficiently low to warrant a non-scheduled status. However, approval was contingent upon the development of an innovative proactive surveillance program, to be overseen by an independent steering committee, which would detect unexpectedly high levels of abuse. The postmarketing surveillance program consisted of systematic collection and scientific evaluation of reports of suspected abuse in high-risk populations surveyed through an extensive key informant network of drug abuse specialists and all spontaneous reports of abuse received through the FDA MedWatch system. Methods to estimate the number of patients prescribed tramadol were also developed. Monthly rates of abuse were calculated as an index of the risk-benefit ratio (i.e., abuse cases per 100,000 patients prescribed the drug). The data for the 3 years since the drug was introduced show that the reported rate of abuse has been low. Although a period of experimentation seemed to occur in the first 18 months after its introduction--which reached a peak rate of approximately two cases per 100,000 patients exposed--during the 2 year period prior to June 1998, the reported rate of abuse has significantly (P = 0.011) declined, reaching levels of less than one case per 100,000 patients in the last 18 months. The overwhelming majority of abuse cases (97%) have been found to occur among individuals with a history of substance abuse and the abuse has been confined to isolated pockets around the country-notably none of which have significant populations of street drug abusers. Thus, the data support the decision not to schedule tramadol and, furthermore, suggest that a proactive post-marketing surveillance program can be successfully developed to effectively monitor abuse of new medications.

Analgesics, Opioid↗

PubMed1999

Effects of self-administered cocaine on plasma adrenocorticotropic hormone and cortisol in male rhesus monkeys.

This study was designed to examine the effects of self-administered cocaine on hypothalamic-pituitary-adrenal (HPA) axis activity in rhesus monkeys. Initially, basal release of cortisol and adrenocorticotropic hormone (ACTH) was measured in singly housed male and female monkeys (n = 9) over a 24-h period using plasma samples obtained from indwelling venous catheters. Basal cortisol and ACTH levels in both male and female rhesus monkeys demonstrated a circadian pattern of release, with peak levels for cortisol (19.60 +/- 2.16 microgram/dl) and ACTH (19.63 +/- 2.56 pg/ml) measured at 6:00 AM. The nadir for ACTH (6.27 +/- 0.62 pg/ml) occurred at 6:00 PM, preceding the cortisol nadir (5.55 +/- 1.21 microgram/dl) at 9:00 PM. The reinforcing effects of saline, 0.01, 0.03, 0.1, and 0.3 mg/kg/injection cocaine were then evaluated using a fixed-ratio 30, time-out 10-min schedule of reinforcement in seven male monkeys. Blood was sampled before, during, and after self-administration sessions. Self-administration of cocaine produced dose-dependent increases in cortisol and ACTH. One dose of cocaine (0.03 mg/kg/injection), although reliably self-administered, did not produce a significant increase in HPA axis activity. These results indicate that although cocaine dose-dependently increases HPA axis activity, the HPA effect is more likely a consequence of overall cocaine intake than it is an indicator of cocaine doses that are sufficient to maintain self-administration behavior.

Adrenocorticotropic Hormone↗

PubMed1999

Effects of response contingent and noncontingent cocaine injection on hypothalamic-pituitary-adrenal activity in rhesus monkeys.

Earlier studies of cocaine's effects on the hypothalamic-pituitary-adrenal (HPA) axis used nonresponse-contingent designs in which the investigator determined dose, timing, and route of administration. It is important to evaluate whether "control" over cocaine delivery is a significant determinant of cocaine's HPA axis effect. This study measured cocaine's effects on plasma adrenocorticotropic hormone and cortisol, using nonresponse-contingent injections followed later by response-contingent cocaine delivery. In addition, the effects of cocaine history on the HPA response to a noncontingent injection of 1 mg/kg of cocaine were measured. HPA effects of corticotropin-releasing hormone (CRF) were also measured. Male and female rhesus monkeys, with surgically placed venous catheters, were tested in their home cages. Up to 13 injections of saline and cocaine (0.01-, 0.03-, 0.1-, and 0.3-mg/kg/injection) were administered at 10-min intervals (nonresponse-contingent condition) and on a fixed ratio 30, time out 10-min schedule of reinforcement. Overall, cocaine delivered response contingently produced larger, more dose-dependent HPA responses than did noncontingent delivery. The HPA response to a 1 mg/kg cocaine infusion in cocaine-naive monkeys was not predictive of the HPA effect of this dose subsequent to acquisition of cocaine self-administration. Overall, male monkeys had larger HPA responses to cocaine than did female monkeys. Finally, the HPA effects of CRF were significantly correlated with those of large cocaine doses delivered nonresponse contingently, but not with response-contingent administration.

Adrenocorticotropic Hormone↗

PubMed1998

Nitric oxide mediates mecamylamine- and naloxone-precipitated nicotine withdrawal.

A nitric oxide synthase inhibitor blocked nicotine abstinence signs and increased weight loss in male, nicotine-dependent rats during withdrawal precipitated by the nicotinic receptor antagonist mecamylamine or the opioid receptor antagonist naloxone. These results indicate that nitric oxide systems mediate important aspects of the expression of nicotine physical dependence and suggest the potential use of nitric oxide synthase inhibitors as aids in tobacco smoking cessation.

Animals↗

PubMed1998

Alcohol intoxication and withdrawal: the role of nitric oxide.

Nitric oxide is an important messenger in the central nervous system and several types of evidence suggest that it mediates various alcohol effects. Treatment with a nitric oxide synthase inhibitor enhances the acute central depressant or anesthetic effect of alcohol and decreases some stimulatory effects of alcohol withdrawal after chronic alcohol treatment. Conversely, treatment with a nitric oxide donor inhibits the anesthetic effect of alcohol, blocks the effect of the nitric oxide synthase inhibitor on alcohol anesthesia, and enhances the severity of some alcohol withdrawal signs. These results indicate that changes in nitric oxide synthesis mediate some aspects of alcohol intoxication and withdrawal and that nitric oxide systems represent an important therapeutic target for the development of agents to treat alcoholism and alcohol intoxication.

Alcoholic Intoxication↗

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↗

PubMed1998

Chronic exposure to morphine decreases physiologically active corticosterone in both male and female rats but by different mechanisms.

We previously reported that chronic exposure of male rats to morphine markedly increases the concentration of corticosteroid-binding globulin (CBG) in blood. This in turn appears to greatly reduce the amount of corticosterone available to intracellular receptors. In the study reported here, we found that in contrast to the effect in males, morphine has no apparent effect on CBG in females. This pronounced sex difference does not appear to be attributable to differences in morphine pharmacokinetics, short-term actions of gonadal hormones in adulthood or sex differences in CBG or corticosterone levels. In any case, it is evident that morphine does not decrease the level of physiologically active corticosterone through CBG in females as it appears to do in males. On the other hand, we also found a distinct sex difference with regard to the effects of morphine on corticosterone. Chronic exposure to morphine had no apparent effect on corticosterone levels in males but resulted in markedly lower levels in females. Thus, morphine appears to cause a deficit in physiologically active corticosterone in both sexes but by different mechanisms.

Adrenalectomy↗

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↗

PubMed1997

Chronic exposure to morphine increases corticosteroid-binding globulin.

Although it appears that corticosterone may play an important role in determining vulnerability to drugs of abuse, few studies have examined drug effects on factors that affect corticosterone efficacy. Thus, studies were carried out to assess the effects of morphine on corticosteroid-binding globulin (CBG), the major glucocorticoid binder in blood. Since CBG-bound hormone is thought to be physiologically inactive, changes in CBG levels could affect corticosterone action independently of hormone levels per se. We found that morphine caused a marked naltrexone-preventable increase (approximately 160%) in CBG in adult male rats. Elevated levels were seen by three days and were maximal at seven days after morphine pellet (75 mg) implantation. CBG levels remained elevated while morphine was detectable in blood and returned toward normal as the drug cleared from the system. A single morphine pellet was sufficient to induce a marked increase in the concentration of CBG and two or more pellets caused maximal upregulation. Baseline and stress levels of total corticosterone (bound and unbound) were normal after chronic exposure to morphine. However, due to the elevated level of CBG, the amount of free, physiologically active hormone was dramatically reduced. These results suggest that morphine may exert potent effects on corticosterone action that are not revealed by measurement of corticosterone alone. Furthermore, the increase in CBG resulting from chronic exposure to morphine might contribute to the perpetuation of drug use and to adverse effects of drug exposure by impairing normal functions of corticosterone.

Analgesics, Opioid↗

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↗