RESUMO
Pathological gambling (PG) is a serious psychiatric disorder afflicting 1-3% of the general population. Experimental evidence indicates shared neurochemical substrates for PG and psychostimulant addiction. Impulsivity characterizes one key subtype of PG. Therefore, medications that ameliorate psychostimulant addiction and impulsive syndromes might also benefit impulsive PG subjects. The atypical stimulant, modafinil reduces cocaine abuse and impulsivity in patients with ADHD. The present study sought to determine if modafinil (200 mg) would reduce the reinforcing effects of slot machine gambling in PG subjects, and if this effect was stronger in high (H-I) vs. low (L-I) impulsivity subjects (N = 20). A placebo-controlled, double-blind, counterbalanced, repeated measures design was employed. Apart from bet size, which declined uniformly in both groups under drug, modafinil had bi-directional effects in the two groups. In H-I subjects, the drug decreased desire to gamble, salience of Gambling words, disinhibition and risky decision-making. In L-I subjects, modafinil increased scores on these indices. Modafinil also differentially affected blood pressure response to the game in the two groups. These findings for modafinil appear to fit well with a growing literature demonstrating bi-directional effects of D2 agonists as a function of trait impulsivity. Impulsivity could critically moderate medication response in PG.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Jogo de Azar/psicologia , Comportamento Impulsivo/tratamento farmacológico , Comportamento Impulsivo/psicologia , Compostos Benzidrílicos/efeitos adversos , Estimulantes do Sistema Nervoso Central/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Modafinila , Motivação , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Tempo de Reação/efeitos dos fármacos , Reprodutibilidade dos TestesRESUMO
Considerable research with animals indicates that the GABA-benzodiazepine (BZ) system plays a key role in alcohol reinforcement. However, only limited research appears to have assessed this issue directly in humans. The present study investigated whether low-dose diazepam would cross-prime motivation for alcohol in problem drinkers. Twelve male problem drinkers (Alcohol Dependence Scale; ADS score > or =9) received oral diazepam (5 mg) and placebo, in a counterbalanced manner on separate sessions. There were three measures of primed motivation for alcohol: self-reported desire for alcohol, consumption of placebo beer in an ostensible taste test procedure, and automatically executed vocal reading responses to Alcohol versus Neutral words on a computer-based task. Diazepam significantly increased beer consumption, and produced a marginally significant increase in reported desire for alcohol. On the reading task, diazepam significantly decreased response latency to Alcohol words relative to Neutral words. Latency to Alcohol words correlated significantly with beer consumption under the drug. Moreover, response latency to Alcohol words under the drug also predicted ADS scores. Thus, severity of dependence was directly linked with vulnerability to a BZ priming effect on motivation for alcohol. These findings provide direct evidence that the GABA-BZ system plays an important role in alcohol reinforcement in problem drinkers.
Assuntos
Consumo de Bebidas Alcoólicas , Alcoolismo/fisiopatologia , Diazepam/farmacologia , Moduladores GABAérgicos/farmacologia , Motivação , Administração Oral , Adulto , Diazepam/administração & dosagem , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de GABA/fisiologia , Reforço Psicológico , SemânticaRESUMO
We have recently shown that priming injections of alcohol and footshock stress reinstate alcohol seeking in drug-free rats. Here we tested whether naltrexone and fluoxetine, two drugs used in the treatment of alcohol dependence, would affect reinstatement of alcohol seeking induced by these events. We also determined the effects of these drugs on alcohol self-administration during the maintenance phase. Rats were trained to press a lever for a 12% w/v alcohol solution. After stable drug-taking behavior was obtained, lever pressing for alcohol was extinguished. Reinstatement of drug seeking was then determined after priming injections of alcohol (0.24-0.96 g/kg) or exposure to intermittent footshock (5 and 15 min). Rats were pretreated with naltrexone (0.2-0.4 mg/kg) or fluoxetine (2.5-5 mg/kg) during maintenance or during tests for reinstatement. Both naltrexone and fluoxetine decreased lever presses for alcohol during the maintenance phase. Naltrexone blocked alcohol-induced, but not stress-induced reinstatement. In contrast, fluoxetine blocked stress-induced reinstatement, while its effect on alcohol-induced reinstatement was less consistent. The implications of these data to the understanding of relapse to alcohol are discussed.
Assuntos
Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Fluoxetina/farmacologia , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Estresse Fisiológico/tratamento farmacológico , Animais , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Masculino , Ratos , Autoadministração , Estresse Fisiológico/complicaçõesRESUMO
A delay-of-reward paradigm was used to assess impulsivity in rats. Previous research with this paradigm has found that normally occurring impulsivity scores predict magnitude of voluntary alcohol intake. The authors' primary findings were (a) injected alcohol produced a dose-dependent increase in impulsivity, (b) varying the intervals between alcohol and testing yielded orderly effects, (c) there were extreme individual differences in impulsive reactivity to alcohol, (d) these individual differences did not reflect differences in alcohol pharmacokinetics, (e) subject selection procedures ensured that differences in impulsive reactivity to alcohol were independent of significant variations in baseline impulsivity scores, and (f) individual differences in impulsive reactivity to injected alcohol strongly predicted magnitude of voluntary alcohol intake. The findings are discussed in terms of evidence for a dysfunctional alcohol-induced positive feedback loop ("loss-of-control drinking"), alcohol disinhibition, and the relationship between impulse control and the regulation of alcohol consumption.
Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Etanol/farmacologia , Comportamento Impulsivo/induzido quimicamente , Aprendizagem em Labirinto/efeitos dos fármacos , Análise de Variância , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Individualidade , Inibição Psicológica , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Fatores de TempoRESUMO
1. The development and implementation of standardized basic and clinical research strategies is necessary for the discovery and testing of new and effective pharmacotherapies for alcohol dependence. While many animal studies have indicated the involvement of central serotonin, endogenous opioids and dopamine, their exact mechanisms of action have not been fully discerned. One problem is the use of various animal models, making it difficult to compare or replicate results from different laboratories. 2. Once a drug appears to decrease alcohol intake in animals, assessing its effects in humans can be even more challenging. 3. Most drugs were developed and may be even registered for another indication, so Phase I trials must be repeated in heavy alcohol users in case the drug has behavioural, pharmacokinetic or pharmacodynamic interactions with alcohol. 4. Phase II trials, assessing the effects of the drug on alcohol intake, are usually radically different from the animal models: most are long (> 6 months), use varied designs, and accept only abstinence as successful outcome. Moderately dependent alcoholics, who comprise the majority of patients, prefer a goal of nonhazardous drinking. 5. In Phase III multicentre trials, especially international ones, it is almost impossible to control for potentially confounding variables, such as patient characteristics and concomitant psychosocial treatment. 6. Also, research in pharmacotherapies for alcoholism is influenced by external factors such as sources of funding and other resources. Thus, this methodical progression from Phase I to Phase III clinical trials is often abbreviated. 7. The authors developed a brief early Phase II clinical paradigm to assess pharmacotherapies for moderately dependent alcoholics, and conducted 3 studies with the serotonin uptake inhibitors, citalopram and fluoxetine, and a serotonin antagonist, ritanserin. This paradigm, which includes a short (1 to 2 weeks) outpatient phase and two experimental drinking sessions, measures alcohol intake, desire to drink, alcohol's subjective effects, and intoxication. While it may have limited relevance to a goal of abstinence, it is efficient and economical to screen drug effects on alcohol intake and suggest mechanisms (desire to drink, subjective effects). It is also the only human model concordant with results in animals. 8. Development of new pharmacotherapies for alcoholism may benefit from acceptance of both abstinence and moderation of drinking as acceptable treatment goals.
Assuntos
Dissuasores de Álcool/uso terapêutico , Alcoolismo/tratamento farmacológico , Ensaios Clínicos como Assunto , HumanosRESUMO
Ritanserin, a 5-HT2 receptor antagonist, decreased alcohol intake in some, but not all, animal studies and in an open clinical study. We tested the short-term effects of ritanserin in 39 (35 male, four female) heavy social drinkers (consuming at least 28 drinks/week), aged 19-63 years, who were not seeking treatment. After an intake assessment, they received placebo for 7 days in a single-blind baseline. They were then randomly assigned to one of three double-blind treatments for 14 days: ritanserin 5 mg/day (n = 12), ritanserin 10 mg/day (n = 13) or placebo (n = 14). Subjects recorded daily outpatient alcohol intake. Feelings of intoxication and interest, desire, craving and liking for alcohol were rated retrospectively at each weekly study visit. Experimental drinking sessions were conducted after baseline (EDS1) and treatment (EDS2); in each session subjects were offered 18 mini-drinks (total = six standard) and rated their desire to drink, intoxication and mood (POMS). Outpatient results: ritanserin 5 mg/day decreased desire and craving for alcohol (vs. baseline, p < 0.05) but not alcohol intake. Liking of alcohol decreased from baseline with ritanserin 10 mg/day (p = 0.01) and placebo (p = 0.05). Changes in alcohol intake from baseline with ritanserin 10 mg/day (increase, p > 0.05) and placebo (decrease, p > 0.05) were different (p < 0.05). EDS results: in EDS2, desire ratings for the first three mini-drinks were lower after ritanserin 5 mg/day than after ritanserin 10 mg/day (p < 0.05), but the decreases were not statistically significant when EDS1 desire ratings were controlled for. Ritanserin 10 mg/day increased alcohol-induced feelings of intoxication and friendliness, compared with placebo (p < 0.05). Both ritanserin 5 mg/day and 10 mg/day enhanced alcohol-induced decreases in fatigue, compared with placebo (p < 0.05). These results indicate that ritanserin may have differential effects on alcohol intake, desire, craving and liking, intoxication and some of alcohol's effects on mood. However, they suggest that ritanserin has limited efficacy in reducing alcohol intake in heavy drinkers.
Assuntos
Consumo de Bebidas Alcoólicas/prevenção & controle , Alcoolismo/reabilitação , Ritanserina/administração & dosagem , Adulto , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/psicologia , Assistência Ambulatorial , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Ritanserina/efeitos adversos , Meio SocialRESUMO
Several scales have been developed to measure self-efficacy for addictive behaviors but there is no such scale applicable to multiple drug users. The Drug Avoidance Self-Efficacy Scale (DASES) was developed to fill this gap. The properties of the scale were evaluated using a sample of 373 young multiple-drug users 16 to 30 years old presenting for treatment at the Addiction Research Foundation. The 16-item scale appeared to be unidimensional. Cronbach's alpha was .9140. Construct validity, evaluated on a subset of the sample, was evident in significant correlations with concurrent measures of drug use severity and differential rates of changes in self-efficacy associated with two types of treatment. The DASES appears to be a reliable and valid scale for the measurement of self-efficacy in multiple-drug users.
Assuntos
Drogas Ilícitas , Inventário de Personalidade/estatística & dados numéricos , Psicotrópicos , Autoimagem , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Adulto , Assistência Ambulatorial , Feminino , Humanos , Masculino , Admissão do Paciente , Psicometria , Reprodutibilidade dos Testes , Transtornos Relacionados ao Uso de Substâncias/reabilitação , Resultado do TratamentoRESUMO
Several serotonin uptake inhibitors, including the long-acting fluoxetine, have been found to decrease alcohol intake in moderately dependent alcoholics. While the mechanism of their effect is not fully elucidated, a previous study with citalopram indicated that decreased desire to drink may be an important factor. Therefore, we tested fluoxetine effects on alcohol intake and desire to drink in a placebo-controlled study. Subjects, recruited by advertisement, were mildly/moderately dependent alcoholics (12 male, four female, aged 19-59 years, healthy, non-depressed) who did not believe they had a drinking problem and were not requesting treatment. After a 1 week baseline they received, single-blind, 2 weeks placebo followed by 2 weeks fluoxetine 60 mg/day. As out-patients, subjects recorded daily standard drinks (13.6 g ethanol) and rated interest, desire, craving and liking for alcohol biweekly. Each out-patient period was immediately followed by a double-blind experimental drinking session. Out-patient daily drinks slightly decreased during fluoxetine to 6.6 +/- 0.9 (mean +/- S.E.M.) compared with during placebo (7.16 +/- 0.95, p = 0.07, N.S.) and baseline (7.18 +/- 1.0, p > 0.1, N.S.). Desire, interest and craving for alcohol decreased during fluoxetine vs placebo baseline (p < 0.05), but not vs placebo. Appetite loss and decrease in food intake (p < 0.01, fluoxetine vs placebo) correlated with each other (r = 0.91, p < 0.01) but neither correlated with decrease in alcohol intake (appetite: r = 0.26, N.S.; food intake: r = 0.22, N.S.). Weight loss occurred during fluoxetine (p < 0.05 vs placebo) but did not correlate with decrease in alcohol intake (r = 0.1, N.S.). In the experimental drinking sessions after placebo and fluoxetine treatments subjects rated their desire for each of 18 mini-drinks (each one-third of a standard drink) offered at 5 min intervals. Fluoxetine decreased desire to drink throughout the sessions; both mean and maximum desire ratings were lower after fluoxetine than after placebo (ANOVA, p < 0.05). Therefore, fluoxetine seems to have a robust effect on decreasing desire for alcohol. We propose that in the absence of intention by subjects to reduce drinking, their habitual drinking patterns mitigated against reduced consumption in the out-patient phase. However, fluoxetine could be a useful adjunct for patients in a treatment context who are motivated to reduce their drinking.
Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/reabilitação , Fluoxetina/uso terapêutico , Motivação , Adulto , Alcoolismo/psicologia , Apetite/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fluoxetina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We have previously reported that the 5-hydroxytryptamine (5-HT) releaser/reuptake blocker dexfenfluramine suppresses voluntary ethanol intake. To further analyse the generality of these findings, in the present study we examined the effect of equivalent doses of dexfenfluramine (0.5-2.5 mg/kg) on the intake of another preferred fluid, saccharin. Saccharin was made available for 2 h daily across a wide concentration range chosen to promote varying degrees of intake. Following stable levels of intake, the behaviour of vehicle-pretreated rats was assessed immediately prior to (anticipatory/preparatory phase) and during (consumatory phase) saccharin access. These behaviours were compared and contrasted with those produced following dexfenfluramine pretreatment at the optimally preferred saccharin concentration (0.2%). In a preliminary study the effects of various 5-HT antagonists were also examined against the dexfenfluramine response. The present results suggest that dexfenfluramine produced a dose-related suppression of saccharin intake at doses similar to those which reduced ethanol intake. However, the magnitude of this suppression was similar across each saccharin concentration. Behavioural analysis indicated that the profile of the dexfenfluramine (0.5- and 1-mg/kg doses only) suppression of the 0.2% solution was similar to that observed in vehicle-pretreated rats presented with saccharin solutions of lesser palatability to this concentration. Pharmacological studies indicated a 5-HT1 (non-5-HT1C) receptor involvement in the dexfenfluramine response. These studies imply that at certain doses dexfenfluramine may produce a subtle alteration in the motivation to consume a preferred fluid.
Assuntos
Comportamento de Ingestão de Líquido/efeitos dos fármacos , Fenfluramina/farmacologia , Animais , Comportamento Consumatório/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Sacarina/farmacologia , Antagonistas da Serotonina/farmacologia , Fatores de TempoRESUMO
Several studies have demonstrated a paradoxical form of antinociception induced by the repeated administration of opioid antagonists accompanied by exposure to a painful stimulus. The underlying mechanism of this naloxone-induced antinociception (NIA) is still unknown, but the results of several studies suggest that it is a non-opioid response. This study was designed to investigate serotonergic and noradrenergic involvement in NIA. Rats were treated daily with systemic injections of 5 mg/kg naloxone, followed by a 45-s hot plate test of nociception (temperature = 51.5 +/- 0.5 degree C). After rats reached plateau levels of NIA, they received a test trial in which they were treated with various doses of different selective 5-HT or alpha 2 adrenoceptor antagonists in addition to naloxone before the hot plate test. Rats treated with 0.16, 0.32 and 0.63 mg/kg pirenperone or 2.5 mg/kg ritanserin showed significant reductions in paw lick latency with respect to rats treated with vehicle. In addition, high doses of yohimbine (7.5-10 mg/kg) also effectively reversed NIA. In contrast, NIA was not affected by acute blockade of 5-HT1 or 5-HT3 receptors by methiothepin or MDL 72222, respectively, or by the alpha 2 adrenoceptor blocker idazoxan. None of the 5-HT or alpha 2 adrenoceptor antagonists had any effect on the paw lick latencies of saline-treated rats. A possible role of 5-HT2 receptors in the antinociception induced by opioid receptor blockade is discussed.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2 , Analgésicos/farmacologia , Naloxona/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Injeções Subcutâneas , Masculino , Naloxona/administração & dosagem , Naloxona/antagonistas & inibidores , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
The effects of naltrexone, naltrindole (a selective delta opiate receptor antagonist) and beta-funaltrexamine (beta-FNA; a selective mu opiate receptor antagonist) on alcohol intake by C57BL/6 mice in a restricted access paradigm were examined. During the pretreatment baseline phase, mice consumed an average of 1.3 g/kg during 1 h access sessions to a 12% alcohol solution. Treatment with naltrexone reduced alcohol consumption to about 50% of that of the saline controls. Treatment with beta-FNA had no effect on alcohol consumption whereas naltrindole reduced consumption to the same extent as that observed with naltrexone. The pattern of findings indicate that naltrexone's ability to reduce alcohol consumption can be attributed to blockade of delta opiate receptors. Implications for treatment in human clinical trials are indicated.
Assuntos
Consumo de Bebidas Alcoólicas , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Animais , Camundongos , Camundongos Endogâmicos C57BL , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologiaRESUMO
When administered repeatedly, in conjunction with hot plate testing, naloxone and naltrexone have the paradoxical effect of producing antinociception in rats and mice. Recently, we have found that the sub-acute selective blockade of mu opioid receptors leads to the development of antinociception and an augmentation of kappa receptor-mediated antinociception. In this study, acute delta/kappa antagonist treatment produced a significant decrease in paw lick latency in rats displaying antinociception induced by sub-acute mu blockade, however, the response level of these animals was still significantly above the baseline. In addition, rats receiving sub-acute combined mu and delta antagonist treatment took longer to develop an antinociceptive response than those treated with a mu antagonist alone. Sub-acute selective blockade of kappa or delta opioid receptors had no overall effect on paw lick latency during the course of 5 days of hot plate testing. The results indicate that delta receptor activity may play a role in the antinociception induced by sub-acute mu blockade. However, while delta antagonist treatment effected the expression, it did not completely attenuate the antinociception induced by sub-acute mu blockade suggesting that there is still a significant non-opioid component to this analgesic response. The results of a final experiment, in which acute delta antagonist treatment had no effect on antinociception induced by repeated systemic injections of naloxone, supported this hypothesis.
Assuntos
Indóis/farmacologia , Morfinanos/farmacologia , Naltrexona/análogos & derivados , Dor/fisiopatologia , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Animais , Masculino , Naltrexona/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides kappa/antagonistas & inibidores , Sensibilidade e EspecificidadeRESUMO
In previous studies serotonin uptake inhibitors such as citalopram decreased alcohol consumption in alcoholics. The mechanism of the effect is not fully understood. This study tested the hypothesis that it is mediated by changes in desire to drink and alcohol effects. After a 1-week baseline period, subjects (13 men and three women; aged 26 to 69 years; healthy, nondepressed, alcohol-dependent drinkers [mean, 6.6 drinks per day]) were randomized in a double-blind fashion to receive 40 mg/day citalopram and placebo for 1 week each, separated by a 1-week washout period. Daily standard alcoholic drinks (13.6 gm ethanol), nonalcoholic drinks, and tobacco use were recorded; evening urine samples were taken; and interest, desire, craving, and liking for alcohol were rated. Medical status, depression, and anxiety were assessed weekly, but no other treatment or advice was given. Daily alcoholic drinks significantly decreased during citalopram treatment (mean +/- SEM = 4.6 +/- 0.6) compared with placebo (5.7 +/- 0.8; p = 0.01), and the average decrease was 17.5%. Percentage of days abstinent increased during citalopram administration (27.7% +/- 5.7%) compared with placebo (15.5% +/- 3.7%; p less than 0.01). Citalopram decreased interest, desire, craving, and liking for alcohol (all p less than 0.05). There was clear internal validation of these measures in that variations in each correlated with alcohol consumption (all r greater than 0.5, p less than 0.05). Nonalcoholic drinks, self-reports of cigarettes smoked (daily smokers), and body weight did not change significantly. In experimental bar sessions, after the citalopram and placebo periods, subjects were required to consume as many of 18 minidrinks as possible (equivalent to six standard drinks) at 5-minute intervals. Subjects rated their desire for alcohol, intoxication, and mood. Citalopram had no significant effects on the desirability of alcohol or subjective feelings of intoxication. The findings indicate that serotonin uptake inhibitors may act by decreasing the urge to drink and the reinforcing effects of alcohol. Also, a naturalistic outpatient trial is a sensitive, simple, and economic procedure for detecting these drug effects.
Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Citalopram/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Adulto , Idoso , Consumo de Bebidas Alcoólicas/fisiopatologia , Alcoolismo/fisiopatologia , Citalopram/efeitos adversos , Complacência (Medida de Distensibilidade) , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Captação de Neurotransmissores/efeitos adversos , Serotonina/metabolismo , Serotonina/fisiologiaRESUMO
At the heart of homeostatic theory is the idea that explicit or implicit behavioral demands placed on physiological systems are required for the biological detection of homeostatic disturbances. The detection of drug-induced disturbances is required to drive the development of all systemic tolerance, both associative and nonassociative (i.e., both forms of tolerance are behaviorally contingent). A wide range of findings ranging from morphine-induced analgesia to ethanol-induced hyposexuality shows that contingent tolerance is pervasive and may be universal. The theory also stipulates that behavioral demands placed on the target system will govern the loss of both associative and nonassociative tolerance (physiological). The present formulation integrates contingent, associative, and nonassociative tolerance and drug-opposite withdrawal reactions within a unified theory.
Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Psicotrópicos/farmacologia , Adaptação Fisiológica/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Tolerância a Medicamentos , Homeostase/fisiologia , Humanos , Psicofisiologia , Meio SocialRESUMO
We have previously demonstrated that, when administered chronically, naloxone and naltrexone have the paradoxical effect of producing analgesia in rats. In this study, rats treated chronically with intracerebroventricular (i.c.v.) microinjections, and mice treated chronically with subcutaneous (s.c.) injections of naloxone or beta-funaltrexamine (beta-FNA) developed analgesia on daily hot plate tests. There was not drug effect on the first day of hot plate testing, but significant increases in paw lick latency developed over subsequent acquisition sessions for animals treated with beta-FNA or naloxone. An augmented analgesic response to a 5 mg/kg s.c. injection of the kappa opioid agonist, U50-488H, was observed in mice previously treated with naloxone or beta-FNA. The primary findings of the present study were: (1) chronic blockade of mu opioid receptors is sufficient to produce analgesia on repeated hot plate tests in both rats and mice; (2) chronic blockade of mu receptors in the presence of stressful stimuli results in augmentation of kappa agonist-induced analgesia; and (3) the phenomenon of opioid blockade-induced analgesia (OBA) occurs in mice as well as rats.
Assuntos
Analgesia , Antagonistas de Entorpecentes , Receptores Opioides/efeitos dos fármacos , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida , Analgésicos/farmacologia , Animais , Injeções Intraventriculares , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor , Pirrolidinas/farmacologia , Ratos , Ratos Endogâmicos , Tempo de Reação , Receptores Opioides kappa , Receptores Opioides mu , Técnicas EstereotáxicasRESUMO
Although analgesia induced by blockade of opioid receptors has been well established, it is still unknown whether its development is mediated by the blockade of centrally located opioid receptors. Therefore, rats were treated with either systemically or ICV applied naloxone or quaternary naltrexone (QN), an opioid antagonist that does not easily penetrate the blood-brain barrier. Following antagonist administration, each animal was tested for paw lick latency on a 51 degrees C hot plate. Hot plate testing and drug injections were carried out for 4 consecutive days. Rats treated with ICV microinjections of QN or naloxone displayed paw lick latencies that were significantly longer than those observed in control animals. In contrast, rats treated with SC injections of QN did not show any increase in paw lick latency, whereas rats treated with SC injections of naloxone displayed paw lick latencies that were significantly longer than those of control rats. These results are consistent with the hypothesis that the blockade of central opioid receptors underlies the development of an analgesic response.
Assuntos
Analgesia , Encéfalo/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Nervos Periféricos/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Animais , Injeções Intraventriculares , Injeções Subcutâneas , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Compostos de Amônio Quaternário , Ratos , Ratos Endogâmicos , Tempo de Reação/efeitos dos fármacosRESUMO
While the hyperphagic effect of chloradizepoxide (CDP) has been reported by some to be enhanced with chronic drug treatment, the processes underlying this phenomenon are not well understood. In the present study, it was predicted that following chronic exposure to CDP-induced hyperphagia, animals given a placebo in place of their usual drug injection might be expected to exhibit evidence of a conditioned, drug-like response. Such a finding would then be consistent with an underlying process of behavioral sensitization. In Experiment 1a, Male Sprague-Dawley rats were randomly assigned to one of two groups receiving intraperitoneal (IP) injections of either 5 mg/kg CDP (Group CDP) or physiological saline (1 ml/kg; Group SAL) administered over 15 drug treatment days. Thirty minutes after each injection, all animals were given 30 min access to sweetened condensed milk. A significant enhancement of CDP-induced hyperphagia was observed over treatment sessions, confirming an earlier report. Unexpectedly, in the Placebo Test, the CDP animals exhibited a supression of milk consumption relative to that of the SAL group. Using the same animals, this finding was successfully replicated in Experiment 1b. In Experiment 2, it was hypothesized that if this conditioned, drug-opposite response were to reflect the involvement of some underlying compensatory, homeostatic mechanism, then it should only be observable under food-contingent conditions of chronic drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Clordiazepóxido/farmacologia , Condicionamento Psicológico , Comportamento Alimentar/efeitos dos fármacos , Hiperfagia/fisiopatologia , Animais , Tolerância a Medicamentos , Hiperfagia/induzido quimicamente , Masculino , Ratos , Ratos EndogâmicosRESUMO
Repeated administrations of naloxone have been found to result in the development of analgesia. Pretreatment with naloxone can also produce supersensitivity to morphine. This study examined whether the development of these phenomena is affected by exposure to pain (hot-plate testing) during opiate blockade. During acquisition, two experimental groups of rats received identical treatment with respect to repeated naloxone injections (5 mg/kg) and the environment in which the injections were administered. A "contingent" group (NAL-C) received hot-plate testing under the influence of naloxone, while a "noncontingent" group (NAL-NC) experienced hot-plate testing and naloxone separated by an interval of 24 h. At test, NAL-C rats manifested naloxone-induced analgesia (NIA) whereas the NAL-NC animals did not. The NAL-C rats also showed supersensitivity to the analgesic effects of morphine (3 mg/kg) and to the cataleptic effects of morphine (17.5 mg/kg) while the NAL-NC rats did not differ from saline controls. Thus, both NIA and morphine supersensitivity were completely dependent on testing in the drug state during acquisition; mere exposure to an identical regime of naloxone injections was insufficient to produce these phenomena.
Assuntos
Analgésicos , Morfina/farmacologia , Naloxona/farmacologia , Medição da Dor , Animais , Catalepsia/induzido quimicamente , Masculino , Ratos , Ratos Endogâmicos , Tempo de Reação/efeitos dos fármacosRESUMO
Recently there have been demonstrations of a form of analgesia in rats that depends on the repeated administration of an opiate antagonist for its occurrence. The mechanism of this naloxone-induced analgesia (NIA) is not clear. This experiment tested the hypothesis that the relationship between behavioral effects of previous experience with opiate agonists and antagonists would be reciprocal with respect to analgesia. Consistent with such an hypothesis, prior exposure to morphine increased sensitivity to the effect of naloxone as measured by the rate of acquisition of NIA. Although receptor functions were not measured, reciprocal changes in the regulation of opiate receptors by opiate receptors by opiate agonists and antagonists may underlie the behavioral effects observed in this experiment.
Assuntos
Analgesia , Condicionamento Psicológico/efeitos dos fármacos , Morfina/farmacologia , Naloxona/farmacologia , Animais , Discriminação Psicológica/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos , Receptores Opioides/efeitos dos fármacosRESUMO
Repeated exposure to pain under the influence of the opiate antagonists naloxone and naltrexone leads to the recruitment of substantial analgesia as measured by paw-lick latency on the hot-plate test (4,11). One hypothesis to explain this naloxone-induced analgesia (NIA) is that nociceptive stimulation in the face of opiate blockade becomes stressful enough to activate an analgesic adaptation that otherwise would not occur. This hypothesis was examined in two experiments by the administration of a benzodiazepine antagonist with anxiogenic properties (Ro 15-1788, in a dose of 10 mg/kg) in conjunction with repeated administrations of naloxone (5 mg/kg). One experiment incorporated defecation as a relatively direct measure of stress. Ro 15-1788 reliably augmented NIA. Defecation was increased by naloxone alone and in combination with Ro 15-1788. Overall, the results were most consistent with the hypothesis that NIA is a form of stress-induced analgesia that is at least partly nonopiate in nature.