Representações sociais de pessoas com câncer em cuidados paliativos sobre a morfina / Social representations of people with cancer in palliative care on morphine

INTRODUÇÃO: A dor se apresenta como sintoma frequente nas pessoas com câncer, e os opioides são os fármacos de escolha para o seu alívio. Dentre eles tem-se a morfina, que é um dos mais utilizados. OBJETIVOS: Descrever as representações sociais de pessoas com câncer em cuidados paliativos sobre a morfina; Analisar tais representações e suas implicações para a adesão ou não a esse opioide no tratamento/alívio da dor do câncer; Propor estratégias de cuidados afinadas às representações das pessoas com câncer que requerem o uso de morfina. MÉTODO: Pesquisa com abordagem qualitativa, do tipo descritiva e exploratória, realizada em uma instituição pública hospitalar. Os participantes foram pessoas com câncer atendidas no Ambulatório. Critérios de inclusão: maiores de 18 anos, com índice ≥ 50% na Escala de Karnofsky (KPS) e prescrição analgésica de morfina. Critérios de exclusão: presença de dor de moderada a intensa no momento da coleta de dados; e aqueles com comprometimento verbal, cognitivo e/ou psiquiátrico. Os dados foram coletados por questionário e entrevista semiestruturada. Os dados do questionário foram analisados por estatística descritiva simples e percentual, e aos conteúdos verbais aplicou-se a análise de conteúdo do tipo lexical, com o uso do software Alceste. Projeto aprovado pelos Comitês de Ética em Pesquisa da instituição proponente e cooperante, com pareceres no 3.296.128 e no 3.453.968, respectivamente. Todos os participantes assinaram o Termo de Consentimento Livre e Esclarecido. RESULTADOS: A média de idade foi de 54,7 anos; sexo feminino (69,7%); predomínio da religião evangélica (60,6%); 81,8% afirmaram seguir corretamente a prescrição da morfina; na Escala de Karnofsky, 45,5% apresentaram índice de 60%, evidenciando a necessidade de assistência ocasional, mas com capacidade de trabalhar; a intensidade da dor pela escala visual analógica variou entre leve (grau 1) e moderada (grau 4), ambas com 21,2% de respostas. O processamento dos dados no Alceste gerou dois blocos, o primeiro com a Classe 1, que expressa a representação medicamentosa do tratamento com a morfina e os fatores associados a esse tratamento; o segundo foi composto pelas Classes 2 e 3 e expressam as relações sociais envolvidas no contexto do tratamento, o vínculo da pessoa que usa morfina com o mundo que a cerca, bem como a relação estabelecida com esse medicamento, o conhecimento sobre a morfina e as atitudes adotadas diante desse uso. Houve ambiguidade nas representações da morfina, colocando-a entre a dor e o temor, pois a indicam como um importante recurso para alívio/tratamento da dor do câncer, mas sinalizam que também pode trazer repercussões negativas associadas aos seus efeitos. CONSIDERAÇÕES FINAIS: Apesar de haver aderência dos pacientes à morfina, a opiofobia ainda precisa ser combatida por meio de estratégias que façam circular informações que possam reconstruir representações sobre a morfina e seu uso terapêutico. A educação terapêutica por meio da atuação de equipe multidisciplinar se destaca como uma boa estratégia de difusão de informações seguras sobre o uso de opioides.

INTRODUCTION: Pain is a frequent symptom in people with cancer, and opioids are the drug of choice for its relief, including morphine, which is one of the most used. OBJECTIVES: To describe the social representations of people with cancer in palliative care about morphine; To analyze such representations and their implications for adherence or not to this opioid in the cancer pain treatment/relief; To propose care strategies related to the representations of people with cancer that require the use of morphine. METHOD: Descriptive and exploratory research with a qualitative approach, carried out in a public hospital. The participants were people with cancer treated at the clinic. Inclusion criteria: over 18 years old, with an index ≥ 50% on the Karnofsky Scale (KPS) and morphine as an analgesic medication prescribed. Exclusion criteria: presence of moderate to severe pain at the time of data collection; and those with verbal, cognitive and/or psychiatric impairment. Data was collected by questionnaire and semi-structured interview. The questionnaire data were analyzed using simple and percentage descriptive statistics, and the verbal content was analyzed using lexical content with the Alceste software. Project approved by the Research Ethics Committees of the proposing and cooperating institution, with opinions No. 3,296,128 and 3,453,968, respectively. All participants signed the Free and Informed Consent Form. RESULTS: The average age was 54.7 years; female gender (69.7%); prevalence of the evangelical religion (60.6%); 81.8% said they correctly followed the prescription of morphine; on the Karnofsky Scale, 45.5% had an index of 60% showing the need for occasional assistance, but with the ability to work; pain intensity by visual analog scale ranged from mild (grade 1) to moderate (grade 4), both with 21.2% responses. The data processing at Alceste generated two blocks, the first with class 1, which expresses the drug representation of the treatment with morphine and the factors associated with that treatment; the second was composed of Classes 2 and 3 and expresses the social relationships involved in the context of the treatment, the bond of the person who uses morphine with the world around her, as well as the relationship established with this medicine, the knowledge about the morphine and the attitudes towards the use of the medicine. There was ambiguity in the representations of morphine, placing it between pain and fear, as they indicate it as an important resource to relieve/treat cancer pain, but it can also bring negative repercussions associated with its effects. FINAL CONSIDERATIONS: Despite patient adherence to morphine, opiophobia still needs to be fought through strategies that spread information that can reconstruct representations about morphine and its therapeutic use. Therapeutic education through the work of a multidisciplinary team stands out as a good strategy to disseminate safe information about the use of opioids.

INTRODUCCIÓN: El dolor es un síntoma frecuente en las personas con cáncer y los opioides son los fármacos de elección para su alivio; entre ellos está la morfina, que es uno de los más utilizados. OBJETIVOS: Describir las representaciones sociales de las personas con cáncer en cuidados paliativos sobre la morfina; analizar tales representaciones y sus implicaciones para la adherencia o no a este opioide en el tratamiento / alivio del dolor producido por el cáncer; Proponer estrategias de cuidados en sintonía con las representaciones de las personas con cáncer que requieren el uso de morfina. MÉTODO: Investigación con enfoque cualitativo, descriptivo y exploratorio, realizada en un hospital público. Los participantes fueron personas con cáncer tratadas en modalidad ambulatorial. Criterios de inclusión: mayores de 18 años, con índice ≥ 50% en la Escala de Karnofsky (KPS) y prescripción analgésica de morfina. Criterios de exclusión: presencia de dolor de moderado a intenso en el momento de la recogida de datos; y aquellos con comprometimiento verbal, cognitivo y/o psiquiátrico. Datos recogidos mediante cuestionario y entrevista semiestructurada. Los datos del cuestionario se analizaron mediante estadística descriptiva simple y porcentual y el contenido verbal fue sometido a análisis de contenido de tipo lexical, utilizándose el software Alceste. Proyecto aprobado por los Comités de Ética en Investigación de la institución proponente y cooperante, con dictámenes núm. 3.296.128 y 3.453.968, respectivamente. Todos los participantes firmaron una declaración de Consentimiento Libre e Informado. RESULTADOS: La edad promedio fue de 54,7 años; sexo femenino (69,7%); predominio de la religión evangélica (60,6%). El 81,8% afirmó que seguía correctamente la prescripción de morfina. En la Escala de Karnofsky, el 45,5% presentó un índice del 60%, lo que indica la necesidad de asistencia ocasional, pero con capacidad para trabajar. La intensidad del dolor, según la escala visual analógica (EVA), varió de leve (grado 1) a moderado (grado 4), ambos con 21,2% de respuestas. El procesamiento de datos en el software Alceste generó dos bloques: el primero con la Clase 1, que expresa la representación farmacológica del tratamiento con morfina y los factores asociados a ese tratamiento; el segundo estaba compuesto por las Clases 2 y 3 y expresa las relaciones sociales involucradas en el contexto del tratamiento, el vínculo de la persona que usa morfina con el mundo que la rodea, así como la relación que establece con ese medicamento, el conocimiento sobre la morfina y las actitudes adoptadas con respecto a su uso. Hubo ambigüedad en las representaciones de la morfina, pues se la situó entre el dolor y el miedo: los participantes la señalaron como un recurso importante para el alivio/tratamiento del dolor oncológico, pero también mencionaron la posibilidad de repercusiones negativas asociadas a sus efectos. CONSIDERACIONES FINALES: A pesar de la adherencia de los pacientes a la morfina, la opiofobia aún debe combatirse mediante estrategias que hagan circular información que permita la reconstrucción de las representaciones sobre la morfina y su uso terapéutico. La educación terapéutica mediante la actuación de un equipo multidisciplinario descolla como una buena estrategia para difundir información segura sobre el uso de opioides.

Oleoyl alanine (HU595): a stable monomethylated oleoyl glycine interferes with acute naloxone precipitated morphine withdrawal in male rats.

RATIONALE: Oleoyl glycine, a little studied fatty acid amide similar in structure to anandamide, interferes with nicotine addiction in mice and acute naloxone-precipitated morphine withdrawal (MWD) in rats. Because endogenous oleoyl glycine is subject to rapid enzymatic deactivation, we evaluated the potential of more stable analogs to interfere with opiate withdrawal. OBJECTIVES: The potential of monomethylated oleoyl glycine (oleoyl alanine, HU595) to interfere with somatic and aversive effects of acute naloxone-precipitated MWD, its duration, and mechanism of action was assessed in male Sprague Dawley rats. The potential of dimethylated oleoyl glycine (HU596) to interfere with the aversive effects of naloxone-precipitated MWD was also investigated. RESULTS: Oleoyl alanine (HU595) interfered with somatic and aversive effects produced by naloxone-precipitated MWD at equivalent doses (1 and 5 mg/kg, i.p.) as we have reported for oleoyl glycine; however, oleoyl alanine produced a longer lasting (60 min) interference, yet did not produce rewarding or aversive effects on its own and did not modify locomotor activity. HU596 was not effective. The interference with aversive effects of naloxone-precipitated MWD by oleoyl alanine was prevented by both a PPARα antagonist and a CB1 receptor antagonist. Accordingly, the compound was found to inhibit FAAH and activate PPARα in vitro. Finally, oleoyl alanine also reduced acute naloxone-precipitated MWD anhedonia, as measured by decreased saccharin preference. CONCLUSIONS: Oleoyl alanine (also an endogenous fatty acid) may be a more stable and effective treatment for opiate withdrawal than oleoyl glycine.

Effect of Yulangsan Polysaccharide on the Reinstatement of Morphine-Induced Conditioned Place Preference in Sprague-Dawley Rats.

We previously reported that Yulangsan polysaccharide (YLSP), which was isolated from the root of Millettia pulchra Kurz, attenuates withdrawal symptoms of morphine dependence by regulating the nitric oxide pathway and modulating monoaminergic neurotransmitters. In this study, we investigated the effects and mechanism of YLSP on the reinstatement of morphine-induced conditioned place preference (CPP) in rats. A CPP procedure was employed to assess the behavior of rats, and indicators of serum and four brain regions (nucleus accumbens, ventral tegmental area, hippocampus and prefrontal cortex) were determined to explore its underlying mechanism. YLSP inhibited priming morphine-induced reinstatement of CPP in a dose-dependent manner. YLSP markedly reduced nitric oxide and nitric oxide synthase levels in the brain. Moreover, YLSP significantly decreased the dopamine and norepinephrine levels in the serum and brain. Furthermore, YLSP significantly decreased cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) concentrations, inhibited the expression of dopamine D1 receptors and cAMP response element binding protein mRNA, and improved the expression of dopamine D2 receptor mRNA in the four brain regions. Our findings indicated that YLSP could inhibit the reinstatement of morphine-induced CPP possibly by modulating the NO-cGMP and D1R-cAMP signaling pathways.

RETRACTED: Exploring the mechanism by which accumbal deep brain stimulation attenuates morphine-induced reinstatement through manganese-enhanced MRI and pharmacological intervention.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors. The authors have requested to retract this paper as the corresponding author had not sought the prior agreement of his co-authors to submit the paper for publication.

The adenosinergic system is involved in sensitization to morphine withdrawal signs in rats-neurochemical and molecular basis in dopaminergic system.

RATIONALE: Experimental data informs that not only do the dose and time duration of dependent drugs affect the severity of withdrawal episodes. Previous withdrawal experiences may intensify this process, which is referred as sensitization to withdrawal signs. Adenosine and dopamine (DA) receptors may be involved in this sensitization. OBJECTIVES: Rats were continuously and sporadically treated with increasing doses of morphine for 8 days. In rats, sporadically treated with morphine, morphine administration was modified by adding three morphine-free periods. Adenosine agonists were given during each of the morphine-free periods (six injections in total). On the 9th day, morphine was injected. One hour later, naloxone was administered to induce morphine withdrawal signs. Then, the animals were placed into cylinders and the number of jumpings was recorded. Next, the rats were decapitated and brain and brain structures (striatum, hippocampus, and prefrontal cortex) were dissected for neurochemical, molecular, and immunohistochemical experiments within DAergic pathways. RESULTS: We demonstrated that previous experiences of opioid withdrawal intensified subsequent withdrawal signs. Adenosine ligands attenuated the sensitization to withdrawal signs. In a neurochemical study, the release of DA and its metabolites was impaired in all structures. Significant alterations were also observed in mRNA and protein expression of DA receptors. CONCLUSIONS: Results demonstrate that intermittent treatment with morphine induces alterations in the DAergic system which may be responsible for sensitization to morphine withdrawal signs. Although adenosine ligands attenuate this type of sensitization, they are not able to fully restore the physiological brain status.

Acupuncture Suppresses Morphine Craving in Progressive Ratio Through the GABA System.

Previous studies revealed that acupuncture suppressed both morphine self-administration and morphine-seeking behavior after abstinence. Based on these results, this study examined whether acupuncture attenuated morphine-craving under a progressive ratio (PR) schedule and investigated the possible neuronal mechanism. Male Sprague-Dawley rats were trained to self-administer morphine (0.5 mg/kg) at a fixed ratio for 9 days, and rats who achieved stable infusion were switched to a PR schedule. When animals had taken no more morphine for 1 hour, the number of infusions was defined as the break point (BP). After PR training, animals that had established a stable BP received acupuncture the next day. Acupuncture was applied for 1 minute immediately before the test session. Bicuculline (1.0 mg/kg) and SCH 50911 (2.0 mg/kg) were given 30 minutes prior to acupuncture. The c-Fos levels in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) were examined. Acupuncture at SI5 reduced the BP significantly. Moreover, the effects of acupuncture were blocked by either bicuculline or SCH 50911. Immunofluorescence revealed that acupuncture at SI5 decreased c-Fos expressions in the VTA and the NAc. This study demonstrates that acupuncture at SI5 is effective for the treatment of morphine-craving and that this effect is mediated via the GABA pathway.

Nanotherapeutic approach for opiate addiction using DARPP-32 gene silencing in an animal model of opiate addiction.

Opiates act on the dopaminergic system of the brain and perturb 32 kDa dopamine and adenosine 3', 5'-monophosphate-regulated phosphoprotein (DARPP-32) function. The DARPP-32 mediated inhibition of protein phosphatase-1 (PP-1) and modulation of transcriptional factor CREB is critical to the changes in neuronal plasticity that result in behavioral responses during drug abuse. To investigate the role of DARPP-32 mediated signaling on withdrawal behavior in a rat model of opiate addiction, we used intracerebral administration of gold nanorods (GNR) complexed to DARPP-32 siRNA to silence DARPP-32 gene expression and measure its effects on the opiate withdrawal syndrome. We hypothesized that DARPP-32 siRNA will suppress the neurochemical changes underlying the withdrawal syndrome and therefore prevent conditioned place aversion by suppressing or removing the constellation of negative effects associated with withdrawal, during the conditioning procedure. Our results showed that opiate addicted animals treated with GNR-DARPP-32 siRNA nanoplex showed lack of condition place aversive behavior consequent to the downregulation of secondary effectors such as PP-1 and CREB which modify transcriptional gene regulation and consequently neuronal plasticity. Thus, nanotechnology based delivery systems could allow sustained knockdown of DARPP-32 gene expression which could be developed into a therapeutic intervention for treating drug addiction by altering reward and motivational systems and interfere with conditioned responses.

Bergenin decreases the morphine-induced physical dependence via antioxidative activity in mice.

Oxidative stress plays a role in the development of physical dependence induced by morphine. Bergenin, a polyphenol found in many Asian, African, and South American medicinal plants, is a potent antinarcotic agent with wide spectrum of pharmacological activities including antioxidant action. In the present study, we observed that bergenin decreased the development of physical dependence induced by morphine in mice and the antioxidant activity of bergenin plays a role in the antinarcotic effects through adapting to morphine-induced oxidative stress in the brain. The naloxone-precipitated withdrawal symptom (jumping frequency) was significantly ameliorated (50% of control group) by administration of bergenin (20 mg/kg) in morphine-treated mice. Furthermore, morphine-induced down-regulation of glutathione (GSH) contents was reversed by bergenin administration in the frontal cortex and liver. Bergenin had no effects on the increased levels of nfr2-dependent antioxidant enzyme HO1 and NQO1 in the frontal cortex, striatum, and liver of morphine-treated mice. However, the morphine-induced increase in nrf2 nuclear translocation in the frontal cortex and striatum was inhibited by bergenin treatment. These results suggest that bergenin has a potential antinarcotic effect via regulation of GSH contents and oxidative stress.

Effects of voluntary and treadmill exercise on spontaneous withdrawal signs, cognitive deficits and alterations in apoptosis-associated proteins in morphine-dependent rats.

Chronic exposure to morphine results in cognitive deficits and alterations of apoptotic proteins in favor of cell death in the hippocampus, a brain region critically involved in learning and memory. Physical activity has been shown to have beneficial effects on brain health. In the current work, we examined the effects of voluntary and treadmill exercise on spontaneous withdrawal signs, the associated cognitive defects, and changes of apoptotic proteins in morphine-dependent rats. Morphine dependence was induced through bi-daily administrations of morphine (10mg/kg) for 10 days. Then, the rats were trained under two different exercise protocols: mild treadmill exercise or voluntary wheel exercise for 10 days. After exercise training, their spatial learning and memory and aversive memory were examined by a water maze and by an inhibitory avoidance task, respectively. The expression of the pro-apoptotic protein Bax and the anti-apoptotic protein Bcl-2 in the hippocampus were determined by immunoblotting. We found that chronic exposure to morphine impaired spatial and aversive memory and remarkably suppressed the expression of Bcl-2, but Bax expression remained constant. Both voluntary and treadmill exercise alleviated memory impairment, increased the expression of Bcl-2 protein, and only the later suppressed the expression of Bax protein in morphine-dependent animals. Moreover, both exercise protocols diminished the occurrence of spontaneous morphine withdrawal signs. Our findings showed that exercise reduces the spontaneous morphine-withdrawal signs, blocks the associated impairment of cognitive performance, and overcomes morphine-induced alterations in apoptotic proteins in favor of cell death. Thus, exercise may be a useful therapeutic strategy for cognitive and behavioral deficits in addict individuals.

Acupuncture at HT7 suppresses morphine self-administration at high dose through GABA system.

In the previous study, acupuncture at HT7 has shown to attenuate the self-administration of morphine at a low dose (0.1mg/kg). In this study, it was further investigated whether acupuncture at HT7 could attenuate the morphine self-administration at a high dose (0.5mg/kg). Male Sprague-Dawley rats weighing 270-300g were used. After surgery of catheterization, animals were trained to self-administer morphine solution (0.5mg/kg) using daily 1h session under fixed ratio 1 schedule for 3 weeks. Animals that had shown stable morphine-taking (establish baseline: variation less than 20% of the mean of three consecutive days) were subjected to the acupuncture treatment. Bicuculline and SCH 50911 were used to investigate the possible relation between the effect of acupuncture and the GABA receptor system. Acupuncture at HT7, but not at control acupoint, LI5, suppressed spontaneous morphine-taking behavior significantly. In addition, the effect of acupuncture was blocked by both GABA receptor antagonists. The results of this study suggest that acupuncture at HT7 suppresses morphine-taking behavior through the mediation of GABA receptor system.

Depletion of perineuronal nets in the amygdala to enhance the erasure of drug memories.

Extinction therapy has been suggested to suppress the conditioned motivational effect of drug cues to prevent relapse. However, extinction forms a new inhibiting memory rather than erasing the original memory trace and drug memories invariably return. Perineuronal nets (PNNs) are a specialized extracellular matrix around interneurons in the brain that have been suggested to be a permissive factor that allows synaptic plasticity in the adolescent brain. The degradation of PNNs caused by chondroitinase ABC (ChABC) may generate induced juvenile-like plasticity (iPlasticity) and promote experience-dependent plasticity in the adult brain. In the present study, we investigated the effect of removing PNNs in the amygdala of rat on the extinction of drug memories. We found that extinction combined with intra-amygdala injections of ChABC (0.01 U/side) prevented the subsequent priming-induced reinstatement of morphine-induced and cocaine-induced, but not food -induced, conditioned place preference (CPP). Intra-amygdala injections of ChABC alone had no effect on the retention, retrieval, or relearning of morphine-induced CPP and storage of acquired food-induced CPP. Moreover, we found that the procedure facilitated the extinction of heroin- and cocaine-seeking behavior and prevented the spontaneous recovery and drug-induced reinstatement of heroin- and cocaine-seeking behavior. We also found that the effect of PNNs degradation combined with extinction may be mediated by the potentiation of several plasticity-related proteins in the amygdala. Altogether, our findings demonstrate that a combination of extinction training with PNNs degradation in the amygdala erases drug memories and suggest that ChABC may be an attractive candidate for the prevention of relapse.

Alterations in phosphorylated CREB expression in different brain regions following short- and long-term morphine exposure: relationship to food intake.

BACKGROUND: Activation of the cyclic adenosine monophosphate (cAMP)/phosphorylated CREB (P-CREB) system in different brain regions has been implicated in mediating opioid tolerance and dependence, while alteration of this system in the lateral hypothalamus (LH) has been suggested to have a role in food intake and body weight. METHODS: Given that opioids regulate food intake, we measured P-CREB in different brain regions in mice exposed to morphine treatments designed to induce different degrees of tolerance and dependence. RESULTS: We found that a single morphine injection or daily morphine injections for 8 days did not influence P-CREB levels, while the escalating dose of morphine regimen raised P-CREB levels only in the ventral tegmental area (VTA). Chronic morphine pellet implantation for 7 days raised P-CREB levels in the LH, VTA, and dorsomedial nucleus of the hypothalamus (DM) but not in the nucleus accumbens and amygdala. Increased P-CREB levels in LH, VTA, and DM following 7-day treatment with morphine pellets and increased P-CREB levels in the VTA following escalating doses of morphine were associated with decreased food intake and body weight. CONCLUSION: The morphine regulation of P-CREB may explain some of the physiological sequelae of opioid exposure including altered food intake and body weight.

Phenylmethanesulfonyl fluoride, a serine protease inhibitor, suppresses naloxone-precipitated withdrawal jumping in morphine-dependent mice.

We have previously shown that intracerebroventricular (i.c.v.) administration of cysteine protease inhibitors suppresses naloxone-precipitated withdrawal jumping in morphine-dependent mice, presumably through the inhibition of dynorphin degradation (see (Tan-No, K., Sato, T., Shimoda, M., Nakagawasai, O., Niijima, F., Kawamura, S., Furuta, S., Sato, T., Satoh, S., Silberring, J., Terenius, L., Tadano, T., 2010. Suppressive effects by cysteine protease inhibitors on naloxone-precipitated withdrawal jumping in morphine-dependent mice. Neuropeptides 44, 279-283)). In the present study, we examined the effect of phenylmethanesulfonyl fluoride (PMSF), a serine protease inhibitor, on naloxone-precipitated withdrawal jumping in morphine-dependent mice. The doses of morphine (mg/kg per injection) were subcutaneously given twice daily for 2 days [day 1 (30) and day 2 (60)]. On day 3, naloxone (8 mg/kg) was intraperitoneally administered 3h after the final injection of morphine (60 mg/kg), and the number of jumps was immediately recorded for 20 min. Naloxone-precipitated withdrawal jumping was significantly suppressed by i.c.v. administration of PMSF (4 nmol), given 5 min before each morphine treatment during the induction phase, with none given on the test day. The expression of tissue plasminogen activator (tPA), a serine protease that converts plasminogen to plasmin, in the prefrontal cortex was significantly increased in morphine-dependent and -withdrawal mice, as compared with saline-treated mice. Moreover, trans-4-(aminomethyl)-cyclohexanecarboxylic acid (300 pmol), an antiplasmin agent, and (Tyr(1))-thrombin receptor activating peptide 7 (0.45 and 2 nmol), an antagonist of protease activated receptor-1 (PAR-1), significantly suppressed naloxone-precipitated withdrawal jumping. The present results suggest that PMSF suppresses naloxone-precipitated withdrawal jumping in morphine-dependent mice, presumably through the inhibition of activities of tPA and plasmin belonging to the serine proteases family, which subsequently activates PAR-1.

[Changes of protein kinase A expressions in central amygdaloid nuclei during the process of chronic morphine-induced conditioned place aversion in rats].

OBJECTIVE: To explore neurobiological mechanisms of the withdrawal-induced aversion. The changes of protein kinase A were measured in central amygdaloid nucleic (CeA) of conditioned place aversion (CPA) model rats. METHODS: (1) All 72 male SD rats were divided into three groups, model group (MN group), and control group (MS group and SN group). MN group was injected with morphine,6.5 days, 10 mg/kg, intraperitoneally (ip), twice per day, naloxone injection, 0.3 mg/kg, ip, along with conditioned place aversion training, to develop the CPA model. The MS group was administrated equivalent volume of morphine and saline. Also the SN group was injected with equivalent volume of saline and naloxone. (2) During the process of morphine-induced CPA, the expression of protein kinase A was assayed with immunohistochemistry in the CeA. RESULTS: In the MN group, protein kinase A expressions in the CeA occurred adaptive changes at different points of CPA (P < 0.05). Protein kinase A expressions after establishment(Day7,134.43 +/- 4.481, P < 0.05), and after extinction (Day 13, 141.01 +/- 3.360, P < 0.01), and after reinstatement (Day 14,137.18 +/- 40.330, P < 0.05) were also lower than those before the establishment of the CPA (Day 5, 124.48 +/- 6.722). However, PKA expressions were not significantly different both in MS group (P > 0.05)and SN group (P > 0.05). CONCLUSION: (1) Protein kinase A expression, in turn regulating the aversion expression, in the CeA probably is a key pathway contributing to the development of CPA. (2) The neuroadaptation mediated by protein kinase A may be one of the important molecular underpinnings of CPA.

Disrupting the memory of places induced by drugs of abuse weakens motivational withdrawal in a context-dependent manner.

Addicts repeatedly relapse to drug seeking even after years of abstinence, and this behavior is frequently induced by the recall of memories of the rewarding effects of the drug. Established memories, including those induced by drugs of abuse, can become transiently fragile if reactivated, and during this labile phase, known as reconsolidation, can be persistently disrupted. Here we show that, in rats, a morphine-induced place preference (mCPP) memory is linked to context-dependent withdrawal as disrupting the reconsolidation of the memory leads to a significant reduction of withdrawal evoked in the same context. Moreover, the hippocampus plays a critical role in linking the place preference memory with the context-conditioned withdrawal, as disrupting hippocampal protein synthesis and cAMP-dependent-protein kinase A after the reactivation of mCPP significantly weakens the withdrawal. Hence, targeting memories induced by drugs may represent an important strategy for attenuating context-conditioned withdrawal and therefore subsequent relapse in opiate addicts.

Blockade of nitric oxide overproduction and oxidative stress by Nigella sativa oil attenuates morphine-induced tolerance and dependence in mice.

The effects of Nigella sativa oil on morphine-induced tolerance and dependence in mice and possible mechanism(s) of these effects were investigated, for the first time, in this study. Repeated administration of Nigella sativa oil (4 ml/kg, p.o.) along with morphine (5 mg/kg, s.c.) attenuated the development of tolerance, as measured by the hot plate test, and dependence, as assessed by naloxone (5 mg/kg, i.p.)-precipitated withdrawal manifestations. Concomitantly, nitric oxide overproduction and increase in brain malondialdehyde level induced by repeated administration of morphine to mice or by administration of naloxone to morphine-dependent mice were inhibited by co-administration of the oil. Also, the decrease in brain intracellular reduced glutathione level and glutathione peroxidase activity induced by both treatments were inhibited by co-administration of the oil. The increase in brain glutamate level induced by both treatments was not inhibited by concurrent administration of the oil. The inhibitory effect of the oil on morphine-induced tolerance and dependence and on naloxone-induced biochemical alterations in morphine-dependent mice was enhanced by concurrent i.p. administration of the NMDA receptor antagonist, dizocilpine (0.25 mg/kg). Similarly, concurrent i.p. administration of the NO synthase inhibitors; L-N (G)-nitroarginine methyl ester (10 mg/kg), aminoguanidine (20 mg/kg) and 7-nitroindazole (25 mg/kg) or the antioxidant, N-acetylcysteine (50 mg/kg) enhanced this inhibitory effect of the oil. On the other hand, this effect was antagonized by concurrent i.p. administration of the nitric oxide precursor, L-arginine (300 mg/kg). These results provide evidence that Nigella sativa oil, through inhibition of morphine-induced NO overproduction and oxidative stress, appears to have a therapeutic potential in opioid tolerance and dependence.

Study of morphine-induced dependence in gonadectomized male and female mice.

In this study we evaluated the effects of sex difference and also sex hormones on the naloxone-precipitated morphine withdrawal in both orchidectomized (ORC) male and ovariectomized (OVX) female mice. Morphine (50, 50 and 75 mg/kg/day for 4 days, s.c.) was administered to animals and at 5th day naloxone (4 mg/kg, i.p.)-precipitated morphine withdrawal signs, jumpings and the percentage of weight loss, were measured. There was no significant alteration in withdrawal jumpings between male and female mice, though weight loss was significantly higher in male ones. Jumpings was significantly lower in both OVX and ORC mice and percentage of weight loss was significantly higher in OVX mice than corresponding non-operated or sham animals. In OVX mice, E(2)V (10 mg/kg, s.c.) increased number of jumpings and decreased percentage of weight loss. Progesterone (25 mg/kg, s.c.) had no effect on jumpings, whereas it decreased weight loss in OVX mice. Testosterone (2.5 mg/kg, s.c.) increased jumpings in ORC mice while it had no effect on percentage of weight loss. Our results demonstrated that sex hormones could play a role in the morphine withdrawal syndrome in both ORC male and OVX female mice.

A survey of acute and chronic heroin dependence in ten inbred mouse strains: evidence of genetic correlation with morphine dependence.

Heroin and morphine exposure can cause physical dependence, with symptoms manifesting during their withdrawal. Inter-individual differences in symptom frequency during morphine withdrawal are a common finding that, in rodents, is demonstrably attributable to genotype. However, it is not known whether inter-individual differences characterize heroin withdrawal, and whether such variation can be similarly influenced by genotype. Therefore, we injected mice of ten inbred strains with acute and chronic heroin doses and compared their jumping frequencies, a common index of withdrawal magnitude, during naloxone-precipitated withdrawal. The data revealed significant strain frequency differences (range after acute and chronic heroin injection: 0-104 and 0-142 jumps, respectively) and substantial heritability (h(2)=0.94 to 0.96), indicating that genetic variance is associated with heroin withdrawal. The rank order of strain sensitivity for acute and chronic heroin withdrawal jumping, and for the current heroin and previous morphine strain data, were significantly correlated (r=0.75-0.94), indicating their genetic and, ultimately, physiological commonality. These data suggest that the genetic liability to heroin dependence remains constant across a period of heroin intake, and that heroin and morphine dependence may benefit from common treatment strategies.

Abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers.

Abuse of prescription opioid medications has increased dramatically in the United States during the past decade, as indicated by a variety of epidemiological sources. However, few studies have systematically examined the relative reinforcing effects of commonly abused opioid medications. The current double-blind, placebo-controlled in-patient study was designed to compare the effects of intravenously delivered fentanyl (0, 0.0625, 0.125, 0.187, and 0.250 mg/70 kg), oxycodone (0, 6.25, 12.5, 25, and 50 mg/70 kg), morphine (0, 6.25, 12.5, 25, and 50 mg/70 kg), buprenorphine (0, 0.125, 0.5, 2, and 8 mg/70 kg), and heroin (0, 3.125, 6.25, 12.5, and 25 mg/70 kg) in morphine-maintained heroin abusers (N=8 completers maintained on 120 mg per day oral morphine in divided doses (30 mg q.i.d.)). All of the participants received all of the drugs tested; drugs and doses were administered in non-systematic order. All of the drugs produced statistically significant, dose-related increases in positive subjective ratings, such as 'I feel a good drug effect' and 'I like the drug.' In general, the order of potency in producing these effects, from most to least potent, was fentanyl>buprenorphine>or=heroin >morphine=oxycodone. In contrast, buprenorphine was the only drug that produced statistically significant increases in ratings of 'I feel a bad drug effect' and it was the only drug that was not self-administered above placebo levels at any dose tested. These data suggest that the abuse liability of buprenorphine in heroin-dependent individuals may be low, despite the fact that it produces increases in positive subjective ratings. The abuse liabilities of fentanyl, morphine, oxycodone, and heroin, however, appear to be similar under these experimental conditions.