Opium Alkaloids

Opium alkaloids, derived from crude Papaver somniferum L. plant, are potent analgesic drugs, but their use is limited because of dependence and withdrawal. Opium alkaloids activate the mesocorticolimbic dopaminergic system, which project from the ventral tegmental area to the nucleus accumbens and medial prefrontal cortex, and dopamine is critically important in opioid consumption and sustaining. The reward effect resulting from the activation of the dopaminergic system leads to continued opioid consumption and occurs opioid dependence. After the development of opioid dependence, consumption continues to avoid withdrawal syndrome. Opioid dependence is accompanied with tolerance, which requires the use of high doses to achieve the same effect. When tolerance develops, the chronic consumer continues to use opioid above known toxic doses to produce the same effect, which can result in death regardless of the type of opioid used. Raw Papaver somniferum L. has five high-density main opium alkaloids including morphine, noscapine, codeine, thebaine, and papaverine. Some of these alkaloids bind to classical opioid receptors to produce an opioid-like effect, while the other part mediates non-opioid effects. This chapter reviews the opiod history, receptors, mechanism of action, dependence, withdrawal. In addition, general information about five main opium alkaloids, their effects, uses, routes of administration, pharmacokinetics, adverse reactions, contraindications; effects on reproduction, pregnancy, and lactation were compiled

The Effects of Topiramate Applied to the Nucleus Accumbens Region on Morphine Withdrawal Syndrome

Aim:Nucleus accumbens, one of the nuclei of the basal ganglia, and dopamine, the neurotransmitter play a critical role in opioid dependence and withdrawal. In opioid withdrawal, the importance of neurotransmitters such as glutamate and gamma aminobutyric acid (GABA), as well as dopamine, is known. In this study, we aimed to investigate the effects of local injections of topiramate, an antiepileptic agent affecting GABAergic and glutamatergic pathways, into the nucleus accumbens on withdrawal signs and locomotor activity during naloxone-induced withdrawal in morphine-dependent rats.Materials and Methods:Twenty male Sprague-Dawley rats were divided in topiramate treatment and control groups. All animals received morphine pellets and guide cannulas were placed bilaterally in the nucleus accumbens regions by stereotaxic surgery. On the last day of the experiment, following the bilateral topiramate or saline (control group) microinjections, morphine withdrawal was triggered by naloxone.Results:Topiramate microinjections into the nucleus accumbens region significantly suppressed the signs of naloxone-induced morphine withdrawal such as number of jumpings and weight loss. No significant difference was observed in wet dog shakes, one of the withdrawal signs, after local topiramate treatment. Although topiramate microinjections increased stereotypical activity it did not change locomotor activity behavior such as vertical and ambulatory activity, and total covered distance.Conclusion:These findings show that local microinjection of topiramate into the nucleus accumbens is effective in preventing opioid deprivation symptoms without significant effect on locomotor activity

The Effects of L-NAME and Agmatine in The Nucleus Accumbens Core Regıon on Morphine Withdrawal Syndrome

Aim:The mesocorticolimbic dopaminergic system, especially the nucleus accumbens, is an important region in opioid dependence and withdrawal. Studies have shown that nitric oxide synthase inhibitors modulate the development of tolerance to opioids, opioid dependence, and withdrawal. In this study, we aimed to investigate the effects of local injections of L-NAME and agmatine into the nucleus accumbens core (NAcc), one of the nucleus accumbens subregions on withdrawal signs and locomotor activity behavior during naloxone-induced withdrawal in morphine-dependent rats.Materials and Methods:Twenty-four adult Sprague-Dawley rats were used in the study. Morphine dependence was developed in all animals after guide cannula implantation into the NAcc region. On the last day of experiment, following bilateral L-NAME, agmatine or artificial cerebrospinal fluid (aCSF, control group) microinjections morphine withdrawal was induced by naloxone.Results:Local administration of agmatine and L-NAME into the NAcc significantly suppressed the jumping number during naloxone induced withdrawal. Local agmatine treatment significantly suppressed the score of teeth chattering, although the L-NAME did not change. No significant difference was observed in withdrawal symptoms such as wet dog shakes and defecation after local agmatine and L-NAME treatment. Agmatine increased stereotypic movements, but did not change locomotor activity behaviors such as ambulatory activity and total covered distance. Local administration of L-NAME into the NAcc did not increase stereotypic and ambulatory movements, and total covered distance during naloxone-induced withdrawal.Conclusion:These results suggest that inhibition of nitric oxide synthesis in NAcc plays a role in morphine withdrawal symptoms, but it is not responsible alone

Effects of Injection of Gamma-Aminobutyric Acid Agonists into the Nucleus Accumbens on Naloxone-Induced Morphine Withdrawal

Aims: This study was to investigate the effects of local administration of gamma-aminobutyric acid (GABA) agonists into the nucleus accumbens (NAc) on naloxone-induced morphine withdrawal symptoms. Methods: Bilateral guide cannulas were stereotaxically implanted in the shell or core regions of the NAc of Sprague-Dawley rats. After a recovery period, 3 morphine pellets, each consisting of 75 mg morphine base, were placed subcutaneously on the first and third days of the study with the rats under mild ether anaesthesia. The GABA agonists, baclofen hydrochloride or muscimol hydrobromide, were injected into the NAc, and morphine withdrawal was induced by naloxone on the fifth day. Results: Administration of baclofen to the shell or core regions of the NAc of Sprague-Dawley rats led to statistically significant decreases in both behavioural and locomotor activity parameters during the morphine withdrawal period, compared to the control group. However, there were no statistically significant changes in locomotor activity or withdrawal behavioural parameters, with the exception of wet dog shakes, between control and muscimol-treated groups. Conclusion: These findings show that GABAergic conduction in the NAc is effective on the morphine withdrawal symptoms, and that both the shell and core regions of the NAc are associated with this effect. (C) 2017 S. Karger AG, Base

The effect of oral administration of monosodium glutamate on epileptogenesis in infant rats

Aim. Glutamate is an excitatory neurotransmitter that is widely distributed throughout the brain. An increase in glutamate concentration or sensitivity of glutamate receptors triggers neurodegenerative diseases, epilepsy in particular. Monosodium glutamate is a substance added to foods to enhance flavour. We investigated the effect of monosodium glutamate on epileptogenesis, as well asheight and weight, in rats that were just weaned. Methods. Twenty-four male and female 21-day-old Wistar Albino rats were divided into two groups: one with monosodium glutamate added to the drinking water, and a control in which NaCl was added to the drinking water. The electrical stimulation threshold values were determined in animals to which the hippocampal kindling process was applied, and the stimulations at these threshold values were invariably applied to the animals until they were kindled. Results. The electrical stimulation threshold values of the monosodium glutamate group did not statistically change, whereas the number of required stimulations for kindled rats was significantly lower compared with the control group. Conclusion. These results reveal that long-term oral administration of glutamate salts causes an increase in excitability in the central nervous system during ontogenetic development

5-hydroxytryptamine release in the anterior hypothalamic and the hippocampal areas of cholestatic rats

Cholestasis contributes to the genesis of fatigue through several mechanisms. Among these mechanisms, affected serotonergic neurotransmission is important in the pathogenesis of central fatigue. Previously, elevated levels of 5-hydroxyindole acetic acid (5-HIAA), the metabolite of 5-hydroxytryptamine (5-HT) and increased 5-HT(2) receptor density were demonstrated in the anterior hypothalamus and in the hippocampus of bile duct resected rats (BDR), respectively. The aim of this paper is to demonstrate evoked 5-HT release in selected brain regions like anterior hypothalamus and hippocampal CA1 regions of cholestatic rats using BDR rats as an experimental model for cholestasis. In this study, we analyzed the K(+) evoked 5-HT and its metabolite 5-HIAA levels by using HPLC with electrochemical detection in the microdialysis samples collected from anterior hypothalamic and hippocampal CA1 regions of sham-operated and BDR rats (n = 6). The ratios of [5-HIAA] to [5-HT] following perfusion with 100 mM K(+) artificial cerebrospinal fluid was used for the comparison of the evoked release of 5-HT. Locomotor activity was used to assess the signs of cholestasis associated fatigue in the BDR rats. The vertical and horizontal activity counts within 15 min were found to be decreased in the BDR rats compared to sham-operated rats (p < 0.05). Besides, the number of fecal boli (an index of emotionality) was also significantly fewer in the cholestatic rats (p < 0.05). No significant difference between the sham-operated and the BDR rats was detected in the basal 5-HT and 5-HIAA levels of anterior hypothalamus. K+ stimulation yielded a more profound increase in the [5-HIAA/[5-HT] in the BDR rats (p < 0.05). The basal levels of 5-HT in CAI region of the BDR rats was found to be lower than that of sham-operated group (p < 0.05), but no significant difference was observed in terms of evoked 5-HT release in both sham-operated and BDR rats. These findings imply the presence of affected serotonergic system in cholestasis. (c) 2005 Elsevier Inc. All rights reserved

Effect of U-92032, T-Type Ca(2+)Channel Blocker, on Rats with Genetic Absence Epilepsy

Introduction:Absence epilepsy is associated with diffuse spike-and-wave discharges (SWD) on the electroencephalogram (EEG). Recent studies have demonstrated that the primary somatosensory cortex is also implicated in the generation of the SWDs.Objective:This study investigated the effects of systemic and local administrations of U-92032 into the brain of Genetic Absence Epilepsy Rats from Strasbourg (GAERS).Methods:GAERS animals underwent stereotaxic surgery for the placement of EEG recording electrodes and guide cannulas for U-92032 administration into the lateral ventricle (intracerebroventricular [i.c.v.]), upper lips area (S1Ulp) or barrel field area (S1B) of primary somatosensory cortex. Following 7 days of recovery, electrical activity was recorded continuously for 1 h before and 6 h after intraperitoneal (0.25; 1; 5 mg/kg i.p.) or local U-92032 or dimethyl sulfoxide (DMSO) injections.Results:No changes were detected in the cumulative duration, mean duration, and number of SWDs following i.p. U-92032 injections. Local i.c.v. injections of U-92032 caused a significant decrease in the cumulative duration (i.c.v., 50 and 100 nmol/L), mean duration (i.c.v., 50, 100, and 250 nmol/L), and the number (i.c.v., 250 nmol/L) of SWDs compared to DMSO groups. Intra-cortical (S1Ulp and S1B) U-92032 injections caused a significant decrease in all 3 parameters compared to DMSO groups, as well.Conclusion:Intra-cortical injection of U-92032 caused almost complete removal of SWDs in GAERS and i.c.v. administration resulted in a significant reduction. However, systemic i.p. administration did not cause a significant change with the applied -doses

Nukleus Akumbens Bölgesine Uygulanan Topiramatın Morfin Yoksunluk Sendromuna Etkileri

Aim: Nucleus accumbens, one of the nuclei of the basal ganglia, and dopamine, the neurotransmitter play a critical role in opioiddependence and withdrawal. In opioid withdrawal, the importance of neurotransmitters such as glutamate and gamma aminobutyric acid(GABA), as well as dopamine, is known. In this study, we aimed to investigate the effects of local injections of topiramate, anantiepileptic agent affecting GABAergic and glutamatergic pathways, into the nucleus accumbens on withdrawal signs and locomotoractivity during naloxone-induced withdrawal in morphine-dependent rats.Materials and Methods: Twenty male Sprague-Dawley rats were divided in topiramate treatment and control groups. All animalsreceived morphine pellets and guide cannulas were placed bilaterally in the nucleus accumbens regions by stereotaxic surgery. On thelast day of the experiment, following the bilateral topiramate or saline (control group) microinjections, morphine withdrawal was triggeredby naloxone.Results: Topiramate microinjections into the nucleus accumbens region significantly suppressed the signs of naloxone-inducedmorphine withdrawal such as number of jumpings and weight loss. No significant difference was observed in wet dog shakes, one of thewithdrawal signs, after local topiramate treatment. Although topiramate microinjections increased stereotypical activity it did not changelocomotor activity behavior such as vertical and ambulatory activity, and total covered distance.Conclusion: These findings show that local microinjection of topiramate into the nucleus accumbens is effective in preventing opioiddeprivation symptoms without significant effect on locomotor activity.Amaç: Bazal gangliyon çekirdeklerinden biri olan nukleus akumbens ve nörotransmitter olan dopamin opioid bağımlılığı ve_x000D_ yoksunluğunda kritik rol oynamaktadır. Opioid yoksunluğunda dopaminin yanı sıra glutamat ve GABA gibi nörotransmitterlerin de önemi_x000D_ bilinmektedir. Biz bu çalışmada morfin bağımlılığı oluşturulan hayvanlarda GABAerjik ve glutamaterjik yolakları etkileyen antiepileptik_x000D_ ajan olan topiramatın nukleus akumbens bölgesine lokal uygulamasının naloksonla tetiklenen yoksunluk sendromunda yoksunluk_x000D_ bulguları ve lokomotor aktivite üzerine etkilerini araştırmayı amaçladık._x000D_ Materyal ve Metot: Yirmi adet erkek Sprague-Dawley sıçanları topiramat tedavi grubu ve kontrol grubu olarak ikiye ayrıldı. Hayvanların_x000D_ hepsine morfin peletleri uygulandı, stereotaksik cerrahi işlemle nukleus akumbens bölgelerine kılavuz kanüller bilaretal yerleştirildi._x000D_ Deneyin son gününde bilateral topiramat veya serum fizyolojik (kontrol grubu) mikroenjeksiyonlarını takiben nalokson uygulanarak morfin_x000D_ yoksunluğu tetiklendi._x000D_ Bulgular: Nukleus akumbens bölgesine lokal uygulanan topiramat naloksonla tetiklenen morfin yoksunluk bulgularından sıçrama_x000D_ sayısını ve ağırlık kaybını anlamlı düzeyde baskıladı. Lokal topiramat uygulaması yoksunluk bulgularından ıslak köpek silkinmesinde ise_x000D_ anlamlı değişiklik yapmadı. Topiramat mikroenjeksiyonları stereotipik hareketleri artırdığı halde vertikal hareketler, ambulatuvar_x000D_ hareketler ve toplam kat edilen mesafe gibi lokomotor aktivite davranışlarını değiştirmedi._x000D_ Sonuç: Bu bulgular antikonvülzan ilaç olan topiramatın nukleus akumbens bölgesine lokal uygulanmasının lokomotor aktivitede anlamlı_x000D_ baskılanma yapmadan opioid yoksunluk belirtilerinin önlenmesinde etkili olduğunu göstermektedir