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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent research in our laboratory has demonstrated that stress activates an endogenous cannabinoid mechanism that suppresses sensitivity to pain [Nature 435 (2005) 1108]. In this work, CB(1) antagonists administered systemically blocked stress-induced analgesia induced by brief, continuous foot-shock. The present studies were conducted to examine the role of cannabinoid CB(1) receptors in the brainstem rostral ventromedial medulla (RVM) and midbrain dorsolateral periaqueductal gray (PAG) in cannabinoid stress-induced analgesia (SIA). Pharmacological blockade of vanilloid TRPV1 receptors with capsazepine, administered systemically, did not alter cannabinoid SIA, suggesting that cannabinoid SIA was not dependent upon TRPV1. Microinjection of the competitive CB(1) antagonist rimonabant (SR141716A) into either the RVM or dorsolateral PAG suppressed stress antinociception in this model. Rimonabant was maximally effective following microinjection into the dorsolateral PAG. The fatty-acid amide hydrolase (FAAH) inhibitor arachidonoyl serotonin (AA-5-HT) was subsequently used to block hydrolysis of endocannabinoids and enhance SIA. Systemic and site-specific injections of AA-5-HT into either the dorsolateral PAG or RVM induced CB(1)-mediated enhancements of SIA. Palmitoyltrifluoromethylketone, a potent inhibitor of FAAH and phospholipase A2 activity, administered systemically, exerted similar effects. In all conditions, the antinociceptive effects of each FAAH inhibitor were completely blocked by coadministration of the CB(1) antagonist rimonabant. The present results provide evidence that a descending cannabinergic neural system is activated by environmental stressors to modulate pain sensitivity in a CB(1)-dependent manner.
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PMID:Inhibition of fatty-acid amide hydrolase enhances cannabinoid stress-induced analgesia: sites of action in the dorsolateral periaqueductal gray and rostral ventromedial medulla. 1612 56

The endocannabinoid system (EC) plays a significant role in appetite drive and associated behaviours. Therefore attenuation of the activity of the EC system would have therapeutic benefit in treating disorders that might have a component of excess appetite drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Antagonists of cannabinoid receptors have been designed through rational drug discovery essential to exploit these novel targets for potential in obesity, metabolism, addiction, pain and neurologic disorders. Rimonabant is the only compound in this group which along this pathway is now approved as a selective CB (1) (cannabinoid receptor subtype 1) antagonist, or inverse agonist, in the European Union and India and under regulatory review in the United States for the treatment of obesity and associated cardiometabolic risk.
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PMID:Endocannabinoid system--a novel target for cardiometabolic risk. 1787

The endocannabinoid system is a complex system with endogenous ligands, synthesis and transport processes, specific receptors (CB1 and CB2) and intracellular degrading enzymes. It is widely distributed in the central nervous system, but also in peripheral organs. In the brain, endocannabinoids and CB1 receptors are almost ubiquitous and play a role in synaptic plasticity: they modulate, through an inhibitory retrograde action, the release of classical neurotransmitters such as amines, acetylcholine or amino acids. They may exert a neuroprotective effect, but are also involved in appetite and alcohol/drug dependence. At the periphery, they are present (and overexpressed in case of abdominal obesity) in various organs involved in energy control and metabolic regulation. Furthermore, CB2 receptors are also present in the brain, although less numerous than CB1 receptors. They could attenuate pain and also be neuroprotective. Selective agonists, antagonists and inverse agonists of CB1 and CB2 receptors are currently developed and open new interesting therapeutic perspectives. Rimonabant, a CB1 antagonist, has been recently launched for the treatment of obese or overweight patients at high cardiometabolic risk.
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PMID:[Endocannabinoid system in the brain...and elsewhere]. 1866 6

Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and surgery, among which the diet is still the most common way. However, none of these therapeutic measures available is ideal, making it necessary to find an effective medical treatment. The endocannabinoid system, which is well known for its contributions in certain mental processes such as relaxation, amelioration of pain and anxiety, and sedation initiation, has been recently reported to play an essential role in regulating appetite and metabolism to maintain energy balance, leading to the belief that endocannabinoid system is closely related to obesity. This new discovery deepens our understanding of obesity, and provides us with a new direction for clinical obesity treatment. Rimonabant is an antagonist for CB1, and has entered the market in some countries. However, although effective as an anti-obesity drug, rimonabant also causes obviously adverse side-effects, thus is being doubted and denied for medical usage.
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PMID:The endocannabinoid system: a new pharmacological target for obesity treatment? 1944 89

The basolateral amygdala (BLA) contains a high density of cannabinoid CB1 receptors and is critically involved in pain and fear-related behaviour. We investigated the effects of bilateral intra-BLA administration of the CB1 receptor antagonist/inverse agonist, rimonabant, on formalin-evoked nociceptive behaviour, fear-conditioned behaviour including analgesia, and associated brain regional alterations in Fos expression in rats. Intra-BLA administration of rimonabant significantly reduced formalin-evoked nociceptive behaviour in the absence, but not presence, of conditioned fear. Rimonabant attenuated a formalin-evoked reduction in freezing while emitting 22 kHz ultrasonic vocalisation in the early part of the fear expression trial. Formalin-evoked nociceptive behaviour was associated with increased Fos immunoreactivity (FI) in the CA2/3 region of the hippocampus and rostral ventromedial medulla, effects attenuated by intra-BLA rimonabant. Formalin also decreased FI in the cingulate cortex, an effect which was not observed in fear-conditioned rats. Contextually-induced fear was associated with increased FI in the dorsal caudal periaqueductal grey in the absence, but not presence, of formalin-evoked nociceptive tone. In conclusion, bilateral intra-BLA administration of rimonabant reduces nociceptive behaviour in a model of tonic, persistent inflammatory pain, an effect associated with reduced activation of neurons in the CA2/3 hippocampus and rostral ventromedial medulla. The data also provide evidence for differential pain- and fear-related brain regional activity in the presence or absence of contextually-induced aversion and nociceptive tone.
Eur J Pain 2010 May
PMID:Effects of intra-basolateral amygdala administration of rimonabant on nociceptive behaviour and neuronal activity in the presence or absence of contextual fear. 1978 58

Diabetes is one of the leading causes of painful neuropathy and to date, besides a tight glycemic control, a viable treatment for this complication is not available. Rimonabant is a selective cannabinoid CB(1) receptor antagonist that produces a significant increase in insulin sensitivity and a reduction of HbA(1c) in diabetic patients. This study aimed to investigate the therapeutic potential of rimonabant in relieving diabetes-induced neuropathic pain. The repeated treatment with rimonabant evoked a significant attenuation of mechanical allodynia in diabetic mice that was dose- and time-dependent. This effect occurred without alteration of hyperglycemia, but it was associated with significant effects on many key players in the pathogenesis of diabetic neuropathy. Metabolic changes induced by hyperglycemia lead to oxidative stress, deregulation of cytokine control and reduced production and transport of nerve growth factor (NGF), and all these factors contribute to neuropathic pain. Rimonabant treatment reduced oxidative stress in peripheral nerve, as revealed by the ability of the compound to counteract the reduced glutathione (GSH) depletion. The same repeated treatment inhibited tumor necrosis factor (TNFalpha) overproduction in the spinal cord and increased the NGF support. This rimonabant-induced improvement might favour the nerve regeneration; accordingly, the histological analysis of sciatic nerves showed a marked degeneration of myelinated fibers in diabetic mice, that was substantially reduced after rimonabant administration. These findings support the hypothesis that CB(1) antagonists would represent a new opportunity for diabetic patients, since currently there are no treatments for painful diabetic neuropathy other than treating the diabetic condition per se.
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PMID:Rimonabant, a cannabinoid CB1 receptor antagonist, attenuates mechanical allodynia and counteracts oxidative stress and nerve growth factor deficit in diabetic mice. 2039 4

Obesity is a world wide epidemic; it is becoming more usual to be overweight or obese than to be normal weight. Obesity increases the risk of an extensive range of diseases such as cardiovascular disease, diabetes mellitus type 2, hypertension, depression and some types of cancer. Adipose tissue is more than a storage organ for surplus energy - it is also a setting for complex metabolic processes and adipose tissue releases substances that interact with other parts of the body to influence several systems including food intake and energy metabolism. The endocannabinoid system (ECS) is one of the signalling systems that control feeding behaviour. The ECS is implicated in many functions, such as pain, memory, addiction, inflammation, and feeding, and could be considered a stress recovery system. It also seems to integrate nutrient intake, metabolism and storage maintaining homeostatic balance. The ECS is a recently discovered system, and research indicates hyperactivity in obesity. The aim of this thesis is to elaborate on the relationships of this widespread system and its elements in adipose tissue in obesity. Study I is a 4 weeks rat intervention study to investigate whether weight independent effect of Rimonabant treatment exists. We found that food intake-tolerance development could be circumvented by cyclic administration of Rimonabant and implications of weight independent effects of treatment. Study II is a cross-sectional study to establish the expression of cannabinoid receptor 1 from various adipose tissue depots of lean and obese persons. In this study we conclude, that the subcutaneous adipose tissue express more CBR1 than the visceral depot in lean, but comparable levels in obese. Study III is a 10 weeks human intervention study to asses the effects on the ECS of 10% weight loss. We found reduction in the ECS in obesity that normalised with weight loss. Our results clearly show the presence of all the components of the ECS in human adipose tissue, and suggest that the ECS is reduced in adipose tissue in obesity. Our results do not support the hypothesis of hyperactivity of the ECS in human obesity. Possible future treatment of obesity with CBR1 antagonist could involve cyclic treatment of specific peripheral compounds.
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PMID:Investigations of the endocannabinoid system in adipose tissue: effects of obesity/ weight loss and treatment options. 2146 69

The field of cannabinoid (CB) drug research is experiencing a challenge as the CB(1) antagonist Rimonabant, launched in 2006 as an anorectic/anti-obesity drug, was withdrawn from the European market due to the complications of suicide and depression as side effects. There is interest in developing CB(2) drugs without CB(1) psychotropic side effects for drug-abuse treatment and therapeutic medication. The CB(1) receptor was discovered predominantly in the brain, whereas the CB(2) is mainly expressed in peripheral cells and tissues, and is involved in immune signal transduction. Conversely, the CB(2) receptor was recently detected in the CNS, for example, in the microglial cells and the neurons. While the CB(2) neurons activity remains controversial, the CB(2) receptor is an attractive therapeutic target for neuropathic pain, immune system, cancer and osteoporosis without psychoactivity. This review addresses CB drug abuse and therapeutic potential with a focus on the most recent advances on new CB(2) ligands from the literature as well as patents.
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PMID:Latest advances in novel cannabinoid CB(2) ligands for drug abuse and their therapeutic potential. 2230 98

The cannabinoid receptor subtype 2 (CB2) is a promising therapeutic target for blood cancer, pain relief, osteoporosis, and immune system disease. The recent withdrawal of Rimonabant, which targets another closely related cannabinoid receptor (CB1), accentuates the importance of selectivity for the development of CB2 ligands in order to minimize their effects on the CB1 receptor. In our previous study, LiCABEDS (Ligand Classifier of Adaptively Boosting Ensemble Decision Stumps) was reported as a generic ligand classification algorithm for the prediction of categorical molecular properties. Here, we report extension of the application of LiCABEDS to the modeling of cannabinoid ligand selectivity with molecular fingerprints as descriptors. The performance of LiCABEDS was systematically compared with another popular classification algorithm, support vector machine (SVM), according to prediction precision and recall rate. In addition, the examination of LiCABEDS models revealed the difference in structure diversity of CB1 and CB2 selective ligands. The structure determination from data mining could be useful for the design of novel cannabinoid lead compounds. More importantly, the potential of LiCABEDS was demonstrated through successful identification of newly synthesized CB2 selective compounds.
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PMID:LiCABEDS II. Modeling of ligand selectivity for G-protein-coupled cannabinoid receptors. 2327 50

Over the past decade, pharmacological manipulation of cannabinoid 1 receptor (CB1R) has become an interesting approach for the management of food ingestion disorders, among other physiological functions. Searching for new substances with similar desirable effects, but fewer side-effects we have synthesized a SR141716A (a cannabinoid receptor inverse agonist also called Rimonabant) analog, 1-(2,4-Difluorophenyl)-4-methyl-N-(1-piperidinyl)-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, ENP11, that so far, as we have previously shown, has induced changes in glucose availability, i.e. hypoglycemia, in rats. In this study we tested the effects, if any, of ENP11 (0.5, 1.0, and 3.0mg/kg) in food ingestion, core temperature, pain perception and motor control in adult Wistar rats. Results showed that ENP11 reduced food ingestion during the first hour immediately after administration. Likewise, ENP11 (1.0mg/kg) blocked anandamide (AEA)-induced hyperphagia during the first 4h of the dark phase of the light-dark cycle, and it also blocked AEA-induced hypothermia. However, none of the ENP11 doses used affected pain perception or motor control. We believe that ENP11 is a potential useful CB1R antagonist that reduces food ingestion and regulates core temperature.
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PMID:ENP11, a potential CB1R antagonist, induces anorexia in rats. 2607 92


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