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Sample records for cannabinoid agonist win

  1. Central effects of the cannabinoid receptor agonist WIN55212-2 on respiratory and cardiovascular regulation in anaesthetised rats

    OpenAIRE

    Pfitzer, Torsten; Niederhoffer, Nathalie; Szabo, Bela

    2004-01-01

    The primary aim was to study the central respiratory effects of cannabinoids (CB). To this end, the cannabinoid receptor agonist WIN55212-2 was injected into the cisterna magna of urethane-anaesthetised rats and changes in respiratory parameters were observed. The secondary aim was to observe the centrally elicited cardiovascular actions of WIN55212-2. Involvement of opioid mechanisms in the central effects of WIN55212-2 was also studied.Intracisternal (i.c.) application of WIN55212-2 (1, 3, ...

  2. Involvement of PPAR receptors in the anticonvulsant effects of a cannabinoid agonist, WIN 55,212-2.

    Science.gov (United States)

    Payandemehr, Borna; Ebrahimi, Ali; Gholizadeh, Ramtin; Rahimian, Reza; Varastehmoradi, Bardia; Gooshe, Maziar; Aghaei, Hossein Nayeb; Mousavizadeh, Kazem; Dehpour, Ahmad Reza

    2015-03-01

    Cannabinoid and PPAR receptors show well established interactions in a set of physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study aimed to evaluate the roles of the PPAR-gamma, PPAR-alpha and CB1 receptors on the anticonvulsant effects of WIN 55,212-2 (WIN, a non selective cannabinoid agonist). The clonic seizure thresholds after intravenous administration of pentylenetetrazole (PTZ) were assessed in mice weighing 23-30 g. WIN increased the seizure threshold dose dependently. Pretreatment with pioglitazone, as a PPARγ agonist, potentiated the anticonvulsant effects of WIN, while PPARγ antagonist inhibited these anticonvulsant effects partially. On the other hand PPARα antagonist reduced the anticonvulsant effects of WIN significantly. Finally the combination of CB1 antagonist and PPARα antagonist could completely block the anticonvulsant properties of WIN. Taken together, these results show for the first time that a functional interaction exists between cannabinoid and PPAR receptors in the modulation of seizure susceptibility. PMID:25448777

  3. The Study of Destructive Effects of Exposure to WIN 55212-2, an Agonist of Cannabinoid Receptor, during Pregnancy on CNS Function of Rats’ Offspring

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    Mohammad Shabani

    2011-08-01

    Full Text Available Introduction: Cannabinoid consumption including hashish and WIN55212-2 during pregnancy has destructive affect on the development of fetus and the performance of CNS. Method: WIN treated group received daily 0.5 or 1mg/kg WIN suspended in 1% tween 80 saline (s.c. at a volume of 1 ml/kg from days 5 to 20 of pregnancy. Third, fifth and seventh weeks after birth, the effects of maternal WIN consumption on infants body weight, mortality, histological changes, motor performance and memory function were assessed. Results: Prenatal WIN consumption associated with atrophy of cerebellum cortex in granular and Purkinje cells layers. WIN treatment of pregnant rats produced a significant decrease in the rearing frequency of the offspring, but significantly increased the grooming frequency at 22, 36 and 50 days of age. During the acquisition trials, approach latencies were not significantly different between all groups of rats (50 days old.When the trial was repeated 24 hours and seven days later (retention trial, the avoidance latencies of the WIN-exposed group were significantly shorter than those of control and sham animals. The mortality percent was increased significantly and litter size was decreased significantly in WIN (1mg/kg treated rats compared to the control, sham and WIN (0/5 mg/kg treatment groups. Conclusion: These findings suggest that prenatal exposure to WIN, cannabinoid agonist, induces possibly a long-term alteration on histological, motor performance and learning and memory parameters.

  4. Differential effects of repeated low dose treatment with the cannabinoid agonist WIN 55,212-2 in experimental models of bone cancer pain and neuropathic pain

    DEFF Research Database (Denmark)

    Hald, Andreas; Ding, Ming; Egerod, Kristoffer Lihme;

    2008-01-01

    Pain due to bone malignancies is one of the most difficult types of cancer pain to fully control and may further decrease the patients' quality of life. Animal models of chronic pain conditions resulting from peripheral inflammatory reactions or nerve injuries are responsive to treatment with....... Furthermore, this treatment strategy was not found to induce measurable CNS related side effects or tolerance. Cancer cell viability assays and bone volume fraction assessed by micro computed tomography (microCT) demonstrated that these effects were not due to changes in cancer progression. The difference in...... cannabinoid agonists. However, the use of cannabinoid agonists in humans may be hampered by CNS related side effects and development of tolerance. In the present study, we investigated the effect of repeated low dose administration of the synthetic cannabinoid agonist WIN 55,212-2 on bone cancer pain and...

  5. Effect of the CB1 cannabinoid agonist WIN 55212-2 on the acquisition and reinstatement of MDMA-induced conditioned place preference in mice

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    Miñarro José

    2010-03-01

    Full Text Available Abstract Background Numerous reports indicate that MDMA users consume other psychoactive drugs, among which cannabis is one of the most common. The aim of the present study was to evaluate, using the conditioned place preference, the effect of the cannabinoid agonist WIN 55,212-2 on the rewarding effects of MDMA in mice. Methods In the first experiment adolescent mice were initially conditioned with 1.25, 2.5 or 5 mg/kg of MDMA or 0.1 or 0.5 mg/kg of WIN and subsequently with both drugs. Reinstatement of the extinguished preference by priming doses was performed in the groups that showed CPP. In the second experiment, animals were conditioned with 2.5 or 5 mg/kg of MDMA and, after extinction, reinstatement of the preference was induced by 0.5 or 0.1 mg/kg of WIN. Results A low dose of WIN 55212-2 (0.1 mg/kg increased the rewarding effects of low doses of MDMA (1.25 mg/kg, although a decrease in the preference induced by MDMA (5 and 2.5 mg/kg was observed when the dose of WIN 55212-2 was raised (0.5 mg/kg. The CB1 antagonist SR 141716 also increased the rewarding effects of the lowest MDMA dose and did not block the effects of WIN. Animals treated with the highest WIN dose plus a non-neurotoxic dose of MDMA exhibited decreases of striatal DA and serotonin in the cortex. On the other hand, WIN 55212-2-induced CPP was reinstated by priming injections of MDMA, although WIN did not reinstate the MDMA-induced CPP. Conclusions These results confirm that the cannabinoid system plays a role in the rewarding effects of MDMA and highlights the risks that sporadic drug use can pose in terms of relapse to dependence. Finally, the potential neuroprotective action of cannabinoids is not supported by our data; on the contrary, they are evidence of the potential neurotoxic effect of said drugs when administered with MDMA.

  6. The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins

    OpenAIRE

    Lauckner, Jane E.; Hille, Bertil; Mackie, Ken

    2005-01-01

    Central nervous system responses to cannabis are primarily mediated by CB1 receptors, which couple preferentially to Gi/o G proteins. Here, we used calcium photometry to monitor the effect of CB1 activation on intracellular calcium concentration. Perfusion with 5 μM CB1 aminoalkylindole agonist, WIN55,212-2 (WIN), increased intracellular calcium by several hundred nanomolar in human embryonic kidney 293 cells stably expressing CB1 and in cultured hippocampal neurons. The increase was blocked ...

  7. Effects of WIN 55,212-2 (a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6 Hz psychomotor seizure model

    OpenAIRE

    Florek-Luszczki, Magdalena; Wlaz, Aleksandra; Kondrat-Wrobel, Maria W.; Tutka, Piotr; Jarogniew J Luszczki

    2014-01-01

    The aim of this study was to characterize the influence of WIN 55,212-2 (WIN—a non-selective cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant effects of various classical antiepileptic drugs (clobazam, clonazepam, phenobarbital and valproate) in the mouse 6 Hz-induced psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes. Drug-related adverse effects were...

  8. Differential Effects of Cannabinoid Receptor Agonist on Social Discrimination and Contextual Fear in Amygdala and Hippocampus

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    Segev, Amir; Akirav, Irit

    2011-01-01

    We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 [mu]g/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval.…

  9. Chronic co-administration of the cannabinoid receptor agonist WIN55,212-2 during puberty or adulthood reverses 3,4 methylenedioxymetamphetamine (MDMA)-induced deficits in recognition memory but not in effort-based decision making.

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    Schulz, Sybille; Becker, Thorsten; Nagel, Ulrich; von Ameln-Mayerhofer, Andreas; Koch, Michael

    2013-05-01

    Cannabis and 3,4 methylenedioxymetamphetamine (MDMA, "ecstasy") are the most frequently combined illegal drugs among young adults in western societies. This study examined the effects of chronic co-administration of the cannabinoid receptor agonist WIN55,212-2 (WIN) and MDMA on working memory and effort-based decision making in rats. Treatment consisted of MDMA (7.5 mg/kg), WIN (1.2 mg/kg), a combination of these substances (MDMA+WIN) or vehicle over a period of 25 days during puberty (PD40-65) or adulthood (PD80-105). Ten days after the last treatment, WIN reversed MDMA-induced working memory deficits in the object recognition test in animals treated during adulthood or puberty, but had no influence on impairment of adult rats in the effort-based T-maze task. No differences were observed between groups of pubertally treated rats in the decision making task. During a subsequent acute drug challenge MDMA and MDMA+WIN decreased high reward choices in both age groups, indicating MDMA-induced cost-aversive choice. Differential long-term interactions on the neuronal level in the hippocampus and MDMA-induced disturbances in cortico-limbic connections are suggested. PMID:23541493

  10. A synthetic cannabinoid agonist promotes oligodendrogliogenesis during viral encephalitis in rats

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    Solbrig, Marylou V.; Fan, Yijun; Hermanowicz, Neal; Morgese, Maria Grazia; Giuffrida, Andrea

    2010-01-01

    Chronic CNS infection by several families of viruses can produce deficits in prefrontal cortex (PFC) and striatal function. Cannabinoid drugs have been long known for their anti-inflammatory properties and their ability to modulate adult neuro and gliogenesis. Therefore, we explored the effects of systemic administration of the cannabinoid agonist WIN55,212-2(WIN) on prefrontal cortex(PFC) and striatal cytogenesis in a viral model of CNS injury and inflammation based on Borna Disease (BD) vir...

  11. The cannabinoid agonist HU-210: pseudo-irreversible discriminative stimulus effects in rhesus monkeys

    OpenAIRE

    Hruba, Lenka; McMahon, Lance R.

    2014-01-01

    Synthetic cannabinoid abuse and case reports of adverse effects have raised concerns about the pharmacologic mechanisms underlying in vivo effects. Here, a synthetic cannabinoid identified in abused products (HU-210) was compared to the effects of Δ9-THC and two other synthetic cannabinoid agonists used extensively in pre-clinical studies (CP 55,940 and WIN 55,212-2). One group of monkeys discriminated Δ9-THC (0.1 mg/kg i.v.); a separate group received chronic Δ9-THC (1 mg/kg/12 h s.c.) and d...

  12. Therapeutic Potentials and uses of Cannabinoid Agonists in Health and Disease Conditions

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    A.O. Ibegbu

    2012-04-01

    Full Text Available Cannabis and its derivatives have great therapeutic potential and have been used for centuries for medicinal purposes. The side effects of cannabinoids include euphoric mood changes, acute psychotic episodes, initiation and exacerbation of schizophrenic psychosis in predisposed persons, impaired cognitive and psychomotor performance, tachycardia and hypotension. The production of complex behavioural effects by cannabinoids are mediated by cannabinoid receptors (CB1 and CB2 and by interactions with other neurochemical systems. It has been shown that the therapeutic and physiological effects of cannabinoids are dependent upon whether the administration is acute or chronic and on the route of administration. The physiological effects of cannabis and its derivatives include: reduction in psychomotor coordination and performance, alterations in thermoregulation, endocrine and reproductive functions and gut motility. There is also evidence of agonist selectivity for CB1 receptors coupled to different subtypes of Gi proteins or to Gi versus Go proteins. Cannabinoid-activated receptors distinct from CB1 or CB2 exist in the central nervous system. Cannabinoids are known to inhibit GABA-mediated inhibitory postsynaptic currents in the hippocampus via a presynaptic action at CB1 receptors located on GABAergic terminals. CB1 receptors have also been implicated in the inhibition of glutamatergic excitatory postsynaptic currents. The synthetic cannabinoid, Win 55,212-2, a mixed CB1-CB2 cannabinoid receptor agonist, was found to attenuate hyperalgesia in a rat model of neuropathic pain and suppress opioid-induced emesis in ferrets.

  13. Effects of Cannabinoid Exposure during Adolescence on the Conditioned Rewarding Effects of WIN 55212-2 and Cocaine in Mice: Influence of the Novelty-Seeking Trait

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    Rodríguez-Arias, M.; Roger-Sánchez, C.; Vilanova, I.; Revert, N.; Manzanedo, C.; Miñarro, J.; M. A. Aguilar

    2016-01-01

    Adolescent exposure to cannabinoids enhances the behavioural effects of cocaine, and high novelty-seeking trait predicts greater sensitivity to the conditioned place preference (CPP) induced by this drug. Our aim was to evaluate the influence of novelty-seeking on the effects of adolescent cannabinoid exposure. Adolescent male mice were classified as high or low novelty seekers (HNS and LNS) in the hole-board test. First, we evaluated the CPP induced by the cannabinoid agonist WIN 55212-2 (0....

  14. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    Science.gov (United States)

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  15. Effects of Cannabinoid Exposure during Adolescence on the Conditioned Rewarding Effects of WIN 55212-2 and Cocaine in Mice: Influence of the Novelty-Seeking Trait.

    Science.gov (United States)

    Rodríguez-Arias, M; Roger-Sánchez, C; Vilanova, I; Revert, N; Manzanedo, C; Miñarro, J; Aguilar, M A

    2016-01-01

    Adolescent exposure to cannabinoids enhances the behavioural effects of cocaine, and high novelty-seeking trait predicts greater sensitivity to the conditioned place preference (CPP) induced by this drug. Our aim was to evaluate the influence of novelty-seeking on the effects of adolescent cannabinoid exposure. Adolescent male mice were classified as high or low novelty seekers (HNS and LNS) in the hole-board test. First, we evaluated the CPP induced by the cannabinoid agonist WIN 55212-2 (0.05 and 0.075 mg/kg, i.p.) in HNS and LNS mice. Then, HNS and LNS mice were pretreated i.p. with vehicle, WIN 55212-2 (0.1 mg/kg), or cannabinoid antagonist rimonabant (1 mg/kg) and were subsequently conditioned with WIN 55212-2 (0.05 mg/kg, i.p.) or cocaine (1 or 6 mg/kg, i.p.). Only HNS mice conditioned with the 0.075 mg/kg dose acquired CPP with WIN 55212-2. Adolescent exposure to this cannabinoid agonist increased the rewarding effects of 1 mg/kg of cocaine in both HNS and LNS mice, and in HNS mice it also increased the reinstating effect of a low dose of cocaine. Our results endorse a role for individual differences such as a higher propensity for sensation-seeking in the development of addiction. PMID:26881125

  16. Effects of Cannabinoid Exposure during Adolescence on the Conditioned Rewarding Effects of WIN 55212-2 and Cocaine in Mice: Influence of the Novelty-Seeking Trait

    Directory of Open Access Journals (Sweden)

    M. Rodríguez-Arias

    2016-01-01

    Full Text Available Adolescent exposure to cannabinoids enhances the behavioural effects of cocaine, and high novelty-seeking trait predicts greater sensitivity to the conditioned place preference (CPP induced by this drug. Our aim was to evaluate the influence of novelty-seeking on the effects of adolescent cannabinoid exposure. Adolescent male mice were classified as high or low novelty seekers (HNS and LNS in the hole-board test. First, we evaluated the CPP induced by the cannabinoid agonist WIN 55212-2 (0.05 and 0.075 mg/kg, i.p. in HNS and LNS mice. Then, HNS and LNS mice were pretreated i.p. with vehicle, WIN 55212-2 (0.1 mg/kg, or cannabinoid antagonist rimonabant (1 mg/kg and were subsequently conditioned with WIN 55212-2 (0.05 mg/kg, i.p. or cocaine (1 or 6 mg/kg, i.p.. Only HNS mice conditioned with the 0.075 mg/kg dose acquired CPP with WIN 55212-2. Adolescent exposure to this cannabinoid agonist increased the rewarding effects of 1 mg/kg of cocaine in both HNS and LNS mice, and in HNS mice it also increased the reinstating effect of a low dose of cocaine. Our results endorse a role for individual differences such as a higher propensity for sensation-seeking in the development of addiction.

  17. Novel endogenous peptide agonists of cannabinoid receptors

    OpenAIRE

    Gomes, Ivone; Grushko, Julia S.; Golebiewska, Urszula; Hoogendoorn, Sascha; Gupta, Achla; Heimann, Andrea S.; Ferro, Emer S.; Scarlata, Suzanne; Fricker, Lloyd D.; Devi, Lakshmi A.

    2009-01-01

    Hemopressin (Hp), a 9-residue α-hemoglobin-derived peptide, was previously reported to function as a CB1 cannabinoid receptor antagonist (1). In this study, we report that mass spectrometry (MS) data from peptidomics analyses of mouse brain extracts identified N-terminally extended forms of Hp containing either three (RVD-Hpα) or two (VD-Hpα) additional amino acids, as well as a β-hemoglobin-derived peptide with sequence similarity to that of hemopressin (VD-Hpβ). Characterization of the α-he...

  18. Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain.

    Science.gov (United States)

    Gutierrez, Tannia; Crystal, Jonathon D; Zvonok, Alexander M; Makriyannis, Alexandros; Hohmann, Andrea G

    2011-09-01

    Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB(2) agonist to attenuate a neuropathic pain state. Self-medication of the CB(2) agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal thresholds in sham-operated or naive animals. The percentage of active lever responding was similar in naive groups self-administering vehicle or (R,S)-AM1241. The CB(2) antagonist SR144528 blocked both antiallodynic effects of (R,S)-AM1241 self-medication and the percentage of active lever responding in neuropathic (but not naive) rats. Neuropathic and sham groups exhibited similar percentages of active lever responding for (R,S)-AM1241 on a fixed ratio 1 (FR1) schedule. However, neuropathic animals worked harder than shams to obtain (R,S)-AM1241 when the schedule of reinforcement was increased (to FR6). (R,S)-AM1241 self-medication on FR1, FR3, or FR6 schedules attenuated nerve injury-induced mechanical allodynia. (R,S)-AM1241 (900μg intravenously) failed to produce motor ataxia observed after administration of the mixed CB(1)/CB(2) agonist WIN55,212-2 (0.5mg/kg intravenously). Our results suggest that cannabinoid CB(2) agonists may be exploited to treat neuropathic pain with limited drug abuse liability and central nervous system side effects. These studies validate the use of drug self-administration methods for identifying nonpsychotropic analgesics possessing limited abuse potential. These methods offer potential to elucidate novel analgesics that suppress spontaneous neuropathic pain that is not measured by traditional assessments of evoked pain. PMID:21550725

  19. Involvement of TRPV1 channels in the activity of the cannabinoid WIN 55,212-2 in an acute rat model of temporal lobe epilepsy.

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    Carletti, Fabio; Gambino, Giuditta; Rizzo, Valerio; Ferraro, Giuseppe; Sardo, Pierangelo

    2016-05-01

    The exogenous cannabinoid agonist WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone (WIN), has revealed to play a role on modulating the hyperexcitability phenomena in the hippocampus. Cannabinoid-mediated mechanisms of neuroprotection have recently been found to imply the modulation of transient receptor potential vanilloid 1 (TRPV1), a cationic channel subfamily that regulate synaptic excitation. In our study, we assessed the influence of pharmacological manipulation of TRPV1 function, alone and on WIN antiepileptic activity, in the Maximal Dentate Activation (MDA) acute model of temporal lobe epilepsy. Our results showed that the TRPV1 agonist, capsaicin, increased epileptic outcomes; whilst antagonizing TRPV1 with capsazepine exerts a protective role on paroxysmal discharge. When capsaicin is co-administered with WIN effective dose of 10mg/kg is able to reduce its antiepileptic strength, especially on the triggering of MDA response. Accordingly, capsazepine at the protective dose of 2mg/kg managed to potentiate WIN antiepileptic effects, when co-treated. Moreover, WIN subeffective dose of 5mg/kg was turned into effective when capsazepine comes into play. This evidence suggests that systemic administration of TRPV1-active drugs influences electrically induced epilepsy, with a noticeable protective activity for capsazepine. Furthermore, results from the pharmacological interaction with WIN support an interplay between cannabinoid and TRPV1 signaling that could represent a promising approach for a future pharmacological strategy to challenge hyperexcitability-based diseases. PMID:26970948

  20. Effects of cannabinoid receptor agonists on neuronally-evoked contractions of urinary bladder tissues isolated from rat, mouse, pig, dog, monkey and human

    OpenAIRE

    Martin, R S; Luong, L A; Welsh, N. J.; Eglen, R. M.; Martin, G R; MacLennan, S J

    2000-01-01

    This study investigated the cannabinoid receptor, known to inhibit neuronally-evoked contractions of the mouse isolated urinary bladder, in bladder sections isolated from mouse, rat, dog, pig non-human primate or human.The CB1-like pharmacology of the cannabinoid receptor in mouse isolated bladder observed previously was confirmed in this study by the rank order of agonist potencies: CP 55940⩾WIN 55212-2>HU 210>JWH 015>anandamide, the high affinity of the CB1 selective antagonist, SR 141716A ...

  1. Cannabinoid agonists rearrange synaptic vesicles at excitatory synapses and depress motoneuron activity in vivo.

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    García-Morales, Victoria; Montero, Fernando; Moreno-López, Bernardo

    2015-05-01

    Impairment of motor skills is one of the most common acute adverse effects of cannabis. Related studies have focused mainly on psychomotor alterations, and little is known about the direct impact of cannabinoids (CBs) on motoneuron physiology. As key modulators of synaptic function, CBs regulate multiple neuronal functions and behaviors. Presynaptic CB1 mediates synaptic strength depression by inhibiting neurotransmitter release, via a poorly understood mechanism. The present study examined the effect of CB agonists on excitatory synaptic inputs incoming to hypoglossal motoneurons (HMNs) in vitro and in vivo. The endocannabinoid anandamide (AEA) and the synthetic CB agonist WIN 55,212-2 rapidly and reversibly induced short-term depression (STD) of glutamatergic synapses on motoneurons by a presynaptic mechanism. Presynaptic effects were fully reversed by the CB1-selective antagonist AM281. Electrophysiological and electron microscopy analysis showed that WIN 55,212-2 reduced the number of synaptic vesicles (SVs) docked to active zones in excitatory boutons. Given that AM281 fully abolished depolarization-induced depression of excitation, motoneurons can be feasible sources of CBs, which in turn act as retrograde messengers regulating synaptic function. Finally, microiontophoretic application of the CB agonist O-2545 reversibly depressed, presumably via CB1, glutamatergic inspiratory-related activity of HMNs in vivo. Therefore, evidence support that CBs, via presynaptic CB1, induce excitatory STD by reducing the readily releasable pool of SVs at excitatory synapses, then attenuating motoneuron activity. These outcomes contribute a possible mechanistic basis for cannabis-associated motor performance disturbances such as ataxia, dysarthria and dyscoordination. PMID:25595101

  2. CHROMENOPYRAZOLES: NON-PSYCHOACTIVE AND SELECTIVE CB1 CANNABINOID AGONISTS WITH PERIPHERAL ANTINOCICEPTIVE PROPERTIES

    OpenAIRE

    Cumella, Jose; Hernández-Folgado, Laura; Girón, Rocio; Sánchez, Eva; Morales, Paula; Hurst, Dow P.; Gómez-Cañas, Maria; Gómez-Ruiz, Maria; Pinto, Diana C. G. A.; Goya, Pilar; Reggio, Patricia H; Martin, María Isabel; Fernández-Ruiz, Javier; Artur M. S. Silva; Jagerovic, Nadine

    2012-01-01

    The unwanted psychoactive effects of cannabinoid receptor agonists have limited their development as medicines. These CB1 mediated side effects are due to the fact that CB1 receptors are largely expressed in the Central Nervous System (CNS). Since it is known that CB1 receptors are also located peripherally, there is a growing interest in targeting cannabinoid receptors located outside the brain. A library of chromenopyrazoles designed in analogy to the classical cannabinoid cannabinol were s...

  3. Inhibition of the production of endothelium-derived hyperpolarizing factor by cannabinoid receptor agonists

    OpenAIRE

    Fleming, I.; Schermer, B; Popp, R; Busse, R.

    1999-01-01

    The endogenous cannabinoid, anandamide, has been reported to induce an 'endothelium-derived hyperpolarizing factor (EDHF)-like' relaxation in vitro. We therefore investigated the effects of cannabinoid CB1 receptor agonists; HU 210, Δ9-tetrahydrocannabinol (Δ9-THC) and anandamide, and a CB1 antagonist/inverse agonist, SR 141716A, on nitric oxide (NO) and EDHF-mediated relaxation in precontracted rings of porcine coronary, rabbit carotid and mesenteric arteries.In rings of mesenteric artery HU...

  4. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

    Science.gov (United States)

    Pertwee, Roger G

    2012-12-01

    Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'. PMID:23108552

  5. CANNABINOID AND OPIOID MODULATION OF SOCIAL PLAY BEHAVIOR IN ADOLESCENT RATS: DIFFERENTIAL BEHAVIORAL MECHANISMS

    OpenAIRE

    Trezza, Viviana; Vanderschuren, Louk J. M. J.

    2008-01-01

    We have recently shown that the pharmacological mechanisms through which cannabinoid and opioid drugs influence social play behavior in adolescent rats can be partially dissociated. Here, we characterize the effects of the direct cannabinoid agonist WIN55,212-2, the indirect cannabinoid agonist URB597 and the opioid agonist morphine on social play at the behavioral level. By treating either one or both partners of the test dyad, we show that these drugs differentially affect play solicitation...

  6. Enhanced self-administration of the CB1 receptor agonist WIN55,212-2 in olfactory bulbectomized rats: evaluation of possible serotonergic and dopaminergic underlying mechanisms

    Directory of Open Access Journals (Sweden)

    Petra eAmchova

    2014-03-01

    Full Text Available Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed higher voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 µg/kg/infusion. To this aim, olfactory-bulbectomized (OBX and sham-operated (SHAM Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous (FR-1 schedule of reinforcement in 2h daily sessions. Data showed that both OBX and SHAM rats developed stable WIN intake; yet, responses in OBX were constantly higher than in SHAM rats soon after the first week of training. In addition, OBX rats took significantly longer to extinguish the drug-seeking behaviour after vehicle substitution. Acute pre-treatment with serotonin 5HT1B receptor agonist, CGS-12066B (2.5-10 mg/kg, did not significantly modify WIN intake in OBX and SHAM Lister Hooded rats. Furthermore, acute pre-treatment with CGS-12066B (10 and 15 mg/kg did not alter responses in parallel groups of OBX and SHAM Sprague Dawley rats self-administering methamphetamine under higher (FR-2 reinforcement schedule with nose-poking as operandum. Finally, dopamine levels in the nucleus accumbens of OBX rats did not increase in response to a WIN challenge, as in SHAM rats, indicating a dopaminergic dysfunction in bulbectomized rats. Altogether, our findings suggest that a depressive state may alter cannabinoid CB1 receptor agonist-induced brain reward function and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats.

  7. Intrathecal cannabinoid-1 receptor agonist prevents referred hyperalgesia in acute acrolein-induced cystitis in rats

    OpenAIRE

    Jones, Marsha Ritter; Wang, Zun-Yi; Bjorling, Dale E

    2015-01-01

    We investigated the capacity of intrathecal arachidonyl-2’-chloroethylamide (ACEA), a cannabinoid-1 receptor (CB1R) agonist, to inhibit referred hyperalgesia and increased bladder contractility resulting from acute acrolein-induced cystitis in rats. 24 female rats were divided into 4 groups: 1) intrathecal vehicle/intravesical saline; 2) intrathecal vehicle/intravesical acrolein; 3) intrathecal ACEA/intravesical saline; and 4) intrathecal ACEA/intravesical acrolein. Bladder catheters were pla...

  8. Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain

    OpenAIRE

    Gutierrez, Tannia; Crystal, Jonathon D.; Zvonok, Alexander M.; Makriyannis, Alexandros; Hohmann, Andrea G.

    2011-01-01

    Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB2 agonist to attenuate a neuropathic pain state. Self-medication of the CB2 agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal threshol...

  9. Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors

    OpenAIRE

    Leggett, James D; Aspley, S; Beckett, S R G; D'Antona, A M; Kendall, D A

    2004-01-01

    The ability of the endogenous fatty acid amide, cis-oleamide (ODA), to bind to and activate cannabinoid CB1 and CB2 receptors was investigated.ODA competitively inhibited binding of the nonselective cannabinoid agonist [3H]CP55,940 and the selective CB1 antagonist [3H]SR141716A to rat whole-brain membranes with Ki values of 1.14 μM (0.52–2.53 μM, Hill slope=0.80, n=6) and 2.63 μM (0.62–11.20 μM, Hill slope=0.92, n=4), respectively. AEA inhibited [3H]CP55,940 binding in rat whole-brain membran...

  10. Intracerebroventricular injections of dronabinol, a cannabinoid receptor agonist, does not attenuate serotonin-induced apnea in Sprague-Dawley rats

    OpenAIRE

    Calik, Michael W.; Carley, David W

    2016-01-01

    Background Evidence suggests that vagal nerve activity may play a role in sleep apnea induction. In anesthetized rats, dronabinol, a cannabinoid (CB) receptor agonist, injected into the nodose ganglia attenuates reflex apnea and increases genioglossus activity, and reflex apnea attenuation is blocked by systemic pre-treatment with cannabinoid type 1 and/or type 2 receptor antagonists. However, it is unclear whether dronabinol has similar effects in the central nervous system; CB receptors are...

  11. Similar anxiolytic effects of agonists targeting serotonin 5-HT1A or cannabinoid CB receptors on zebrafish behavior in novel environments.

    Science.gov (United States)

    Connors, Kristin A; Valenti, Theodore W; Lawless, Kelly; Sackerman, James; Onaivi, Emmanuel S; Brooks, Bryan W; Gould, Georgianna G

    2014-06-01

    The discovery that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are present and bioaccumulate in aquatic ecosystems have spurred studies of fish serotonin transporters (SERTs) and changes in SSRI-sensitive behaviors as adverse outcomes relevant for risk assessment. Many SSRIs also act at serotonin 5-HT1A receptors. Since capitalizing on this action may improve treatments of clinical depression and other psychiatric disorders, novel multimodal drugs that agonize 5-HT1A and block SERT were introduced. In mammals both 5-HT1A and CB agonists, such as buspirone and WIN55,212-2, reduce anxious behaviors. Immunological and behavioral evidence suggests that 5-HT1A-like receptors may function similarly in zebrafish (Danio rerio), yet their pharmacological properties are not well characterized. Herein we compared the density of [(3)H] 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) binding to 5-HT1A-like sites in the zebrafish brain, to that of similarly Gαi/o-coupled cannabinoid receptors. [(3)H] 8-OH-DPAT specific binding was 176±8, 275±32, and 230±36fmol/mg protein in the hypothalamus, optic tectum, and telencephalon. [(3)H] WIN55,212-2 binding density was higher in those same brain regions at 6±0.3, 5.5±0.4 and 7.3±0.3pm/mg protein. The aquatic light-dark plus maze was used to examine behavioral effects of 5-HT1A and CB receptor agonists on zebrafish novelty-based anxiety. With acute exposure to the 5-HT1A partial-agonist buspirone (50mg/L), or dietary exposure to WIN55,212-2 (7μg/week) zebrafish spent more time in and/or entered white arms more often than controls (pecological risks of azapirones and multimodal antidepressants in the future. PMID:24411165

  12. Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity

    NARCIS (Netherlands)

    Campolongo, P.; Morena, M.; Scaccianoce, S.; Trezza, V.; Chiarotti, F.; Schelling, G.; Cuomo, V.; Roozendaal, B.

    2013-01-01

    Although it is well established that cannabinoid drugs can influence cognitive performance, the findings-describing both enhancing and impairing effects-have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.

  13. Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

    Institute of Scientific and Technical Information of China (English)

    Wei CHEN; Cheng XU; Hong-ying LIU; Long LONG; Wei ZHANG; Zhi-bing ZHENG; Yun-de XIE; Li-li WANG; Song LI

    2011-01-01

    To characterize the biological profiles of M J08,a novel selective CB1 receptor antagonist.Methods:Radioligand binding assays were performed using rat brain and spleen membrane preparations.CB1 and CB2 receptor redistribution and intracellular Ca2+ ([Ca2+]1) assays were performed with IN CELL Analyzer.Inverse agonism was studied using intracellular cAMP assays,and in guinea-pig ileum and mouse vas deferens smooth muscle preparations.In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice.Results:In radioligand binding assay,M J08 selectively antagonized CB1 receptor (IC50=99.9 nmol/L).In EGFP-CB1_U20S cells,its IC50 value against CB1 receptor activation was 30.23 nmol/L (SR141716A:32.16 nmol/L).WIN 55,212-2 (1 μmol/L) increased [Ca2+]1 in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB1 cells.M J08 (10 nmol/L-1O μmol/L)blocked both the WIN 55,212-2-induced effects.Furthermore,M J08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA2=10.29±1.05).M J08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle.M J08 significantly increased the cAMP level in CHO-hCB1 cells with an EC50 value of 78.6 nmol/L,which was lower than the EC50 value for SR141716A (159.2 nmol/L).Besides the more potent pharmacological effects of cannabinoid CB1 receptor antagonism in DIO mice,such as reducing food intake,decreasing body weight,and ameliorating dyslipidemia,M J08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo.Conclusion:M J08 is a novel,potent and selective CB1 receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB1 receptors.

  14. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Moran, Jeffery H. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States); Prather, Paul L., E-mail: pratherpaull@uams.edu [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)

    2013-06-01

    K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB{sub 1}Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB{sub 2}Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB{sub 2}Rs (hCB{sub 2}Rs). The affinity of cannabinoids for hCB{sub 2}Rs was determined by competition binding studies employing CHO-hCB{sub 2} membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB{sub 2} cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB{sub 2}Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB{sub 2}Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB{sub 2}R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB{sub 2}Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB{sub 2}Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB{sub 1} and CB{sub 2}Rs. - Highlights: • JWH-018

  15. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

    International Nuclear Information System (INIS)

    K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB1Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB2Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB2Rs (hCB2Rs). The affinity of cannabinoids for hCB2Rs was determined by competition binding studies employing CHO-hCB2 membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB2 cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB2Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB2Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ9-tetrahydrocannabinol (Δ9-THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB2R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB2Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB2Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB1 and CB2Rs. - Highlights: • JWH-018 and JWH-073 are synthetic cannabinoids present in abused K2 products. • JWH-018, JWH-073 and

  16. Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain.

    Science.gov (United States)

    Seltzman, Herbert H; Shiner, Craig; Hirt, Erin E; Gilliam, Anne F; Thomas, Brian F; Maitra, Rangan; Snyder, Rod; Black, Sherry L; Patel, Purvi R; Mulpuri, Yatendra; Spigelman, Igor

    2016-08-25

    Alleviation of neuropathic pain by cannabinoids is limited by their central nervous system (CNS) side effects. Indole and indene compounds were engineered for high hCB1R affinity, peripheral selectivity, metabolic stability, and in vivo efficacy. An epithelial cell line assay identified candidates with <1% blood-brain barrier penetration for testing in a rat neuropathy induced by unilateral sciatic nerve entrapment (SNE). The SNE-induced mechanical allodynia was reversibly suppressed, partially or completely, after intraperitoneal or oral administration of several indenes. At doses that relieve neuropathy symptoms, the indenes completely lacked, while the brain-permeant CB1R agonist HU-210 (1) exhibited strong CNS side effects, in catalepsy, hypothermia, and motor incoordination assays. Pharmacokinetic findings of ∼0.001 cerebrospinal fluid:plasma ratio further supported limited CNS penetration. Pretreatment with selective CB1R or CB2R blockers suggested mainly CB1R contribution to an indene's antiallodynic effects. Therefore, this class of CB1R agonists holds promise as a viable treatment for neuropathic pain. PMID:27482723

  17. Cannabinoid CB1 receptor inverse agonists and neutral antagonists: Effects on food intake, food-reinforced behavior and food aversions

    OpenAIRE

    Salamone, John D.; McLaughlin, Peter J; Sink, Kelly; Makriyannis, Alexandros; Parker, Linda A

    2007-01-01

    Drugs that interfere with cannabinoid CB1 receptor transmission suppress a number of food-related behaviors, and these compounds are currently being assessed for their potential utility as appetite suppressants. In addition to rimonabant (SR141716A), several other compounds have been evaluated, including AM251 and AM1387. Biochemical studies indicate that most of the drugs assessed thus far have been CB1 inverse agonists, and these drugs all act to suppress food intake and disrupt food-reinfo...

  18. Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent

    Science.gov (United States)

    Hanlon, Katherine E; Lozano-Ondoua, Alysia N; Umaretiya, Puja J; Symons-Liguori, Ashley M; Chandramouli, Anupama; Moy, Jamie K; Kwass, William K; Mantyh, Patrick W; Nelson, Mark A; Vanderah, Todd W

    2016-01-01

    Introduction Cannabinoid compounds, both nonspecific as well as agonists selective for either cannabinoid receptor 1 (CB1) or cannabinoid receptor 2 (CB2), have been shown to modulate the tumor microenvironment by inducing apoptosis in tumor cells in several model systems. The mechanism of this modulation remains only partially delineated, and activity induced via the CB1 and CB2 receptors may be distinct despite significant sequence homology and structural similarity of ligands. Methods The CB2-selective agonist JWH-015 was used to investigate mechanisms downstream of CB2 activation in mouse and human breast cancer cell lines in vitro and in a murine mammary tumor model. Results JWH-015 treatment significantly reduced primary tumor burden and metastasis of luciferase-tagged murine mammary carcinoma 4T1 cells in immunocompetent mice in vivo. Furthermore, JWH-015 reduced the viability of murine 4T1 and human MCF7 mammary carcinoma cells in vitro by inducing apoptosis. JWH-015-mediated reduction of breast cancer cell viability was not dependent on Gαi signaling in vitro or modified by classical pharmacological blockade of CB1, GPR55, TRPV1, or TRPA1 receptors. JWH-015 effects were calcium dependent and induced changes in MAPK/ERK signaling. Conclusion The results of this work characterize the actions of a CB2-selective agonist on breast cancer cells in a syngeneic murine model representing how a clinical presentation of cancer progression and metastasis may be significantly modulated by a G-protein-coupled receptor. PMID:27186076

  19. Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.

    Science.gov (United States)

    Schindler, Charles W; Redhi, Godfrey H; Vemuri, Kiran; Makriyannis, Alexandros; Le Foll, Bernard; Bergman, Jack; Goldberg, Steven R; Justinova, Zuzana

    2016-08-01

    Nicotine, the main psychoactive component of tobacco, and (-)-Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence. PMID:26888056

  20. The discovery of taranabant, a selective cannabinoid-1 receptor inverse agonist for the treatment of obesity.

    Science.gov (United States)

    Hagmann, William K

    2008-07-01

    The cannabinoid-1 receptor (CB1R) has emerged as one of the most important targets for the treatment of obesity. Pioneering studies with rimonabant helped to validate animal models of food intake reduction and weight loss and made the connection to weight loss in the clinic. A novel, acyclic amide was identified from a high throughput screen (HTS) of the Merck sample collection and found to be a potent and selective CB1R inhibitor. Further optimization led to more potent compounds that were orally active in reducing food intake and weight loss in diet-induced obese (DIO) rats. However, many of these analogues exhibited a high potential for bioactivation and the formation of reactive intermediates and covalent protein binding. Identification of the products of oxidative metabolism guided medicinal chemistry efforts to minimize the formation of these unwanted products. These efforts resulted in the identification of the CB1R inverse agonist, taranabant, which is currently in Phase-III clinical studies for the treatment of obesity. This mini-review will describe some of the medicinal chemistry strategies that were followed from the original high throughput screen hit to the discovery of taranabant. PMID:18574849

  1. Mead ethanolamide, a novel eicosanoid, is an agonist for the central (CB1) and peripheral (CB2) cannabinoid receptors.

    Science.gov (United States)

    Priller, J; Briley, E M; Mansouri, J; Devane, W A; Mackie, K; Felder, C C

    1995-08-01

    The recently discovered endogenous agonist for the cannabinoid receptor, anandamide (arachidonylethanolamide), can be formed enzymatically by the condensation of arachidonic acid with ethanolamine. 5Z,8Z,11Z-Eicosatrienoic acid (mead acid) has been found to substitute for arachidonic acid in the sn-2 position of phospholipids and accumulate during periods of dietary fatty acid deprivation in rats. In the present study, the chemically synthesized ethanolamide of mead acid was evaluated as a potential agonist at the two known subtypes of cannabinoid receptor: CB1 (central) and CB2 (peripheral). This compound was equipotent to anandamide in competing with [3H]CP55,940 binding to plasma membranes prepared from L cells expressing the human CB1 receptor and from ATt-20 cells expressing the human CB2 receptor. Mead ethanolamide was also equipotent to anandamide in inhibiting forskolin-stimulated cAMP accumulation in cells expressing the CB1 receptor. It inhibited N-type calcium currents with a lower potency than anandamide. Mead and arachidonic acid were equally efficacious as substrates for the enzymatic synthesis of their respective ethanolamides in rat and adult human hippocampal P2 membranes. Palmitic acid was not an effective substrate for the enzymatic synthesis of palmitoyl ethanolamide. Mead ethanolamide exhibits several characteristics of a novel agonist to CB1 and CB2 receptors and may represent another candidate endogenous ligand for the CB1 receptor. Due to the anticonvulsant properties of GABA and the positional similarity of L-serine to ethanolamine in membrane phospholipids, these compounds were synthetically coupled to arachidonic acid, and their resulting arachidonamides were tested as potential cannabinoid agonists. The arachidonamides of GABA and L-serine were inactive in both binding and functional assays at the CB1 receptor. PMID:7651362

  2. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

    OpenAIRE

    Pertwee, Roger G.

    2012-01-01

    Human tissues express cannabinoid CB1 and CB2 receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB1/CB2 receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ9-tetrahydrocannabinol (Δ9-THC)) and Sativex (Δ9-THC with cannabidiol). These can be presc...

  3. Cannabinoid receptor agonist protects cultured dopaminergic neurons from the death by the proteasomal dysfunction

    OpenAIRE

    Jeon, Posung; Yang, Sungjun; Jeong, Hojoong; Kim, Hyun

    2011-01-01

    Cannabinoids have been proposed to possess neuroprotective properties; though their mechanism of action remains contentious, they are posited to prevent neurodegenerative disorders, including Parkinson's disease, the pathogenesis of which has not been established. Recent studies have demonstrated that induction of proteasomal dysfunction in animal models results in a phenotype similar to Parkinson's disease. Here, we investigated the neuroprotective function of a synthetic cannabinoid-recepto...

  4. Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent

    Directory of Open Access Journals (Sweden)

    Hanlon KE

    2016-04-01

    Full Text Available Katherine E Hanlon,1,2 Alysia N Lozano-Ondoua,1 Puja J Umaretiya,1 Ashley M Symons-Liguori,1 Anupama Chandramouli,1 Jamie K Moy,1 William K Kwass,1 Patrick W Mantyh,1 Mark A Nelson,3 Todd W Vanderah,11Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA; 2Department of Biomedical Sciences, University of New England College of Osteopathic Medicine, Biddeford, ME, USA; 3Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA Introduction: Cannabinoid compounds, both nonspecific as well as agonists selective for either cannabinoid receptor 1 (CB1 or cannabinoid receptor 2 (CB2, have been shown to modulate the tumor microenvironment by inducing apoptosis in tumor cells in several model systems. The mechanism of this modulation remains only partially delineated, and activity induced via the CB1 and CB2 receptors may be distinct despite significant sequence homology and structural similarity of ligands. Methods: The CB2-selective agonist JWH-015 was used to investigate mechanisms downstream of CB2 activation in mouse and human breast cancer cell lines in vitro and in a murine mammary tumor model. Results: JWH-015 treatment significantly reduced primary tumor burden and metastasis of luciferase-tagged murine mammary carcinoma 4T1 cells in immunocompetent mice in vivo. Furthermore, JWH-015 reduced the viability of murine 4T1 and human MCF7 mammary carcinoma cells in vitro by inducing apoptosis. JWH-015-mediated reduction of breast cancer cell viability was not dependent on Gαi signaling in vitro or modified by classical pharmacological blockade of CB1, GPR55, TRPV1, or TRPA1 receptors. JWH-015 effects were calcium dependent and induced changes in MAPK/ERK signaling. Conclusion: The results of this work characterize the actions of a CB2-selective agonist on breast cancer cells in a syngeneic murine model representing how a clinical presentation of cancer progression and metastasis may be

  5. Neuroprotective effects of the cannabinoid agonist HU210 on retinal degeneration

    OpenAIRE

    Lax Zapata, Pedro; Esquiva Sobrino, Gema; Altavilla, Cesare; Cuenca Navarro, Nicolás

    2014-01-01

    Cannabinoids have been demonstrated to exert neuroprotective effects on different types of neuronal insults. Here we have addressed the therapeutic potential of the synthetic cannabinoid HU210 on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model for autosomal dominant retinitis pigmentosa (RP). In P23H rats administered with HU210 (100 μg/kg, i.p.) from P24 to P90, ERG recordings showed an amelioration of vision...

  6. Retention and Extinction of Delay Eyeblink Conditioning Are Modulated by Central Cannabinoids

    Science.gov (United States)

    Steinmetz, Adam B.; Freeman, John H.

    2011-01-01

    Rats administered the cannabinoid agonist WIN55,212-2 or the antagonist SR141716A exhibit marked deficits during acquisition of delay eyeblink conditioning, as noted by Steinmetz and Freeman in an earlier study. However, the effects of these drugs on retention and extinction of eyeblink conditioning have not been assessed. The present study…

  7. Cannabinoid receptor subtype 2 (CB2R) agonist, GW405833 reduces agonist-induced Ca2+ oscillations in mouse pancreatic acinar cells

    Science.gov (United States)

    Huang, Zebing; Wang, Haiyan; Wang, Jingke; Zhao, Mengqin; Sun, Nana; Sun, Fangfang; Shen, Jianxin; Zhang, Haiying; Xia, Kunkun; Chen, Dejie; Gao, Ming; Hammer, Ronald P.; Liu, Qingrong; Xi, Zhengxiong; Fan, Xuegong; Wu, Jie

    2016-01-01

    Emerging evidence demonstrates that the blockade of intracellular Ca2+ signals may protect pancreatic acinar cells against Ca2+ overload, intracellular protease activation, and necrosis. The activation of cannabinoid receptor subtype 2 (CB2R) prevents acinar cell pathogenesis in animal models of acute pancreatitis. However, whether CB2Rs modulate intracellular Ca2+ signals in pancreatic acinar cells is largely unknown. We evaluated the roles of CB2R agonist, GW405833 (GW) in agonist-induced Ca2+ oscillations in pancreatic acinar cells using multiple experimental approaches with acute dissociated pancreatic acinar cells prepared from wild type, CB1R-knockout (KO), and CB2R-KO mice. Immunohistochemical labeling revealed that CB2R protein was expressed in mouse pancreatic acinar cells. Electrophysiological experiments showed that activation of CB2Rs by GW reduced acetylcholine (ACh)-, but not cholecystokinin (CCK)-induced Ca2+ oscillations in a concentration-dependent manner; this inhibition was prevented by a selective CB2R antagonist, AM630, or was absent in CB2R-KO but not CB1R-KO mice. In addition, GW eliminated L-arginine-induced enhancement of Ca2+ oscillations, pancreatic amylase, and pulmonary myeloperoxidase. Collectively, we provide novel evidence that activation of CB2Rs eliminates ACh-induced Ca2+ oscillations and L-arginine-induced enhancement of Ca2+ signaling in mouse pancreatic acinar cells, which suggests a potential cellular mechanism of CB2R-mediated protection in acute pancreatitis. PMID:27432473

  8. Cannabinoid receptor subtype 2 (CB2R) agonist, GW405833 reduces agonist-induced Ca(2+) oscillations in mouse pancreatic acinar cells.

    Science.gov (United States)

    Huang, Zebing; Wang, Haiyan; Wang, Jingke; Zhao, Mengqin; Sun, Nana; Sun, Fangfang; Shen, Jianxin; Zhang, Haiying; Xia, Kunkun; Chen, Dejie; Gao, Ming; Hammer, Ronald P; Liu, Qingrong; Xi, Zhengxiong; Fan, Xuegong; Wu, Jie

    2016-01-01

    Emerging evidence demonstrates that the blockade of intracellular Ca(2+) signals may protect pancreatic acinar cells against Ca(2+) overload, intracellular protease activation, and necrosis. The activation of cannabinoid receptor subtype 2 (CB2R) prevents acinar cell pathogenesis in animal models of acute pancreatitis. However, whether CB2Rs modulate intracellular Ca(2+) signals in pancreatic acinar cells is largely unknown. We evaluated the roles of CB2R agonist, GW405833 (GW) in agonist-induced Ca(2+) oscillations in pancreatic acinar cells using multiple experimental approaches with acute dissociated pancreatic acinar cells prepared from wild type, CB1R-knockout (KO), and CB2R-KO mice. Immunohistochemical labeling revealed that CB2R protein was expressed in mouse pancreatic acinar cells. Electrophysiological experiments showed that activation of CB2Rs by GW reduced acetylcholine (ACh)-, but not cholecystokinin (CCK)-induced Ca(2+) oscillations in a concentration-dependent manner; this inhibition was prevented by a selective CB2R antagonist, AM630, or was absent in CB2R-KO but not CB1R-KO mice. In addition, GW eliminated L-arginine-induced enhancement of Ca(2+) oscillations, pancreatic amylase, and pulmonary myeloperoxidase. Collectively, we provide novel evidence that activation of CB2Rs eliminates ACh-induced Ca(2+) oscillations and L-arginine-induced enhancement of Ca(2+) signaling in mouse pancreatic acinar cells, which suggests a potential cellular mechanism of CB2R-mediated protection in acute pancreatitis. PMID:27432473

  9. Neuroprotective effects of the cannabinoid agonist HU210 on retinal degeneration.

    Science.gov (United States)

    Lax, Pedro; Esquiva, Gema; Altavilla, Cesare; Cuenca, Nicolás

    2014-03-01

    Cannabinoids have been demonstrated to exert neuroprotective effects on different types of neuronal insults. Here we have addressed the therapeutic potential of the synthetic cannabinoid HU210 on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model for autosomal dominant retinitis pigmentosa (RP). In P23H rats administered with HU210 (100 μg/kg, i.p.) from P24 to P90, ERG recordings showed an amelioration of vision loss, as compared to vehicle-administered animals. Under scotopic conditions, the maximum a-wave amplitudes recorded at P60 and P90 were higher in HU210-treated animals, as compared to the values obtained in untreated animals. The scotopic b-waves were significantly higher in treated animals than in untreated rats at P30, P60 and P90. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. HU210-treated animals had 40% more photoreceptors than untreated animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were also preserved in HU210-treated P23H rats. These results indicate that HU210 preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in P23H rats. These data suggest that cannabinoids are potentially useful to delay retinal degeneration in RP patients. PMID:24495949

  10. Normal aging in rats and pathological aging in human Alzheimer's disease decrease FAAH activity: modulation by cannabinoid agonists.

    Science.gov (United States)

    Pascual, A C; Martín-Moreno, A M; Giusto, N M; de Ceballos, M L; Pasquaré, S J

    2014-12-01

    Anandamide is an endocannabinoid involved in several physiological functions including neuroprotection. Anandamide is synthesized on demand and its endogenous level is regulated through its degradation, where fatty acid amide hydrolase plays a major role. The aim of this study was to characterize anandamide breakdown in physiological and pathological aging and its regulation by CB1 and CB2 receptor agonists. Fatty acid amide hydrolase activity was analyzed in an independent cohort of human cortical membrane samples from control and Alzheimer's disease patients, and in membrane and synaptosomes from adult and aged rat cerebral cortex. Our results demonstrate that fatty acid amide hydrolase activity decreases in the frontal cortex from human patients with Alzheimer's disease and this effect is mimicked by Aβ(1-40) peptide. This activity increases and decreases in aged rat cerebrocortical membranes and synaptosomes, respectively. Also, while the presence of JWH-133, a CB2 selective agonist, slightly increases anandamide hydrolysis in human controls, it decreases this activity in adults and aged rat cerebrocortical membranes and synaptosomes. In the presence of WIN55,212-2, a mixed CB1/CB2 agonist, anandamide hydrolysis increases in Alzheimer's disease patients but decreases in human controls as well as in adult and aged rat cerebrocortical membranes and synaptosomes. Although a similar profile is observed in fatty acid amide hydrolase activity between aged rat synaptic endings and human Alzheimer's disease brains, it is differently modulated by CB1/CB2 agonists. This modulation leads to a reduced availability of anandamide in Alzheimer's disease and to an increased availability of this endocannabinoid in aging. PMID:25456842

  11. Cannabinoids alter spontaneous firing, bursting and cell synchrony of hippocampal principal cells

    OpenAIRE

    Goonawardena, Anushka V.; Riedel, Gernot; Hampson, Robert E.

    2011-01-01

    Both natural and synthetic cannabinoid receptor (e.g. CB1) agonists such as Δ9-THC, WIN 55,212-2 (WIN-2) and HU-210 disrupt spatial cognition presumably through the inhibition of synchrony of hippocampal ensemble firing to task-related events (Hampson and Deadwyler, J. of Neuroscience, 2000; 20:8932-8942; Robinson et al., Brit. J. Pharmacology, 2007; 151:688-700). And although the CB1 receptor agonist CP 55,940 also disrupts the synchronous firing of hippocampal neurons, it does not seem to a...

  12. Cannabinoid Receptor Type 2 Agonist Attenuates Apoptosis by Activation of Phosphorylated CREB-Bcl-2 Pathway After Subarachnoid Hemorrhage in Rats

    OpenAIRE

    Fujii, Mutsumi; Sherchan, Prativa; Soejima, Yoshiteru; Hasegawa, Yu; Flores, Jerry; Doycheva, Desislava; Zhang, John H.

    2014-01-01

    Early brain injury (EBI) which comprises of vasogenic edema and apoptotic cell death is an important component of subarachnoid hemorrhage (SAH) pathophysiology. This study evaluated whether Cannabinoid receptor type 2 (CB2R) agonist, JWH133, attenuates EBI after SAH and whether CB2R stimulation reduces pro-apoptotic caspase-3 via up-regulation of cAMP response element-binding protein (CREB)-Bcl-2 signaling pathway. Male Sprague Dawley rats (n=123) were subjected to SAH by endovascular perfora...

  13. Novelty-Induced Emotional Arousal Modulates Cannabinoid Effects on Recognition Memory and Adrenocortical Activity

    OpenAIRE

    Campolongo, Patrizia; Morena, Maria; Scaccianoce, Sergio; Trezza, Viviana; Chiarotti, Flavia; Schelling, Gustav; Cuomo, Vincenzo; Roozendaal, Benno

    2013-01-01

    Although it is well established that cannabinoid drugs can influence cognitive performance, the findings—describing both enhancing and impairing effects—have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.1, 0.3, or 1.0 mg/kg) on short- and long-term retention of object recognition memory under two conditions that differed in their training-associated arousal level. In male Sprague-Dawley rats that ...

  14. Lipid Bilayer Molecular Dynamics Study of Lipid-Derived Agonists of the Putative Cannabinoid Receptor, GPR55

    OpenAIRE

    Kotsikorou, Evangelia; Lynch, Diane L.; Abood, Mary E.; Reggio, Patricia H.

    2010-01-01

    Both L-α-lysophosphatidylinositol (LPI) and 2-arachidonoyl-sn-glycero-3-phosphoinositol (2-AGPI) have been reported to activate the putative cannabinoid receptor, GPR55. Recent microsecond time-scale molecular dynamics (MD) simulations and isothiocyanate covalent labeling studies have suggested that a transmembrane helix 6/7 (TMH6/7) lipid pathway for ligand entry may be necessary for interaction with cannabinoid receptors. Because LPI and 2-AGPI are lipid-derived ligands, conformations that ...

  15. Pharmacology of cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo

    2004-01-01

    Dronabinol (Delta 9-tetrahydocannabinol, THC), the main source of the pharmacological effects caused by the use of cannabis, is an agonist to both the CB1 and the CB2 subtype of cannabinoid receptors. It is available on prescription in several countries. The non-psychotropic cannabidiol (CBD), some analogues of natural cannabinoids and their metabolites, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues including spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart. Five endogenous cannabinoids have been detected so far, of whom anandamide and 2-arachidonylglycerol are best characterized. There is evidence that besides the two cannabinoid receptor subtypes cloned so far additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of the cannabinoid system that include motor coordination, memory procession, control of appetite, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects. PMID:15159677

  16. Effect of synthetic cannabinoids on spontaneous neuronal activity: Evaluation using Ca(2+) spiking and multi-electrode arrays.

    Science.gov (United States)

    Tauskela, Joseph S; Comas, Tanya; Hewitt, Melissa; Aylsworth, Amy; Zhao, Xigeng; Martina, Marzia; Costain, Willard J

    2016-09-01

    Activation of cannabinoid receptor 1 (CB1) inhibits synaptic transmission in hippocampal neurons. The goal of this study was to evaluate the ability of benchmark and emerging synthetic cannabinoids to suppress neuronal activity in vitro using two complementary techniques, Ca(2+) spiking and multi-electrode arrays (MEAs). Neuron culture and fluorescence imaging conditions were extensively optimized to provide maximum sensitivity for detection of suppression of neural activity by cannabinoids. The neuronal Ca(2+) spiking frequency was significantly suppressed within 10min by the prototypic aminoalkylindole cannabinoid, WIN 55,212-2 (10µM). Suppression by WIN 55,212-2 was not improved by pharmacological intervention with signaling pathways known to interfere with CB1 signaling. The naphthoylindole CB1 agonist, JWH-018 suppressed Ca(2+) spiking at a lower concentration (2.5µM), and the CB1 antagonist rimonabant (5µM), reversed this suppression. In the MEA assay, the ability of synthetic CB1 agonists to suppress spontaneous electrical activity of hippocampal neurons was evaluated over 80min sessions. All benchmark (WIN 55,212-2, HU-210, CP 55,940 and JWH-018) and emerging synthetic cannabinoids (XLR-11, JWH-250, 5F-PB-22, AB-PINACA and MAM-2201) suppressed neural activity at a concentration of 10µM; furthermore, several of these compounds also significantly suppressed activity at 1µM concentrations. Rimonabant partially reversed spiking suppression of 5F-PB-22 and, to a lesser extent, of MAM-2201, supporting CB1-mediated involvement, although the inactive WIN 55,212-3 also partially suppressed activity. Taken together, synthetic cannabinoid CB1-mediated suppression of neuronal activity was detected using Ca(2+) spiking and MEAs. PMID:27262380

  17. Cannabinoid CB1 receptor agonists do not decrease, but may increase, acoustic trauma-induced tinnitus in rats

    Directory of Open Access Journals (Sweden)

    Yiwen eZheng

    2015-03-01

    Full Text Available Tinnitus has been suggested to arise from neuronal hyperactivity in auditory areas of the brain and anti-epileptic drugs are sometimes used to provide relief from tinnitus. Recently, the anti-epileptic properties of the cannabinoid drugs have gained increasing interest; however, the use of cannabinoids as a form of treatment for tinnitus is controversial. In the present study, we tested whether a combination of delta-9-tetrahydrocannabinol (delta-9-THC and cannabidiol (CBD, delivered in a 1:1 ratio, could affect tinnitus perception in a rat model of acoustic trauma-induced tinnitus. Following sham treatment or acoustic trauma, the animals were divided into the following groups: 1 sham (i.e. no acoustic trauma with vehicle treatment; 2 sham with drug treatment (i.e. delta-9-THC + CBD; 3 acoustic trauma-exposed exhibiting tinnitus, with drug treatment; and 4 acoustic trauma-exposed exhibiting no tinnitus, with drug treatment. The animals received either the vehicle or the cannabinoid drugs every day, 30 min before the tinnitus behavioural testing. Acoustic trauma caused a significant increase in the auditory brainstem response (ABR thresholds in the exposed animals, indicating hearing loss; however, there was a partial recovery over 6 months. Acoustic trauma did not always result in tinnitus; however among those that did exhibit tinnitus, some of them had tinnitus at multiple frequencies while others had it only at a single frequency. The cannabinoids significantly increased the number of tinnitus animals in the exposed-tinnitus group, but not in the sham group. The results suggest that cannabinoids may promote the development of tinnitus, especially when there is pre-existing hearing damage.

  18. Triphasic blood pressure responses to cannabinoids: do we understand the mechanism?

    Science.gov (United States)

    Malinowska, Barbara; Baranowska-Kuczko, Marta; Schlicker, Eberhard

    2012-04-01

    The cannabinoids comprise three major classes of substances, including compounds derived from the cannabis plant (e.g. Δ(9) -tetrahydrocannabinol and the chemically related substances CP55940 and HU210), endogenously formed (e.g. anandamide) and synthetic compounds (e.g. WIN55212-2). Beyond their psychotropic effects, cannabinoids have complex effects on blood pressure, including biphasic changes of Δ(9) -tetrahydrocannabinol and WIN55212-2 and an even triphasic effect of anandamide. The differing pattern of blood pressure changes displayed by the three types of compounds is not really surprising since, although they share an agonistic effect at cannabinoid CB(1) and CB(2) receptors, some compounds have additional effects. In particular, anandamide is known for its pleiotropic effects, and there is overwhelming evidence that anandamide influences blood pressure via (i) CB(1) receptors, (ii) TRPV1 receptors, (iii) endothelial cannabinoid receptors and (iv) degradation products. This review is dedicated to the description of the effects of externally added cannabinoids on cardiovascular parameters in vivo. First, the cardiovascular effects of cannabinoids in anaesthetized animals will be highlighted since most data have been generated in experiments of that type. The text will follow the three phases of anandamide on blood pressure, and we will check to which extent cardiovascular changes elicited by other cannabinoids show overlap with those effects or differ. The second part will be dedicated to the cardiovascular effects of the cannabinoids in conscious animals. In the third part, cardiovascular effects in humans will be discussed, and similarities and differences with respect to the data from animals will be examined. PMID:22022923

  19. Effects of CP 55,940 — agonist of CB1 cannabinoid receptors on ghrelin and somatostatin producing cells in the rat pancreas

    Directory of Open Access Journals (Sweden)

    Alicja Lewandowska

    2012-04-01

    Full Text Available Cannabinoids participate in the modulation of numerous functions in the human organism, increasing the sense of hunger, affecting carbohydrate and lipid metabolism, and controlling systemic energy balance mechanisms. Moreover, they influence the endocrine system functions, acting via two types of receptors, CB1 and CB2. The aim of the present study was to examine the number, distribution and activity of ghrelin and somatostatin producing endocrine cells in the pancreas of rats after a single administration of selective CP 55,940 agonist of CB1 receptor. The study was performed on 20 rats. Neuroendocrine cells were identified by immunohistochemical reactions, involving specific antibodies against ghrelin and somatostatin. The distribution and number of ghrelin- and somatostatin-immunoreactive cells were separately studied in five pancreas islets of each section. A performed analysis showed a decreased number of somatostatin-immunoreactive cells and a weak immunoreactivity of ghrelin and somatostatin containing neuroendocrine cells in the pancreatic islets of experimental rats, compared to control animals. The obtained results suggest that a single administration of a selective CP 55,940 agonist of CB1 receptor influences the immunoreactivity of endocrine cells with ghrelin and somatostatin expression in the pancreas islets.

  20. Molecular-Interaction and Signaling Profiles of AM3677, a Novel Covalent Agonist Selective for the Cannabinoid 1 Receptor

    OpenAIRE

    David R Janero; Yaddanapudi, Suma; Zvonok, Nikolai; Subramanian, Kumar V.; Shukla, Vidyanand G.; Stahl, Edward; Zhou, Lei; Hurst, Dow; Wager-Miller, James; Bohn, Laura M.; Reggio, Patricia H.; Mackie, Ken; Makriyannis, Alexandros

    2015-01-01

    The cannabinoid 1 receptor (CB1R) is one of the most abundant G protein-coupled receptors (GPCRs) in the central nervous system. CB1R involvement in multiple physiological processes, especially neurotransmitter release and synaptic function, has made this GPCR a prime drug discovery target, and pharmacological CB1R activation has been demonstrated to be a tenable therapeutic modality. Accordingly, the design and profiling of novel, drug-like CB1R modulators to inform the receptor’s ligand-int...

  1. Selective lack of tolerance to delayed gastric emptying after daily administration of WIN 55,212-2 in the rat.

    Science.gov (United States)

    Abalo, R; Cabezos, P A; López-Miranda, V; Vera, G; González, C; Castillo, M; Fernández-Pujol, R; Martín, M I

    2009-09-01

    The use of cannabinoids to treat gastrointestinal (GI) motor disorders has considerable potential. However, it is not clear if tolerance to their actions develops peripherally, as it does centrally. The aim of this study was to examine the chronic effects of the cannabinoid agonist WIN 55,212-2 (WIN) on GI motility, as well as those in the central nervous and cardiovascular systems. WIN was administered for 14 days, at either non-psychoactive or psychoactive doses. Cardiovascular parameters were measured in anaesthetized rats, whereas central effects and alterations in GI motor function were assessed in conscious animals using the cannabinoid tetrad and non-invasive radiographic methods, respectively. Tests were performed after first (acute effects) and last (chronic effects) administration of WIN, and 1 week after discontinuing treatment (residual effects). Food intake and body weight were also recorded throughout treatment. Blood pressure and heart rate remained unchanged after acute or chronic administration of WIN. Central activity and GI motility were acutely depressed at psychoactive doses, whereas non-psychoactive doses only slightly reduced intestinal transit. Most effects were reduced after the last administration. However, delayed gastric emptying was not and could, at least partially, account for a concomitant reduction in food intake and body weight gain. The remaining effects of WIN administration in GI motility were blocked by the CB1 antagonist AM 251, which slightly accelerated motility when administered alone. No residual effects were found 1 week after discontinuing cannabinoid treatment. The different systems show differential sensitivity to cannabinoids and tolerance developed at different rates, with delayed gastric emptying being particularly resistant to attenuation upon chronic treatment. PMID:19413685

  2. Exogenous delta⁹-tetrahydrocannabinol influences circulating endogenous cannabinoids in humans.

    Science.gov (United States)

    Walter, Carmen; Ferreirós, Nerea; Bishay, Philipp; Geisslinger, Gerd; Tegeder, Irmgard; Lötsch, Jörn

    2013-10-01

    Delta⁹-tetrahydrocannabinol (THC) competes with the endogenous cannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) at cannabinoid receptors. This may cause adaptive changes in the endocannabinoid signaling cascade with possible consequences for the biological functions of the endocannabinoid system. We show that administration of a single oral dose of 20 mg THC to 30 healthy volunteers resulted in higher circulating concentrations of anandamide, 2-AG, palmitoyl ethanolamide, and oleoylethanolamide at 2 and 3 hours after administration as compared with placebo. At 2 hours after THC administration, changes in oleoylethanolamide plasma concentrations from baseline were linearly related to the THC plasma concentrations. In rats, treatment with the CB₁/CB₂ agonist WIN 55,212 also increased plasma endocannabinoid concentrations. However, this was associated with a decrease of ethanolamide endocannabinoids in specific brain regions including spinal cord, cortex, and hypothalamus; whereas 2-arachidonoyl glycerol increased in the cortex. Thus, administration of THC to human volunteers influenced the concentrations of circulating endocannabinoids, which was mimicked by WIN-55,212 in rats, suggesting that exogenous cannabinoids may lead to changes in the endocannabinoid system that can be detected in plasma. PMID:23899642

  3. Cannabinoid conditioned reward and aversion: behavioral and neural processes.

    Science.gov (United States)

    Murray, Jennifer E; Bevins, Rick A

    2010-03-10

    The discovery that delta-9-tetrahydrocannabinol (Δ(9)-THC) is the primary psychoactive ingredient in marijuana prompted research that helped elucidate the endogenous cannabinoid system of the brain. Δ(9)-THC and other cannabinoid ligands with agonist action (CP 55,940, HU210, and WIN 55,212-2) increase firing of dopamine neurons and increase synaptic dopamine in brain regions associated with reward and drug addiction. Such changes in cellular processes have prompted investigators to examine the conditioned rewarding effects of the cannabinoid ligands using the place conditioning task with rats and mice. As reviewed here, these cannabinoid ligands can condition place preferences (evidence for rewarding effects) and place aversions (evidence for aversive qualities). Notably, the procedural details used in these place conditioning studies have varied across laboratories. Such variation includes differences in apparatus type, existence of procedural biases, dose, number of conditioning trials, injection-to-placement intervals, and pre-training drug exposure. Some differences in outcome across studies can be explained by these procedural variables. For example, low doses of Δ(9)-THC appear to have conditioned rewarding effects, whereas higher doses have aversive effects that either mask these rewarding effects or condition a place aversion. Throughout this review we highlight key areas that need further research. PMID:20495676

  4. Cannabinoid receptor agonism suppresses tremor, cognition disturbances and anxiety-like behaviors in a rat model of essential tremor.

    Science.gov (United States)

    Abbassian, Hassan; Esmaeili, Parisa; Tahamtan, Mahshid; Aghaei, Iraj; Vaziri, Zohreh; Sheibani, Vahid; Whalley, Benjamin J; Shabani, Mohammad

    2016-10-01

    Cognitive and motor disturbances are serious consequences of tremor induced by motor disorders. Despite a lack of effective clinical treatment, some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of tremor. In the current study, the effects of WIN55, 212-2 (WIN), a cannabinoid receptor (CBR) agonist, on harmaline-induced motor and cognitive impairments were studied. Adult rats were treated with WIN (0.5mg/kg; i.p.) 15min before harmaline administration (10mg/kg; ip) after which exploratory and anxiety related behaviors, and cognitive function were assessed using open-field behavior and shuttle box tests. Rats that received harmaline only exhibited a markedly reduced number of central square entries when compared to harmaline vehicle-treated controls, whereas those treated with WIN and harmaline showed a significant increase in central square entries, compared to harmaline only treated. The passive avoidance memory impairments observed in harmaline treated rats, was reversed somewhat by administration of WIN. The neuroprotective and anxiolytic effects of WIN demonstrated in the current study can be offered cannabinoid receptor (CBR) agonism as a potential neuroprotective agent in the treatment of patients with tremor that manifest mental dysfunctions. PMID:27317835

  5. Contrasting effects of different cannabinoid receptor ligands on mouse ingestive behaviour.

    Science.gov (United States)

    Grey, Jonathan; Terry, Phil; Higgs, Suzanne

    2012-09-01

    This study characterized the effects of seven diverse cannabinoid receptor agonists (and one antagonist) on ingestive behaviour in nondeprived adult, male CD1 mice. Microstructural analysis of licking for a range of concentrations of condensed milk (10, 15 and 20%) was carried out following administration of vehicle or: Δ⁹-tetrahydrocannabinol (Δ⁹-THC) at 1, 3 or 6 mg/kg; CP55,940 at 10, 30 or 50 µg/kg; Win 55,212-2 at 0.5, 1 or 3 mg/kg; HU-210 at 0.01, 0.03 or 0.1 mg/kg; methanandamide at 1, 3 or 6 mg/kg; arachidonyl-2'-chloroethylamide at 1, 3 or 6 mg/kg and JWH133 at 1, 3 or 6 mg/kg. The cannabinoid receptor antagonist/inverse agonist rimonabant was also tested at 0.3, 1 or 3 mg/kg. Test sessions comprised three 30 s presentations of the milk concentrations separated by 10 s interpresentation intervals. The nonselective CB1 receptor agonists Δ⁹-THC, CP55,940 and Win 55,212-2 increased the number of licks for condensed milk, primarily by a significant increase in bout number. The potent and nonselective CB1 receptor agonist HU-210 and the selective CB1 receptor agonists methanandamide and arachidonyl-2'-chloroethylamide did not significantly affect licking behaviour but did significantly increase the latency to start licking. The CB1 receptor antagonist rimonabant produced effects that were opposite in direction to those produced by Δ⁹-THC, CP55,940 and Win 55,212-2. Finally, the selective CB2 receptor agonist JWH133 had no significant effects on behaviour. These data add to reports that cannabinoid agonists can enhance the appetitive aspects of feeding, but they also demonstrate that not all CB1 receptor agonists do this, and therefore the relationship between action at CB1 receptors and appetitive feeding effects is not straightforward. PMID:22772336

  6. Cannabinoids and their medicinal potential

    Directory of Open Access Journals (Sweden)

    Deepika Tikoo

    2012-04-01

    Full Text Available Cannabis sativa L preparations have been used therapeutically since many years. Inspite of their medicinal value, the danger of its abusive potential led to the ban on its use in clinical practice in many countries. The recent research and in depth knowledge about the cannabinoid system which throw a light on their disease management potential has paved way for the cannabinoids to become a new therapeutic focus of attention. Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors which include CB1, predominantly expressed in the brain and CB2 which is primarily found in the cells of the immune system. Despite the addictive properties of cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases such as anorexia, pain, inflammation, obesity, cardiovascular disorders, neurodegenerative diseases, cancer, gastrointestinal diseases, hepatic disorders, skin related diseases, respiratory disorders like asthma and eye diseases like glaucoma have suggested cannabinoid agonists/ antagonists/ cannabinoids related compounds as potential treatment options. Developments of new specific ligands for the cannabinoid receptors are now underway and it needs to be seen, if in future, they can prove to be a boon for the medical world. The paper reviews the current understanding of the cannabinoid receptors, their ligands and their possible role in various diseases supported by preclinical and clinical studies. [Int J Basic Clin Pharmacol 2012; 1(2.000: 48-59

  7. Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood.

    Science.gov (United States)

    Alteba, Shirley; Korem, Nachshon; Akirav, Irit

    2016-07-01

    Early life stress (ES) significantly increases predisposition to psychopathologies. Cannabinoids may cause cognitive deficits and exacerbate the effects of ES. Nevertheless, the endocannabinoid system has been suggested as a therapeutic target for the treatment of stress- and anxiety-related disorders. Here we examined whether cannabinoids administered during "late adolescence" (extensive cannabis use in humans at the ages 18-25) could reverse the long-term adverse effects of ES on neurocognitive function in adulthood. Male and female rats were exposed to ES during post-natal days (P) 7-14, injected with the cannabinoid CB1/2 receptor agonist WIN55,212-2 (WIN; 1.2 mg/kg, i.p.) for 2 wk during late adolescence (P45-60) and tested in adulthood (P90) for working memory, anxiety, and alterations in CB1 receptors (CB1r), and glucocorticoid receptors (GRs) in the stress circuit [hippocampus, prefrontal cortex (PFC), and basolateral amygdala (BLA)]. ES males and females exhibited impaired performance in short-term memory in adulthood in the spatial location and social recognition tasks; males were also impaired in the novel object recognition task. WIN administered during late adolescence prevented these stress-induced impairments and reduced anxiety levels. WIN normalized the ES-induced up-regulation in PFC-GRs and CA1-CB1r in females. In males, WIN normalized the ES-induced up-regulation in PFC-GR and down-regulation in BLA-CB1r. There is a crucial role of the endocannabinoid system in the effects of early life stress on behavior at adulthood. Differences in recognition memory and in the expression of GRs and CB1r in the fear circuit suggest sex differences in the mechanism underlying coping with stress. PMID:27317195

  8. Cannabinoid system and cyclooxygenases inhibitors

    OpenAIRE

    Păunescu, H; Coman, OA; Coman, L.; Ghiţă, I; Georgescu, SR; Drăia, F; Fulga, I

    2011-01-01

    Rationale. The cannabinoid system consists of a complex array of receptors, substances with agonist/antagonist properties for those receptors, biosynthetic machineries and mechanisms for cellular uptake and degradation for endocannabinoids. This system is in interrelation with other systems that comprise lipid mediators like prostaglandins/leukotrienes systems. A clear antagonist, additive or synergic effect of nonsteroidal anti–inflammatory drugs (NSAIDs)–cannabinoid associations was not yet...

  9. Promising cannabinoid-based therapies for Parkinson's disease: motor symptoms to neuroprotection.

    Science.gov (United States)

    More, Sandeep Vasant; Choi, Dong-Kug

    2015-01-01

    Parkinson's disease (PD) is a slow insidious neurological disorder characterized by a loss of dopaminergic neurons in the midbrain. Although several recent preclinical advances have proposed to treat PD, there is hardly any clinically proved new therapeutic for its cure. Increasing evidence suggests a prominent modulatory function of the cannabinoid signaling system in the basal ganglia. Hence, use of cannabinoids as a new therapeutic target has been recommended as a promising therapy for PD. The elements of the endocannabinoid system are highly expressed in the neural circuit of basal ganglia wherein they bidirectionally interact with dopaminergic, glutamatergic, and GABAergic signaling systems. As the cannabinoid signaling system undergoes a biphasic pattern of change during progression of PD, it explains the motor inhibition typically observed in patients with PD. Cannabinoid agonists such as WIN-55,212-2 have been demonstrated experimentally as neuroprotective agents in PD, with respect to their ability to suppress excitotoxicity, glial activation, and oxidative injury that causes degeneration of dopaminergic neurons. Additional benefits provided by cannabinoid related compounds including CE-178253, oleoylethanolamide, nabilone and HU-210 have been reported to possess efficacy against bradykinesia and levodopa-induced dyskinesia in PD. Despite promising preclinical studies for PD, use of cannabinoids has not been studied extensively at the clinical level. In this review, we reassess the existing evidence suggesting involvement of the endocannabinoid system in the cause, symptomatology, and treatment of PD. We will try to identify future threads of research that will help in the understanding of the potential therapeutic benefits of the cannabinoid system for treating PD. PMID:25888232

  10. Human Laboratory Studies on Cannabinoids and Psychosis.

    Science.gov (United States)

    Sherif, Mohamed; Radhakrishnan, Rajiv; D'Souza, Deepak Cyril; Ranganathan, Mohini

    2016-04-01

    Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of

  11. Mitigation win-win

    Science.gov (United States)

    Moran, Dominic; Lucas, Amanda; Barnes, Andrew

    2013-07-01

    Win-win messages regarding climate change mitigation policies in agriculture tend to oversimplify farmer motivation. Contributions from psychology, cultural evolution and behavioural economics should help to design more effective policy.

  12. Effects of various cannabinoid ligands on choice behaviour in a rat model of gambling.

    Science.gov (United States)

    Gueye, Aliou B; Trigo, Jose M; Vemuri, Kiran V; Makriyannis, Alexandros; Le Foll, Bernard

    2016-04-01

    It is estimated that 0.6-1% of the population in the USA and Canada fulfil the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) criteria for gambling disorders (GD). To date, there are no approved pharmacological treatments for GD. The rat gambling task (rGT) is a recently developed rodent analogue of the Iowa gambling task in which rats are trained to associate four response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. Similar to healthy human volunteers, most rats adopt the optimal strategies (optimal group). However, a subset of animals show preference for the disadvantageous options (suboptimal group), mimicking the choice pattern of patients with GD. Here, we explored for the first time the effects of various cannabinoid ligands (WIN 55,212-2, AM 4113, AM 630 and URB 597) on the rGT. Administration of the cannabinoid agonist CB1/CB2 WIN 55,212-2 improved choice strategy and increased choice latency in the suboptimal group, but only increased perseverative behaviour, when punished, in the optimal group. Blockade of CB1 or CB2 receptors or inhibition of fatty-acid amide hydrolase did not affect rGT performance. These results suggest that stimulation of cannabinoid receptors could affect gambling choice behaviours differentially in some subgroups of subjects. PMID:26905189

  13. Effects of various cannabinoid ligands on choice behaviour in a rat model of gambling

    Science.gov (United States)

    Gueye, Aliou B.; Trigo, Jose M.; Vemuri, Kiran V.; Makriyannis, Alexandros

    2016-01-01

    It is estimated that 0.6–1% of the population in the USA and Canada fulfil the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) criteria for gambling disorders (GD). To date, there are no approved pharmacological treatments for GD. The rat gambling task (rGT) is a recently developed rodent analogue of the Iowa gambling task in which rats are trained to associate four response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. Similar to healthy human volunteers, most rats adopt the optimal strategies (optimal group). However, a subset of animals show preference for the disadvantageous options (suboptimal group), mimicking the choice pattern of patients with GD. Here, we explored for the first time the effects of various cannabinoid ligands (WIN 55,212-2, AM 4113, AM 630 and URB 597) on the rGT. Administration of the cannabinoid agonist CB1/CB2 WIN 55,212-2 improved choice strategy and increased choice latency in the suboptimal group, but only increased perseverative behaviour, when punished, in the optimal group. Blockade of CB1 or CB2 receptors or inhibition of fatty-acid amide hydrolase did not affect rGT performance. These results suggest that stimulation of cannabinoid receptors could affect gambling choice behaviours differentially in some subgroups of subjects. PMID:26905189

  14. Pharmacological characterization of emerging synthetic cannabinoids in HEK293T cells and hippocampal neurons.

    Science.gov (United States)

    Costain, Willard J; Tauskela, Joseph S; Rasquinha, Ingrid; Comas, Tanya; Hewitt, Melissa; Marleau, Vincent; Soo, Evelyn C

    2016-09-01

    There has been a worldwide proliferation of synthetic cannabinoids that have become marketed as legal alternatives to cannabis (marijuana). Unfortunately, there is a dearth of information about the pharmacological effects of many of these emerging synthetic cannabinoids (ESCs), which presents a challenge for regulatory authorities that need to take such scientific evidence into consideration in order to regulate ECSs as controlled substances. We aimed to characterize the pharmacological properties of ten ESCs using two cell based assays that enabled the determination of potency and efficacy relative to a panel of well-characterized cannabinoids. Agonist-mediated inhibition of forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels was monitored in live HEK293T cells transfected with human cannabinoid receptor 1 gene (CNR1) and pGloSensor-22F. Pharmacological analysis of this data indicated that all of the ESCs tested were full agonists, with the following rank order of potency: Win 55212-2≈5F-PB-22≈AB-PINACA≈EAM-2201≈MAM-2201>JWH-250≈ PB-22>AKB48 N-(5FP)>AKB-48≈STS-135>XLR-11. Assessment of agonist-stimulated depression of Ca(2+) transients was also used to confirm the efficacy of five ESCs (XLR-11, JWH-250, AB-PINACA, 5F-PB-22, and MAM-2201) in cultured primary hippocampal neurons. This work aims to help inform decisions made by regulatory agencies concerned with the profusion of these poorly characterized recreational drugs. PMID:27260125

  15. Metabolites of 5F-AKB-48, a synthetic cannabinoid receptor agonist, identified in human urine and liver microsomal preparations using liquid chromatography high-resolution mass spectrometry

    DEFF Research Database (Denmark)

    Holm, Niels Bjerre; Pedersen, Anders Just; Dalsgaard, Petur Weihe;

    2015-01-01

    New types of synthetic cannabinoid designer drugs are constantly introduced to the illicit drug market to circumvent legislation. Recently, N-​(1-Adamant​yl)-​1-​(5-​fluoropentyl)-​1H-​indazole-​3-​carboxamide (5F-AKB-48), also known as 5F-APINACA, was identified as an adulterant in herbal products...

  16. Cannabinoids inhibit network-driven synapse loss between hippocampal neurons in culture.

    Science.gov (United States)

    Kim, Hee Jung; Waataja, Jonathan J; Thayer, Stanley A

    2008-06-01

    Dendritic pruning and loss of synaptic contacts are early events in many neurodegenerative diseases. These effects are dynamic and seem to differ mechanistically from the cell death process. Cannabinoids modulate synaptic activity and afford protection in some neurotoxicity models. We investigated the effects of cannabinoids on activity-induced changes in the number of synapses between rat hippocampal neurons in culture. Morphology and synapses were visualized by confocal imaging of neurons expressing DsRed2 and postsynaptic density protein 95 (PSD95) fused to enhanced green fluorescent protein (GFP). Reducing the extracellular Mg2+ concentration to 0.1 mM for 4 h induced intense synaptic activity, which decreased the number of PSD95-GFP puncta by 45 +/- 13%. Synapse loss was an early event, required activation of N-methyl-D-aspartate receptors, and was mediated by the ubiquitin-proteasome pathway. The cannabinoid receptor full agonist WIN55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)-methyl] pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-napthalenyl)-methanone monomethanesulfonate] (EC(50) = 2.5 +/- 0.5 nM) and the partial agonist Delta(9)-tetrahydrocannabinol (THC; EC(50) = 9 +/- 3 nM) inhibited PSD loss in a manner reversed by the CB1 receptor antagonist rimonabant [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide]. The protection was mimicked by inhibition of presynaptic Ca2+ channels, and WIN55,212-2 did not prevent PSD loss elicited by direct application of glutamate, suggesting a presynaptic mechanism. Prolonged exposure to WIN55,212-2, but not THC, desensitized the protective effect. Treating cells that had undergone PSD loss with WIN55,212-2 reversed the loss and enabled recovery of a full compliment of synapses. The modulation of synaptic number by acute and prolonged exposure to cannabinoids may account for some of the effects of these drugs on the plasticity, survival, and function of neural networks. PMID

  17. Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach

    OpenAIRE

    Adami, Maristella; Frati, Paolo; Bertini, Simone; Kulkarni-Narla, Anjali; Brown, David R; Caro, Giuseppe de; Coruzzi, Gabriella; Soldani, Giulio

    2002-01-01

    The role of cannabinoid (CB) receptors in the regulation of gastric acid secretion was investigated in the rat by means of functional experiments and by immunohistochemistry.In anaesthetized rats with lumen-perfused stomach, the non selective CB-receptor agonist WIN 55,212-2 (0.30 – 4.00 μmol kg−1, i.v.) and the selective CB1-receptor agonist HU-210 (0.03 – 1.50 μmol kg−1, i.v.), dose-dependently decreased the acid secretion induced by both pentagastrin (30 nmol kg−1 h−1) and 2-deoxy-D-glucos...

  18. Cannabinoids and Glucocorticoids in the Basolateral Amygdala Modulate Hippocampal-Accumbens Plasticity After Stress.

    Science.gov (United States)

    Segev, Amir; Akirav, Irit

    2016-03-01

    Acute stress results in release of glucocorticoids, which are potent modulators of learning and plasticity. This process is presumably mediated by the basolateral amygdala (BLA) where cannabinoids CB1 receptors have a key role in regulating the hypothalamic-pituitary-adrenal (HPA) axis. Growing attention has been focused on nucleus accumbens (NAc) plasticity, which regulates mood and motivation. The NAc integrates affective and context-dependent input from the BLA and ventral subiculum (vSub), respectively. As our previous data suggest that the CB1/2 receptor agonist WIN55,212-2 (WIN) and glucocorticoid receptor (GR) antagonist RU-38486 (RU) can prevent the effects of stress on emotional memory, we examined whether intra-BLA WIN and RU can reverse the effects of acute stress on NAc plasticity. Bilateral, ipsilateral, and contralateral BLA administration of RU or WIN reversed the stress-induced impairment in vSub-NAc long-term potentiation (LTP) and the decrease in cAMP response element-binding protein (CREB) activity in the NAc. BLA CB1 receptors were found to mediate the preventing effects of WIN on plasticity, but not the preventing effects of RU, after stress. Inactivating the ipsilateral BLA, but not the contralateral BLA, impaired LTP. The possible mechanisms underlying the effects of BLA on NAc plasticity are discussed; the data suggest that BLA-induced changes in the NAc may be mediated through neural pathways in the brain's stress circuit rather than peripheral pathways. The results suggest that glucocorticoid and cannabinoid systems in the BLA can restore normal function of the NAc and hence may have a central role in the treatment of a variety of stress-related disorders. PMID:26289146

  19. Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid exposure during adolescence.

    Science.gov (United States)

    Abboussi, Oualid; Said, Nadia; Fifel, Karim; Lakehayli, Sara; Tazi, Abdelouahhab; El Ganouni, Soumaya

    2016-04-01

    Chronic exposure to cannabinoids during adolescence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the serotoninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were administered separately at 1 mg/kg and 20 mg/kg, and in combination at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor agonist WIN55,212-2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like memory in the open field and novel object recognition tests respectively 30 minutes after the last drug administration. Chronic WIN55,212-2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute administration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses. However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212-2. These findings give further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophrenia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease. PMID:26497809

  20. Functional Selectivity of CB2 Cannabinoid Receptor Ligands at a Canonical and Noncanonical Pathway.

    Science.gov (United States)

    Dhopeshwarkar, Amey; Mackie, Ken

    2016-08-01

    The CB2 cannabinoid receptor (CB2) remains a tantalizing, but unrealized therapeutic target. CB2 receptor ligands belong to varied structural classes and display extreme functional selectivity. Here, we have screened diverse CB2 receptor ligands at canonical (inhibition of adenylyl cyclase) and noncanonical (arrestin recruitment) pathways. The nonclassic cannabinoid (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940) was the most potent agonist for both pathways, while the classic cannabinoid ligand (6aR,10aR)-3-(1,1-Dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran JWH133) was the most efficacious agonist among all the ligands profiled in cyclase assays. In the cyclase assay, other classic cannabinoids showed little [(-)-trans-Δ(9)-tetrahydrocannabinol and (-)-(6aR,7,10,10aR)-tetrahydro-6,6,9-trimethyl-3-(1-methyl-1-phenylethyl)-6H-dibenzo[b,d]pyran-1-ol] (KM233) to no efficacy [(6aR,10aR)-1-methoxy-6,6,9-trimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene(L759633) and (6aR,10aR)-3-(1,1-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-1-methoxy-6,6-dimethyl-9-methylene-6H-dibenzo[b,d]pyran]L759656. Most aminoalkylindoles, including [(3R)-​2,​3-​dihydro-​5-​methyl-​3-​(4-​morpholinylmethyl)pyrrolo[1,​2,​3-​de]-​1,​4-​benzoxazin-​6-​yl]-​1-​naphthalenyl-​methanone,​ monomethanesulfonate (WIN55212-2), were moderate efficacy agonists. The cannabilactone 3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one (AM1710) was equiefficacious to CP55940 to inhibit adenylyl cyclase, albeit with lower potency. In the arrestin recruitment assays, all classic cannabinoid ligands failed to recruit arrestins, indicating a bias toward G-protein coupling for this class of compound. All aminoalkylindoles tested, except for WIN55212-2 and (1-​pentyl-​1H-​indol-​3-​yl)(2,​2,​3,​3-​tetramethylcyclopropyl)-​methanone (UR144), failed

  1. Apparent Inverse Relationship between Cannabinoid Agonist Efficacy and Tolerance/Cross-Tolerance Produced by Δ9-Tetrahydrocannabinol Treatment in Rhesus Monkeys

    OpenAIRE

    Hruba, Lenka; Ginsburg, Brett C.; McMahon, Lance R.

    2012-01-01

    Synthetic cannabinoids (CBs) [naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH-018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073)] are marketed, sold, and used as alternatives to cannabis. Synthetic CBs appear to have effects similar to those of Δ9-tetrahydrocannabinol (Δ9-THC), the drug primarily responsible for the behavioral effects of cannabis. However, synthetic CB products produce atypical effects (e.g., hypertension, seizures, and panic attacks). One potential explanat...

  2. Cannabinoid receptor type 1 protects nigrostriatal dopaminergic neurons against MPTP neurotoxicity by inhibiting microglial activation.

    Science.gov (United States)

    Chung, Young C; Bok, Eugene; Huh, Sue H; Park, Ju-Young; Yoon, Sung-Hwa; Kim, Sang R; Kim, Yoon-Seong; Maeng, Sungho; Park, Sung Hyun; Jin, Byung K

    2011-12-15

    This study examined whether the cannabinoid receptor type 1 (CB(1)) receptor contributes to the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. MPTP induced significant loss of nigrostriatal DA neurons and microglial activation in the substantia nigra (SN), visualized with tyrosine hydroxylase or macrophage Ag complex-1 immunohistochemistry. Real-time PCR, ELISA, Western blotting, and immunohistochemistry disclosed upregulation of proinflammatory cytokines, activation of microglial NADPH oxidase, and subsequent reactive oxygen species production and oxidative damage of DNA and proteins in MPTP-treated SN, resulting in degeneration of DA neurons. Conversely, treatment with nonselective cannabinoid receptor agonists (WIN55,212-2 and HU210) led to increased survival of DA neurons in the SN, their fibers and dopamine levels in the striatum, and improved motor function. This neuroprotection by cannabinoids was accompanied by suppression of NADPH oxidase reactive oxygen species production and reduced expression of proinflammatory cytokines from activated microglia. Interestingly, cannabinoids protected DA neurons against 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia, but not in neuron-enriched mesencephalic cultures devoid of microglia. The observed neuroprotection and inhibition of microglial activation were reversed upon treatment with CB(1) receptor selective antagonists AM251 and/or SR14,716A, confirming the involvement of the CB(1) receptor. The present in vivo and in vitro findings clearly indicate that the CB(1) receptor possesses anti-inflammatory properties and inhibits microglia-mediated oxidative stress. Our results collectively suggest that the cannabinoid system is beneficial for the treatment of Parkinson's disease and other disorders associated with neuroinflammation and microglia-derived oxidative damage

  3. CB2 receptor agonists protect human dopaminergic neurons against damage from HIV-1 gp120.

    Directory of Open Access Journals (Sweden)

    Shuxian Hu

    Full Text Available Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Recent work suggests that the nigrostriatal dopaminergic area is a critical brain region for the neuronal dysfunction and death seen in HAND and that human dopaminergic neurons have a particular sensitivity to gp120-induced damage, manifested as reduced function (decreased dopamine uptake, morphological changes, and reduced viability. Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes. Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model, which contains dopaminergic neurons, microglia, and astrocytes, we were able to show that the CB1/CB2 agonist WIN55,212-2 blunts gp120-induced neuronal damage as measured by dopamine transporter function, apoptosis and lipid peroxidation; these actions were mediated principally by the CB2 receptor. Adding supplementary human microglia to our cultures enhances gp120-induced damage; WIN55,212-2 is able to alleviate this enhanced damage. Additionally, WIN55,212-2 inhibits gp120-induced superoxide production by purified human microglial cells, inhibits migration of human microglia towards supernatants generated from gp120-stimulated human mesencephalic neuronal/glial cultures and reduces chemokine and cytokine production from the human mesencephalic neuronal/glial cultures. These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from

  4. Cannabinoids: Medical implications.

    Science.gov (United States)

    Schrot, Richard J; Hubbard, John R

    2016-05-01

    standards for medical approval, while specific well-characterized cannabinoids have met those standards, and more are being studied. However, herbal cannabis is legal for medical use in certain US states/countries, and patients must usually see a physician who "certifies" that a benefit may result. Participating physicians should be knowledgeable about cannabinoids, closely look at the risk/benefit ratio, and consider certain important criteria in selecting a patient, such as: age, severity, and nature of the medical disorder, prior or current serious psychiatric or substance use disorder, failure of standard medical therapy as well as failure of an approved cannabinoid, serious underlying cardiac/pulmonary disease, agreement to follow-up visits, and acceptance of the detailed explanation of potential adverse risks. The limitations of use of medical cannabis include the following potential adverse effects that are discussed with potential patients: acute central nervous system effects such as deficits in memory, judgment, attention, coordination, and perception (such as time and color), anxiety, dysphoria, and psychosis; chronic central nervous system effects such as cannabis use disorder, cognitive and memory deficits, and increased risk of psychosis; pulmonary effects such as chronic bronchitis; social dysfunction, such as work/school; increased risk of accidents, such as motor vehicle accidents; and preliminary data suggest possible risk for acute cardiovascular event, especially with underlying heart disease. The normal human endocannabinoid system is important in the understanding of such issues as normal physiology, cannabis use disorder, and the development of medications that may act as agonists or antagonists to CB1 and CB2. By understanding the endocannabinoid system, it may be possible to enhance the beneficial effects of cannabinoid-related medication, while reducing the harmful effects. PMID:26912385

  5. Effects of Cannabinoid Drugs on the Deficit of Prepulse Inhibition of Startle in an Animal Model of Schizophrenia: the SHR Strain

    Directory of Open Access Journals (Sweden)

    Raquel eLevin

    2014-02-01

    Full Text Available Clinical and neurobiological findings suggest that the cannabinoids and the endocannabinoid system may be implicated in the pathophysiology and treatment of schizophrenia. We described that the Spontaneously Hypertensive Rats (SHR strain presents a schizophrenia behavioral phenotype that is specifically attenuated by antipsychotic drugs, and potentiated by proschizophrenia manipulations. Based on these findings, we have suggested this strain as an animal model of schizophrenia. The aim of this study was to evaluate the effects of cannabinoid drugs on the deficit of prepulse inhibition of startle (PPI, the main paradigm used to study sensorimotor gating impairment related to schizophrenia, presented by the SHR strain. The following drugs were used: 1 WIN55212,2 (cannabinoid agonist, 2 rimonabant (CB1 antagonist, 3 AM404 (anandamide uptake inhibitor, and 4 cannabidiol (indirect CB1/CB2 receptor antagonist, among other effects. Wistar rats (WR and SHRs were treated with vehicle or different doses of WIN55212 (0.3, 1 or 3 mg/kg, rimonabant (0.75, 1.5 or 3 mg/kg, AM404 (1, 5 or 10 mg/kg or cannabidiol (15, 30 or 60 mg/kg. Vehicle-treated SHRs showed a decreased PPI when compared to WRs. This PPI deficit was reversed by 1 mg/kg WIN and 30 mg/kg cannabidiol. Conversely, 0.75 mg/kg rimonabant decreased PPI in SHR strain, whereas AM404 did not modify it. Our results reinforce the role of the endocannabinoid system in the sensorimotor gating impairment related to schizophrenia, and point to cannabinoid drugs as potential therapeutic strategies.

  6. Cannabinoids in health and disease

    OpenAIRE

    Kogan, Natalya M.; Mechoulam, Raphael

    2007-01-01

    Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Desp...

  7. Effect of delta(9)-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans

    NARCIS (Netherlands)

    H. Beaumont; J. Jensen; A. Carlsson; M. Ruth; A. Lehmann; G.E. Boeckxstaens

    2009-01-01

    Background and purpose: Transient lower oesophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-oesophageal reflux and are a potential pharmacological treatment target. We evaluated the effect of the CB(1)/CB(2) receptor agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC

  8. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology

    Directory of Open Access Journals (Sweden)

    Justine eRenard

    2014-11-01

    Full Text Available Marijuana is the most widely used illicit drug among adolescents and young adults. Unique cognitive, emotional, and social changes occur during this critical period of development from childhood into adulthood. The adolescent brain is in a state of transition and differs from the adult brain with respect to both anatomy (e.g., neuronal connections and morphology and neurochemistry (e.g., dopamine, GABA, and glutamate. These changes are thought to support the emergence of adult cerebral processes and behaviors. The endocannabinoid system plays an important role in development by acting on synaptic plasticity, neuronal cell proliferation, migration, and differentiation. Delta-9-tetrahydrocanabinol (THC, the principal psychoactive component in marijuana, acts as an agonist of the cannabinoid type 1 receptor (CB1R. Thus, over-activation of the endocannabinoid system by chronic exposure to CB1R agonists (e.g. THC, CP-55,940, and WIN55,212-2 during adolescence can dramatically alter brain maturation and cause long-lasting neurobiological changes that ultimately affect the function and behavior of the adult brain. Indeed, emerging evidence from both human and animal studies demonstrates that early-onset marijuana use has long-lasting consequences on cognition; moreover, in humans, this use is associated with a two-fold increase in the risk of developing a psychotic disorder. Here, we review the relationship between cannabinoid exposure during adolescence and the increased risk of neuropsychiatric disorders, focusing on both clinical and animal studies.

  9. Cannabinoid inhibition of the capsaicin-induced calcium response in rat dorsal root ganglion neurones

    OpenAIRE

    Millns, Paul J; Chapman, Victoria; Kendall, David A.

    2001-01-01

    Cannabinoids have marked inhibitory effects on somatosensory processing, which may arise from actions at both peripheral and central cannabinoid receptors. Here, the effect of a synthetic cannabinoid agonist HU210 on capsaicin-evoked responses in adult rat dorsal root ganglion (DRG) neurones was studied. The vanilloid capsaicin produced a concentration-related increase in intracellular calcium in DRG neurones, which was significantly inhibited by HU210 (1 μM). The cannabinoid CB1 receptor ant...

  10. Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists

    DEFF Research Database (Denmark)

    Manera, Clementina; Saccomanni, Giuseppe; Adinolfi, Barbara; Benetti, Veronica; Ligresti, Alessia; Cascio, Maria Grazia; Tuccinardi, Tiziano; Lucchesi, Valentina; Martinelli, Adriano; Nieri, Paola; Masini, Emanuela; Di Marzo, Vincenzo; Ferrarini, Pier Luigi

    2009-01-01

    revealed that compound 12, which presented benzyl and carboxy-4-methylcyclohexylamide substituents bound in the 1 and 3 positions, exerted a CB(2)-mediated inhibitory action on immunological human basophil activation. On the human T cell leukemia line Jurkat the same derivative induced a concentration......-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists....

  11. Interaction between paired-pulse facilitation and long-term potentiation during the stimulation of the cannabinoid and vanilloid systems in the dentate gyrus.

    Science.gov (United States)

    Tahmasebi, Lida; Komaki, Alireza; Karamian, Ruhollah; Shahidi, Siamak; Sarihi, Abdolrahman; Komaki, Hamidreza

    2016-07-15

    Synaptic plasticity includes short-term and long-term changes in synaptic strength. Short-term plasticity can be used to assess the site mediating the long-lasting forms of synaptic plasticity such as long-term potentiation (LTP). The endogenous endocannabinoid systems can modulate LTP, and similarly, the activation of the vanilloid system has been shown to mediate synaptic plasticity in the hippocampus. In this study, we examined the interaction between short-term and long-term plasticity during the stimulation of the cannabinoid and vanilloid systems in the hippocampus of rats in vivo. Forty male Wistar rats, divided into four groups, were treated with the following compounds: control (saline+dimethyl sulfoxide), WIN55,212-2, capsaicin, and WIN55,212-2+capsaicin. The animals were anesthetized with urethane and then recording and stimulating electrodes were positioned at the dentate gyrus(DG) and perforant pathway(PP), respectively. Population spike (PS) amplitudes were measured before and after the induction of LTP, which was induced with high-frequency stimulation (HFS). The paired-pulse ratio (PPR) was measured before and after the induction of LTP in all groups. We showed that WIN55,212-2 reduced the PS amplitude after HFS, whereas the vanilloid agonist increased the induction of LTP compared with the control treatment. In the present study, we found that in the presence of WIN55,212-2 and capsaicin, the induction of LTP changed the PPR. Additionally, we showed that the co-administration of cannabinoid and vanilloid agonists modulate the PPR. These findings suggest the presynaptic expression of this LTP form, and therefore, this form of LTP is caused by the increase of neurotransmitter release. PMID:27130895

  12. Triphasic blood pressure responses to cannabinoids: do we understand the mechanism?

    OpenAIRE

    Malinowska, Barbara; Baranowska-Kuczko, Marta; Schlicker, Eberhard

    2012-01-01

    The cannabinoids comprise three major classes of substances, including compounds derived from the cannabis plant (e.g. Δ9-tetrahydrocannabinol and the chemically related substances CP55940 and HU210), endogenously formed (e.g. anandamide) and synthetic compounds (e.g. WIN55212-2). Beyond their psychotropic effects, cannabinoids have complex effects on blood pressure, including biphasic changes of Δ9-tetrahydrocannabinol and WIN55212-2 and an even triphasic effect of anandamide. The differing ...

  13. [Analgesic effects of cannabinoids on central pain syndrome].

    Science.gov (United States)

    Igon'kina, S I; Churiukanov, M V; Churiukanov, V V; Kukushkin, M L

    2011-01-01

    It was shown that cannabinoids anandamide, HU210 and WIN 55,212-2 inhibit both spontaneous episodes of pain and mechanical allodynia in rats with central pain syndrome caused by disturbance of inhibitory processes in the dorsal horns of lumbar spinal cord. The analgesic effect is most pronounced in the intrathecal route of administration. The intensity of analgesic actions of cannabinoids on the central pain syndrome in rats, depending on the drug is as follows: HU210 > WIN 55,212-2 > anandamide. PMID:22359935

  14. GABA(A) receptors in the central amygdala are involved in memory retention deficits induced by cannabinoids in rats.

    Science.gov (United States)

    Hasanein, Parisa; Sharifi, Maryam

    2015-11-01

    The central nucleus of the amygdala (CeA) as the main output of amygdala plays an important role in memory processes. In this study we first evaluated the effects of intra-CeA administrations of different doses of a cannabinoid CB1 agonist, WIN55, 212-2, GABA(A) receptor agonist and antagonist, muscimol and bicuculline, alone on memory retention using passive avoidance learning (PAL) test in rats. Then we examined the effects of GABA(A) receptor agents on the responses induced by intra-CeA microinjection of different doses of WIN55, 212-2. We found that administration of WIN55, 212-2 (0.05, 0.1, 0.2 and 0.4μg/rat) immediately after training impaired memory retrieval in a dose-dependent fashion. Although pre-test intra-CeA administration of muscimol (125, 250 and 500ng/rat) alone had no effect on the step-through latency, its co-administration (125ng/rat) with different doses of WIN55, 212-2 potentiated the amnesic effects of any doses of WIN55, 212-2. The results also showed that pre-test intra-CeA administration of bicuculline (200, 400 and 800ng/rat) alone had no significant effect, but at dose of 200ng/rat disrupted post-training WIN55, 212-2-induced amnesia in the retention test. Furthermore, the additional effect of muscimol (125ng/rat) on memory impairment induced by WIN55, 212-2 (0.1μg/rat) was prevented by intra-CeA co-injection of bicuculline (200ng/rat). We indicated that stimulating or blocking GAGA(A) receptors in the CeA by muscimol and bicuculline interfere with WIN55, 212-2-induced deficits in memory retention in a PAL task and therefore suggests an interaction between cannabinergic and GABAergic systems of the CeA in memory process. PMID:26368844

  15. Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

    Directory of Open Access Journals (Sweden)

    Michael Halpern

    2010-08-01

    Full Text Available The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD, Huntington’s disease (HD, Parkinson’s disease (PD and vascular dementia (VD. Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies.

  16. Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice

    Energy Technology Data Exchange (ETDEWEB)

    Baireddy, Praveena; Liu, Jing; Hinsdale, Myron; Pope, Carey, E-mail: carey.pope@okstate.edu

    2011-11-15

    Endocannabinoids (eCBs) modulate neurotransmission by inhibiting the release of a variety of neurotransmitters. The cannabinoid receptor agonist WIN 55.212-2 (WIN) can modulate organophosphorus (OP) anticholinesterase toxicity in rats, presumably by inhibiting acetylcholine (ACh) release. Some OP anticholinesterases also inhibit eCB-degrading enzymes. We studied the effects of the OP insecticide chlorpyrifos (CPF) on cholinergic signs of toxicity, cholinesterase activity and ACh release in tissues from wild type (+/+) and cannabinoid CB1 receptor knockout (-/-) mice. Mice of both genotypes (n = 5-6/treatment group) were challenged with CPF (300 mg/kg, 2 ml/kg in peanut oil, sc) and evaluated for functional and neurochemical changes. Both genotypes exhibited similar cholinergic signs and cholinesterase inhibition (82-95% at 48 h after dosing) in cortex, cerebellum and heart. WIN reduced depolarization-induced ACh release in vitro in hippocampal slices from wild type mice, but had no effect in hippocampal slices from knockouts or in striatal slices from either genotype. Chlorpyrifos oxon (CPO, 100 {mu}M) reduced release in hippocampal slices from both genotypes in vitro, but with a greater reduction in tissues from wild types (21% vs 12%). CPO had no significant in vitro effect on ACh release in striatum. CPF reduced ACh release in hippocampus from both genotypes ex vivo, but reduction was again significantly greater in tissues from wild types (52% vs 36%). In striatum, CPF led to a similar reduction (20-23%) in tissues from both genotypes. Thus, while CB1 deletion in mice had little influence on the expression of acute toxicity following CPF, CPF- or CPO-induced changes in ACh release appeared sensitive to modulation by CB1-mediated eCB signaling in a brain-regional manner. -- Highlights: Black-Right-Pointing-Pointer C57Bl/6 mice showed dose-related cholinergic toxicity following subcutaneous chlorpyrifos exposure. Black-Right-Pointing-Pointer Wild type and

  17. Effect of Cannabinoid Receptor Activation on Spreading Depression

    OpenAIRE

    Kazemi, Hadi; Rahgozar, Mehdi; Speckmann, Erwin-Josef; Gorji, Ali

    2012-01-01

    Objective(s):The objective of this study was to evaluate the effect of cannabinoid on cortical spreading depression (CSD) in rat brain. Cannabis has been used for centuries for both symptomatic and prophylactic treatment of different types of headaches including migraine. CSD is believed to be a putative neuronal mechanism underlying migraine aura and subsequent pain. Materials and Methods:The effects of Delta9-tetrahydrocannabinol (THC), as well as, cannabinoid CB1 and CB2 receptor agonists ...

  18. Deuterium labeled cannabinoids

    International Nuclear Information System (INIS)

    Complex reactions involving ring opening, ring closure and rearrangements hamper complete understanding of the fragmentation processes in the mass spectrometric fragmentation patterns of cannabinoids. Specifically labelled compounds are very powerful tools for obtaining more insight into fragmentation mechanisms and ion structures and therefore the synthesis of specifically deuterated cannabinoids was undertaken. For this, it was necessary to investigate the preparation of cannabinoids, appropriately functionalized for specific introduction of deuterium atom labels. The results of mass spectrometry with these labelled cannabinoids are described. (Auth.)

  19. L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons.

    Science.gov (United States)

    Hoddah, Hanaa; Marcantoni, Andrea; Comunanza, Valentina; Carabelli, Valentina; Carbone, Emilio

    2009-01-01

    Using immortalized hypothalamic GT1-7 neurons, which express the CB1 cannabinoid receptor (CB1R) and three Ca2+ channel types (T, R and L), we found that the CB1R agonist WIN 55,212-2 inhibited the voltage-gated Ca2+ currents by about 35%. The inhibition by WIN 55,212-2 (10 microM) was reversible and prevented by nifedipine (3 microM), suggesting a selective action on L-type Ca2+ channels (LTCCs). WIN 55,212-2 action exhibited all the features of voltage-independent Ca2+ channel modulation: (1) no changes of the activation kinetics, (2) equal depressive action at all potentials and (3) no facilitation following strong prepulses. At variance with WIN 55,212-2, the CB1R inverse agonist AM-251 (10 microM) caused 20% increase of Ca2+ currents. The inhibition of LTCCs by WIN 55,212-2 was prevented by overnight PTX-incubation and by intracellular perfusion with GDP-beta-S. The latter caused also a 20% Ca2+ current up-regulation. WIN 55,212-2 action was also prevented by application of the PKA-blocker H89 or by loading the neurons with 8-CPT-cAMP. Our results suggest that LTCCs in GT1-7 neurons are partially inhibited at rest due to a constitutive CB1R activity removed by AM-251 and GDP-beta-S. Activation of CB1R via PTX-sensitive G proteins and cAMP/PKA pathway selectively depresses LTCCs that critically control the synchronized spontaneous firing and pulsatile release of gonadotropin-releasing hormone in GT1-7 neurons. PMID:19818494

  20. Cannabinoids on the Brain

    Directory of Open Access Journals (Sweden)

    Andrew J. Irving

    2002-01-01

    Full Text Available Cannabis has a long history of consumption both for recreational and medicinal uses. Recently there have been significant advances in our understanding of how cannabis and related compounds (cannabinoids affect the brain and this review addresses the current state of knowledge of these effects. Cannabinoids act primarily via two types of receptor, CB1 and CB2, with CB1 receptors mediating most of the central actions of cannabinoids. The presence of a new type of brain cannabinoid receptor is also indicated. Important advances have been made in our understanding of cannabinoid receptor signaling pathways, their modulation of synaptic transmission and plasticity, the cellular targets of cannabinoids in different central nervous system (CNS regions and, in particular, the role of the endogenous brain cannabinoid (endocannabinoid system. Cannabinoids have widespread actions in the brain: in the hippocampus they influence learning and memory; in the basal ganglia they modulate locomotor activity and reward pathways; in the hypothalamus they have a role in the control of appetite. Cannabinoids may also be protective against neurodegeneration and brain damage and exhibit anticonvulsant activity. Some of the analgesic effects of cannabinoids also appear to involve sites within the brain. These advances in our understanding of the actions of cannabinoids and the brain endocannabinoid system have led to important new insights into neuronal function which are likely to result in the development of new therapeutic strategies for the treatment of a number of key CNS disorders.

  1. Differential Regulation of Behavioral Tolerance to WIN55,212-2 by GASP1

    OpenAIRE

    Martini, Lene; Thompson, Dawn; Kharazia, Viktor; Whistler, Jennifer L.

    2010-01-01

    Cannabinoid agonists have shown some promise clinically as analgesics, in particular for cancer pain, in which they have the additional benefit of decreasing nausea. However, as for most other drugs, the long-term use of cannabinoids is limited by the development of tolerance. Several molecular mechanisms have been proposed to explain drug tolerance, including receptor downregulation. The cannabinoid 1 (CB1) receptors can be downregulated in vitro through an interaction with the G-protein-cou...

  2. Cannabinoid Hyperemesis Syndrome

    OpenAIRE

    Galli, Jonathan A.; Sawaya, Ronald Andari; Friedenberg, Frank K.

    2011-01-01

    Coinciding with the increasing rates of cannabis abuse has been the recognition of a new clinical condition known as Cannabinoid Hyperemesis Syndrome. Cannabinoid Hyperemesis Syndrome is characterized by chronic cannabis use, cyclic episodes of nausea and vomiting, and frequent hot bathing. Cannabinoid Hyperemesis Syndrome occurs by an unknown mechanism. Despite the well-established anti-emetic properties of marijuana, there is increasing evidence of its paradoxical effects on the gastrointes...

  3. Novel cannabinoid receptors

    OpenAIRE

    Brown, A J

    2007-01-01

    Cannabinoids have numerous physiological effects. In the years since the molecular identification of the G protein-coupled receptors CB1 and CB2, the ion channel TRPV1, and their corresponding endogenous ligand systems, many cannabinoid-evoked actions have been shown conclusively to be mediated by one of these specific receptor targets. However, there remain several examples where these classical cannabinoid receptors do not explain observed pharmacology. Studies using mice genetically delete...

  4. Cannabinoid receptor activation prevents the effects of chronic mild stress on emotional learning and LTP in a rat model of depression.

    Science.gov (United States)

    Segev, Amir; Rubin, Adva S; Abush, Hila; Richter-Levin, Gal; Akirav, Irit

    2014-03-01

    Most psychiatric disorders are characterized by emotional memory or learning disturbances. Chronic mild stress (CMS) is a common animal model for stress-induced depression. Here we examined whether 3 days of treatment using the CB1/2 receptor agonist WIN55,212-2 could ameliorate the effects of CMS on emotional learning (ie, conditioned avoidance and extinction), long-term potentiation (LTP) in the hippocampal-accumbens pathway, and depression-like symptoms (ie, coping with stress behavior, anhedonia, and weight changes). We also examined whether the ameliorating effects of WIN55,212-2 on behavior and physiology after CMS are mediated by CB1 and glucocorticoid receptors (GRs). Rats were exposed to CMS or handled on days 1-21. The agonist WIN55,212-2 or vehicle were administered on days 19-21 (IP; 0.5 mg/kg) and behavioral and electrophysiological measures were taken on days 23 and 28. The CB1 receptor antagonist AM251 (IP; 0.3 mg/kg) or the GR antagonist RU-38486 (IP; 10 mg/kg) were co-administered with WIN55,212-2. Our results show that CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depression-like symptoms, such as coping with stress behavior, weight gain, and sucrose consumption. The most significant effect observed in this study was that 3 days of WIN55,212-2 administration prevented the CMS-induced alterations in emotional memory (ie, extinction) and plasticity. This effect was mediated by CB1 receptors as the CB1 receptor antagonist AM251 prevented the ameliorating effects of WIN55,212-2 on extinction and LTP. The GR antagonist RU-38486 also prevented the CMS-induced alterations in extinction and plasticity, and when co-administered with WIN55,212-2, the preventive effects after CMS were maintained. The findings suggest that enhancing cannabinoid signaling could represent a novel approach to the treatment of cognitive

  5. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors

    OpenAIRE

    Járai, Zoltán; Wagner, Jens A.; Varga, Károly; Lake, Kristy D.; Compton, David R.; Martin, Billy R.; Zimmer, Anne M.; Bonner, Tom I.; Buckley, Nancy E.; Mezey, Eva; Razdan, Raj K; Zimmer, Andreas; Kunos, George

    1999-01-01

    Cannabinoids, including the endogenous ligand arachidonyl ethanolamide (anandamide), elicit not only neurobehavioral but also cardiovascular effects. Two cannabinoid receptors, CB1 and CB2, have been cloned, and studies with the selective CB1 receptor antagonist SR141716A have implicated peripherally located CB1 receptors in the hypotensive action of cannabinoids. In rat mesenteric arteries, anandamide-induced vasodilation is inhibited by SR141716A, but other potent CB1 receptor agonists, suc...

  6. The extracellular regulated kinases (ERK) 1/2 mediate cannabinoid-induced inhibition of gap junctional communication in endothelial cells

    OpenAIRE

    Brandes, R P; Popp, R; G. Ott; Bredenkötter, D; Wallner, C.; Busse, R.; Fleming, I.

    2002-01-01

    Cannabinoids are potent inhibitors of endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxations. We set out to study the mechanism underlying this effect and the possible role of cannabinoid-induced changes in intercellular gap junction communication.In cultured endothelial cells, Δ9-tetrahydrocannabinol (Δ9-THC) and the cannabinoid receptor agonist HU210, increased the phosphorylation of extracellular regulated kinases 1/2 (ERK1/2) and inhibited gap junctional communication, as ...

  7. Cannabinoids and zebrafish

    NARCIS (Netherlands)

    Akhtar, Muhammad Tayyab

    2013-01-01

    Cannabinoids are a group of terpenophenolic compounds and are naturally found in the cannabis plant (Cannabis sativa L). Δ9-Tetrahydrocannabinol (Δ9-THC) is the psychoactive cannabinoid. The high lipophilicity of Δ9-THC is a hindering factor in the further development of this compound into a large s

  8. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside.

    Science.gov (United States)

    Rahn, Elizabeth J; Hohmann, Andrea G

    2009-10-01

    Neuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults. Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics. Cannabinoids, drugs that share the same target as Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. Here, we review studies evaluating cannabinoids for neuropathic pain management in the clinical and preclinical literature. Neuropathic pain associated with nerve injury, diabetes, chemotherapeutic treatment, human immunodeficiency virus, multiple sclerosis, and herpes zoster infection is considered. In animals, cannabinoids attenuate neuropathic nociception produced by traumatic nerve injury, disease, and toxic insults. Effects of mixed cannabinoid CB(1)/CB(2) agonists, CB(2) selective agonists, and modulators of the endocannabinoid system (i.e., inhibitors of transport or degradation) are compared. Effects of genetic disruption of cannabinoid receptors or enzymes controlling endocannabinoid degradation on neuropathic nociception are described. Specific forms of allodynia and hyperalgesia modulated by cannabinoids are also considered. In humans, effects of smoked marijuana, synthetic Delta(9)-THC analogs (e.g., Marinol, Cesamet) and medicinal cannabis preparations containing both Delta(9)-THC and cannabidiol (e.g., Sativex, Cannador) in neuropathic pain states are reviewed. Clinical studies largely affirm that neuropathic pain patients derive benefits from cannabinoid treatment. Subjective (i.e., rating scales) and objective (i.e., stimulus-evoked) measures of pain and quality of life are considered. Finally, limitations of cannabinoid pharmacotherapies are discussed together with directions for future research. PMID:19789075

  9. Cannabinoid hyperemesis syndrome.

    Science.gov (United States)

    Galli, Jonathan A; Sawaya, Ronald Andari; Friedenberg, Frank K

    2011-12-01

    Coinciding with the increasing rates of cannabis abuse has been the recognition of a new clinical condition known as Cannabinoid Hyperemesis Syndrome. Cannabinoid Hyperemesis Syndrome is characterized by chronic cannabis use, cyclic episodes of nausea and vomiting, and frequent hot bathing. Cannabinoid Hyperemesis Syndrome occurs by an unknown mechanism. Despite the well-established anti-emetic properties of marijuana, there is increasing evidence of its paradoxical effects on the gastrointestinal tract and CNS. Tetrahydrocannabinol, cannabidiol, and cannabigerol are three cannabinoids found in the cannabis plant with opposing effects on the emesis response. The clinical course of Cannabinoid Hyperemesis Syndrome may be divided into three phases: prodromal, hyperemetic, and recovery phase. The hyperemetic phase usually ceases within 48 hours, and treatment involves supportive therapy with fluid resuscitation and anti-emetic medications. Patients often demonstrate the learned behavior of frequent hot bathing, which produces temporary cessation of nausea, vomiting, and abdominal pain. The broad differential diagnosis of nausea and vomiting often leads to delay in the diagnosis of Cannabinoid Hyperemesis Syndrome. Cyclic Vomiting Syndrome shares several similarities with CHS and the two conditions are often confused. Knowledge of the epidemiology, pathophysiology, and natural course of Cannabinoid Hyperemesis Syndrome is limited and requires further investigation. PMID:22150623

  10. Cannabis and Cannabinoids (PDQ)

    Science.gov (United States)

    ... Professionals Questions to Ask about Your Treatment Research Cannabis and Cannabinoids (PDQ®)–Patient Version Overview Go to ... treatment (see Question 9 ). Questions and Answers About Cannabis What is Cannabis ? Cannabis , also known as marijuana , ...

  11. Cannabinoids Regulate Bcl-2 and Cyclin D2 Expression in Pancreatic β Cells

    Science.gov (United States)

    Kim, Jung Seok; Rho, Jun Gi; Shin, Jung Jae; Song, Woo Keun; Lee, Eun Kyung; Egan, Josephine M.; Kim, Wook

    2016-01-01

    Recent reports have shown that cannabinoid 1 receptors (CB1Rs) are expressed in pancreatic β cells, where they induce cell death and cell cycle arrest by directly inhibiting insulin receptor activation. Here, we report that CB1Rs regulate the expression of the anti-apoptotic protein Bcl-2 and cell cycle regulator cyclin D2 in pancreatic β cells. Treatment of MIN6 and βTC6 cells with a synthetic CB1R agonist, WIN55,212–2, led to a decrease in the expression of Bcl-2 and cyclin D2, in turn inducing cell cycle arrest in G0/G1 phase and caspase-3-dependent apoptosis. Additionally, genetic deletion and pharmacological blockade of CB1Rs after injury in mice led to increased levels of Bcl-2 and cyclin D2 in pancreatic β cells. These findings provide evidence for the involvement of Bcl-2 and cyclin D2 mediated by CB1Rs in the regulation of β-cell survival and growth, and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and growth in diabetes. PMID:26967640

  12. Cannabinoids Regulate Bcl-2 and Cyclin D2 Expression in Pancreatic β Cells.

    Directory of Open Access Journals (Sweden)

    Jihye Kim

    Full Text Available Recent reports have shown that cannabinoid 1 receptors (CB1Rs are expressed in pancreatic β cells, where they induce cell death and cell cycle arrest by directly inhibiting insulin receptor activation. Here, we report that CB1Rs regulate the expression of the anti-apoptotic protein Bcl-2 and cell cycle regulator cyclin D2 in pancreatic β cells. Treatment of MIN6 and βTC6 cells with a synthetic CB1R agonist, WIN55,212-2, led to a decrease in the expression of Bcl-2 and cyclin D2, in turn inducing cell cycle arrest in G0/G1 phase and caspase-3-dependent apoptosis. Additionally, genetic deletion and pharmacological blockade of CB1Rs after injury in mice led to increased levels of Bcl-2 and cyclin D2 in pancreatic β cells. These findings provide evidence for the involvement of Bcl-2 and cyclin D2 mediated by CB1Rs in the regulation of β-cell survival and growth, and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and growth in diabetes.

  13. Feeding Induced by Cannabinoids Is Mediated Independently of the Melanocortin System

    OpenAIRE

    Sinnayah, Puspha; Jobst, Erin E.; Rathner, Joseph A.; Caldera-Siu, Angela D.; Tonelli-Lemos, Luciana; Eusterbrock, Aaron J.; Enriori, Pablo J.; Pothos, Emmanuel N.; Grove, Kevin L.; Cowley, Michael A.

    2008-01-01

    Background Cannabinoids, the active components of marijuana, stimulate appetite, and cannabinoid receptor-1 (CB1-R) antagonists suppress appetite and promote weight loss. Little is known about how CB1-R antagonists affect the central neurocircuitry, specifically the melanocortin system that regulates energy balance. Methodology/Principal Findings Here, we show that peripherally administered CB1-R antagonist (AM251) or agonist equally suppressed or stimulated feeding respectively in Ay , which...

  14. Identification of Essential Cannabinoid-binding Domains: STRUCTURAL INSIGHTS INTO EARLY DYNAMIC EVENTS IN RECEPTOR ACTIVATION*

    OpenAIRE

    Shim, Joong-Youn; Bertalovitz, Alexander C.; Kendall, Debra A.

    2011-01-01

    The classical cannabinoid agonist HU210, a structural analog of (−)-Δ9-tetrahydrocannabinol, binds to brain cannabinoid (CB1) receptors and activates signal transduction pathways. To date, an exact molecular description of the CB1 receptor is not yet available. Utilizing the minor binding pocket of the CB1 receptor as the primary ligand interaction site, we explored HU210 binding using lipid bilayer molecular dynamics (MD) simulations. Among the potential ligand contact residues, we identifie...

  15. The periaqueductal gray contributes to bidirectional enhancement of antinociception between morphine and cannabinoids

    OpenAIRE

    Wilson-Poe, Adrianne R.; Pocius, Edvinas; Herschbach, Melissa; Morgan, Michael M

    2012-01-01

    Co-administration of opioids and cannabinoids can enhance pain relief even when administered on different days. Repeated systemic administration of morphine has been shown to enhance the antinociceptive effect of tetrahydrocannbinol (THC) administered 12 hours later, and repeated microinjection of the cannabinoid receptor agonist HU-210 into the ventrolateral periaqueductal gray (PAG) has been shown to enhance the antinociceptive effect of morphine administered one day later. The primary obje...

  16. The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids.

    Science.gov (United States)

    McAllister, Sean D; Soroceanu, Liliana; Desprez, Pierre-Yves

    2015-06-01

    As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ(9)-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment. PMID:25916739

  17. Influence of the CB1 receptor antagonist, AM 251, on the regional haemodynamic effects of WIN-55212-2 or HU 210 in conscious rats

    OpenAIRE

    Gardiner, S. M.; March, J. E.; Kemp, P. A.; Bennett, T.

    2002-01-01

    In conscious, freely-moving, male, Sprague-Dawley rats, the regional haemodynamic responses to the synthetic cannabinoids, WIN-55212-2 and HU 210, were compared. The possible involvement of cannabinoid, CB1-receptors, or β2-adrenoceptors in the responses to WIN-55212-2 and HU 210 were investigated using the CB1-receptor antagonist, AM 251, or the β2-adrenoceptor antagonist, ICI 118551, respectively.Both WIN-55212-2 (150 μg kg−1) and HU 210 (100 μg kg−1) had pressor, renal, and mesenteric vaso...

  18. The influence of cannabinoids on learning and memory processes of the dorsal striatum.

    Science.gov (United States)

    Goodman, Jarid; Packard, Mark G

    2015-11-01

    Extensive evidence indicates that the mammalian endocannabinoid system plays an integral role in learning and memory. Our understanding of how cannabinoids influence memory comes predominantly from studies examining cognitive and emotional memory systems mediated by the hippocampus and amygdala, respectively. However, recent evidence suggests that cannabinoids also affect habit or stimulus-response (S-R) memory mediated by the dorsal striatum. Studies implementing a variety of maze tasks in rats indicate that systemic or intra-dorsolateral striatum infusions of cannabinoid receptor agonists or antagonists impair habit memory. In mice, cannabinoid 1 (CB1) receptor knockdown can enhance or impair habit formation, whereas Δ(9)THC tolerance enhances habit formation. Studies in human cannabis users also suggest an enhancement of S-R/habit memory. A tentative conclusion based on the available data is that acute disruption of the endocannabinoid system with either agonists or antagonists impairs, whereas chronic cannabinoid exposure enhances, dorsal striatum-dependent S-R/habit memory. CB1 receptors are required for multiple forms of striatal synaptic plasticity implicated in memory, including short-term and long-term depression. Interactions with the hippocampus-dependent memory system may also have a role in some of the observed effects of cannabinoids on habit memory. The impairing effect often observed with acute cannabinoid administration argues for cannabinoid-based treatments for human psychopathologies associated with a dysfunctional habit memory system (e.g. post-traumatic stress disorder and drug addiction/relapse). In addition, the enhancing effect of repeated cannabinoid exposure on habit memory suggests a novel neurobehavioral mechanism for marijuana addiction involving the dorsal striatum-dependent memory system. PMID:26092091

  19. Dual intracellular signaling pathways mediated by the human cannabinoid CB1 receptor.

    Science.gov (United States)

    Calandra, B; Portier, M; Kernéis, A; Delpech, M; Carillon, C; Le Fur, G; Ferrara, P; Shire, D

    1999-06-25

    It has long been established that the cannabinoid CB1 receptor transduces signals through a pertussis toxin-sensitive Gi/Go inhibitory pathway. Although there have been reports that the cannabinoid CB1 receptor can also mediate an increase in cyclic AMP levels, in most cases the presence of an adenylyl cyclase costimulant or the use of very high amounts of agonist was necessary. Here, we present evidence for dual coupling of the cannabinoid CB receptor to the classical pathway and to a pertussis toxin-insensitive adenylyl cyclase stimulatory pathway initiated with low quantities of agonist in the absence of any costimulant. Treatment of Chinese hamster ovary (CHO) cells expressing the cannabinoid CB1 receptor with the cannabinoid CP 55,940, {(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hyd roxypropyl) cyclohexan-1-ol} resulted in cyclic AMP accumulation in a dose-response manner, an accumulation blocked by the cannabinoid CB1 receptor-specific antagonist SR 141716A, {N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride}. In CHO cells coexpressing the cannabinoid CB1 receptor and a cyclic AMP response element (CRE)-luciferase reporter gene system, CP 55,940 induced luciferase expression by a pathway blocked by the protein kinase A inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-89). Under the same conditions the peripheral cannabinoid CB2 receptor proved to be incapable of inducing cAMP accumulation or luciferase activity. This incapacity allowed us to study the luciferase activation mediated by CB /CB2 chimeric constructs, from which we determined that the first and second internal loop regions of the cannabinoid CB1 receptor were involved in transducing the pathway leading to luciferase gene expression. PMID:10422789

  20. Residues accessible in the binding-site crevice of transmembrane helix 6 of the CB2 cannabinoid receptor.

    Science.gov (United States)

    Nebane, Ntsang M; Hurst, Dow P; Carrasquer, Carl A; Qiao, Zhuanhong; Reggio, Patricia H; Song, Zhao-Hui

    2008-12-30

    We have used the substituted-cysteine accessibility method (SCAM) to map the residues in the sixth membrane-spanning segment of the CB2 cannabinoid receptor that contribute to the surface of the water-accessible binding-site crevice. Using a background of the mutant C2.59S which is relatively insensitive to the methanethiosulfonate (MTS) reagents, we mutated to cysteine, one at a time, 34 consecutive residues in TMH6 of the CB2 receptor. These mutant receptors were then expressed in HEK293 cells. By incubating HEK293 cells stably transfected with CB2 receptors with the small, charged, hydrophilic, thiol-specific reagent methanethiosulfonate ethylammonium (MTSEA), [(3)H]CP55940 binding was significantly inhibited for six mutant receptors. All six of the mutants that reacted with MTSEA were protected from the reaction when pretreated with the cannabinoid agonist WIN55212-2, suggesting that MTSEA modification occurred within the binding crevice. Therefore, the side chains of the residues at these reactive loci (V6.51, L6.52, L6.54, M6.55, L6.59, and T6.62) are on the water-accessible surface of the binding-site crevice. These residues are extracellular to the TMH6 CWXP hinge motif. The pattern of accessibility is consistent with a alpha-helical conformation for this segment of TMH6. Molecular modeling studies performed in the context of the CB2 model show that V6.51, L6.52, L6.54, M6.55, L6.59, and T6.62 face into the CB2 binding pocket, further confirming our SCAM results. These results are similar to the accessibility patterns determined by SCAM studies of TMH6 in the opioid and dopamine D2 receptors. PMID:19053233

  1. Local activation of cannabinoid CB1 receptors in the urinary bladder reduces the inflammation-induced sensitization of bladder afferents

    Directory of Open Access Journals (Sweden)

    Cervero Fernando

    2011-05-01

    Full Text Available Abstract Background Systemic administration of cannabinoid agonists is known to reduce pain induced by bladder inflammation and to modulate cystometric parameters in vivo. We have previously reported that intravesical administration of a cannabinoid agonist reduces the electrical activity of bladder afferents under normal conditions. However, the effects of local activation of bladder cannabinoid receptors on afferent activity during inflammation are unknown. This study was aimed to assess the effects of intravesical administration of a cannabinoid agonist on the discharges of afferent fibers in inflamed bladders ex vivo. We also characterized the expression of CB1 receptors in the bladder and their localization and co-expression with TRPV1, a marker of nociceptive afferents. Results Compared to untreated animals, afferent fiber activity in inflamed bladders was increased for intravesical pressures between 10 and 40 mmHg. Local treatment with a non selective cannabinoid agonist (AZ12646915 significantly reduced the afferent activity at intravesical pressures above 20 mmHg. This effect was blocked by AM251 but not by AM630 (selective for CB1 and CB2 respectively. Finally, CB1 was co-expressed with TRPV1 in control and inflamed bladders. Conclusion These results demonstrate that sensitization of bladder afferents induced by inflammation is partly suppressed by intravesical activation of cannabinoid receptors, an effect that appears to be mediated by CB1 receptors. Also, TRPV1 positive fibers were found to co-express CB1, supporting the hypothesis of a direct action of the cannabinoid agonist on nociceptive afferents. Taken together, these results indicate a peripheral modulation by the cannabinoid system of bladder hypersensitivity during inflammation.

  2. Stimulation of cannabinoid receptor 2 (CB2 suppresses microglial activation

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    Fernandez Francisco

    2005-12-01

    Full Text Available Abstract Background Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD, multiple sclerosis (MS, and HIV dementia. It is well known that inflammatory mediators such as nitric oxide (NO, cytokines, and chemokines play an important role in microglial cell-associated neuron cell damage. Our previous studies have shown that CD40 signaling is involved in pathological activation of microglial cells. Many data reveal that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of cannabinoid receptor 2 (CB2. Methods In this study, we investigated the effects of a cannabinoid agonist on CD40 expression and function by cultured microglial cells activated by IFN-γ using RT-PCR, Western immunoblotting, flow cytometry, and anti-CB2 small interfering RNA (siRNA analyses. Furthermore, we examined if the stimulation of CB2 could modulate the capacity of microglial cells to phagocytise Aβ1–42 peptide using a phagocytosis assay. Results We found that the selective stimulation of cannabinoid receptor CB2 by JWH-015 suppressed IFN-γ-induced CD40 expression. In addition, this CB2 agonist markedly inhibited IFN-γ-induced phosphorylation of JAK/STAT1. Further, this stimulation was also able to suppress microglial TNF-α and nitric oxide production induced either by IFN-γ or Aβ peptide challenge in the presence of CD40 ligation. Finally, we showed that CB2 activation by JWH-015 markedly attenuated CD40-mediated inhibition of microglial phagocytosis of Aβ1–42 peptide. Taken together, these results provide mechanistic insight into beneficial effects provided by cannabinoid receptor CB2 modulation in neurodegenerative diseases, particularly AD.

  3. Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma.

    Science.gov (United States)

    Oesch, Susanne; Walter, Dagmar; Wachtel, Marco; Pretre, Kathya; Salazar, Maria; Guzmán, Manuel; Velasco, Guillermo; Schäfer, Beat W

    2009-07-01

    Gene expression profiling has revealed that the gene coding for cannabinoid receptor 1 (CB1) is highly up-regulated in rhabdomyosarcoma biopsies bearing the typical chromosomal translocations PAX3/FKHR or PAX7/FKHR. Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis in diverse cancer cells such as glioma, breast cancer, and melanoma, we evaluated whether CB1 is a potential drug target in rhabdomyosarcoma. Our study shows that treatment with the cannabinoid receptor agonists HU210 and Delta(9)-tetrahydrocannabinol lowers the viability of translocation-positive rhabdomyosarcoma cells through the induction of apoptosis. This effect relies on inhibition of AKT signaling and induction of the stress-associated transcription factor p8 because small interfering RNA-mediated down-regulation of p8 rescued cell viability upon cannabinoid treatment. Finally, treatment of xenografts with HU210 led to a significant suppression of tumor growth in vivo. These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma. PMID:19509271

  4. Cannabinoids enhance gastric X/A-like cells activity.

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    Bogusław Sawicki

    2008-06-01

    Full Text Available It has been reported that cannabinoids may cause overeating in humans and in laboratory animals. Although, endogenous cannabinoids and their receptors (CB1 have been found in the hypothalamus, and recently also in gastrointestinal tract, the precise mechanism of appetite control by cannabinoids remains unknown. Recently, ghrelin--a hormone secreted mainly from the stomach X/A-like cells was proposed to be an appetite stimulating agent. The aim of this study was the evaluation of the influence of a single ip injection of a stable analogue of endogenous cannabinoid--anandamide, R-(+-methanandamide (2.5 mg/kg and CP 55,940 (0.25 mg/kg, an exogenous agonist of CB1 receptors, on ghrelin plasma concentration and on ghrelin immunoreactivity in the gastric mucosa of male Wistar rats. Four hours after a single injection of both cannabinoids or vehicle, the animals were anaesthetized and blood was taken from the abdominal aorta to determinate plasma ghrelin concentration by RIA. Subsequently, the animals underwent resection of distal part of stomach. Immunohistochemical study of gastric mucosa, using the EnVision method and specific monoclonal antibodies against ghrelin was performed. The intensity of ghrelin immunoreactivity in X/A-like cells was analyzed using Olympus Cell D image analysis system. The attenuation of ghrelin-immunoreactivity of gastric mucosa, after a single injection of R-(+-methanandamide and CP 55,940 was accompanied by a significant increase of ghrelin plasma concentration. These results indicate that stimulation of appetite exerted by cannabinoids may be connected with an increase of ghrelin secretion from gastric X/A-like cells.

  5. Mastering tricyclic ring systems for desirable functional cannabinoid activity

    Science.gov (United States)

    Petrov, Ravil R.; Knight, Lindsay; Chen, Shao-Rui; Wager-Miller, Jim; McDaniel, Steven W.; Diaz, Fanny; Barth, Francis; Pan, Hui-Lin; Mackie, Ken; Cavasotto, Claudio N.; Diaz, Philippe

    2013-01-01

    There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain and other indications. In continuation of our ongoing program aiming for the development of new small molecule cannabinoid ligands, we have synthesized a novel series of carbazole and γ-carboline derivatives. The affinities of the newly synthesized compounds were determined by a competitive radioligand displacement assay for human CB2 cannabinoid receptor and rat CB1 cannabinoid receptor. Functional activity and selectivity at human CB1 and CB2 receptors were characterized using receptor internalization and [35S]GTP-γ-S assays. The structure-activity relationship and optimization studies of the carbazole series have led to the discovery of a non-selective CB1 and CB2 agonist, compound 4. Our subsequent research efforts to increase CB2 selectivity of this lead compound have led to the discovery of CB2 selective compound 64, which robustly internalized CB2 receptors. Compound 64 had potent inhibitory effects on pain hypersensitivity in a rat model of neuropathic pain. Other potent and CB2 receptor–selective compounds, including compounds 63 and 68, and a selective CB1 agonist, compound 74 were also discovered. In addition, we identified the CB2 ligand 35 which failed to promote CB2 receptor internalization and inhibited compound CP55,940-induced CB2 internalization despite a high CB2 receptor affinity. The present study provides novel tricyclic series as a starting point for further investigations of CB2 pharmacology and pain treatment. PMID:24125850

  6. It's All in the Rhythm: The Role of Cannabinoids in Neural Oscillations and Psychosis.

    Science.gov (United States)

    Skosnik, Patrick D; Cortes-Briones, Jose A; Hajós, Mihály

    2016-04-01

    Evidence has accumulated over the past several decades suggesting that both exocannabinoids and endocannabinoids play a role in the pathophysiology of schizophrenia. The current article presents evidence suggesting that one of the mechanisms whereby cannabinoids induce psychosis is through the alteration in synchronized neural oscillations. Neural oscillations, particularly in the gamma (30-80 Hz) and theta (4-7 Hz) ranges, are disrupted in schizophrenia and are involved in various areas of perceptual and cognitive function. Regarding cannabinoids, preclinical evidence from slice and local field potential recordings has shown that central cannabinoid receptor (cannabinoid receptor type 1) agonists decrease the power of neural oscillations, particularly in the gamma and theta bands. Further, the administration of cannabinoids during critical stages of neural development has been shown to disrupt the brain's ability to generate synchronized neural oscillations in adulthood. In humans, studies examining the effects of chronic cannabis use (utilizing electroencephalography) have shown abnormalities in neural oscillations in a pattern similar to those observed in schizophrenia. Finally, recent studies in humans have also shown disruptions in neural oscillations after the acute administration of delta-9-tetrahydrocannabinol, the primary psychoactive constituent in cannabis. Taken together, these data suggest that both acute and chronic cannabinoids can disrupt the ability of the brain to generate synchronized oscillations at functionally relevant frequencies. Hence, this may represent one of the primary mechanisms whereby cannabinoids induce disruptions in attention, working memory, sensory-motor integration, and many other psychosis-related behavioral effects. PMID:26850792

  7. Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis

    OpenAIRE

    Fukuda, Shin; Kohsaka, Hitoshi; Takayasu, Aiko; Yokoyama, Waka; Miyabe, Chie; Miyabe, Yoshishige; Harigai, Masayoshi; Miyasaka, Nobuyuki; Nanki, Toshihiro

    2014-01-01

    Background Some of cannabinoids, which are chemical compounds contained in marijuana, are immunosuppressive. One of the receptors, CB receptor 1 (CB1), is expressed predominantly by the cells in the central nervous system, whereas CB receptor 2 (CB2) is expressed primarily by immune cells. Theoretically, selective CB2 agonists should be devoid of psychoactive effects. In this study, we investigated therapeutic effects of a selective CB2 agonist on arthritis. Methods The expression of CB2 was ...

  8. Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes

    OpenAIRE

    Manzanares, J.; Julian, MD; Carrascosa, A

    2006-01-01

    Cannabis extracts and synthetic cannabinoids are still widely considered illegal substances. Preclinical and clinical studies have suggested that they may result useful to treat diverse diseases, including those related with acute or chronic pain. The discovery of cannabinoid receptors, their endogenous ligands, and the machinery for the synthesis, transport, and degradation of these retrograde messengers, has equipped us with neurochemical tools for novel drug design. Agonist-activated canna...

  9. Activation of Cannabinoid CB2 receptors Reduces Hyperalgesia in an Experimental Autoimmune Encephalomyelitis Mouse Model of Multiple Sclerosis

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    Fu, Weisi; Taylor, Bradley K.

    2015-01-01

    Clinical trials investigating the analgesic efficacy of cannabinoids in multiple sclerosis have yielded mixed results, possibly due to psychotropic side effects mediated by cannabinoid CB1 receptors. We hypothesized that a CB2-specific agonist (JWH-133) would decrease hyperalgesia in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. 4 weeks after induction of experimental autoimmune encephalomyelitis, we found that intrathecal administration of JWH-133 (10–100 μg...

  10. Distribution of CB1 Cannabinoid Receptors and Their Relationship with Mu-Opioid Receptors in the Rat Periaqueductal Gray

    OpenAIRE

    Wilson-Poe, A R; Morgan, M.M.; Aicher, S.A.; Hegarty, D.M.

    2012-01-01

    The periaqueductal gray (PAG) is part of a descending pain modulatory system that, when activated, produces widespread and profound antinociception. Microinjection of either opioids or cannabinoids into the PAG elicits antinociception. Moreover, microinjection of the cannabinoid 1 (CB1) receptor agonist HU-210 into the PAG enhances the antinociceptive effect of subsequent morphine injections, indicating a direct relationship between these two systems. The objective of this study was to charac...

  11. Pharmacokinetics of Cannabinoids

    OpenAIRE

    McGilveray, Iain J

    2005-01-01

    Delta-9-tetrahydrocannabinol (Δ-9-THC) is the main psychoactive ingredient of cannabis (marijuana). The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC) and nabilone. The variability of THC in plant material (0.3% to 30%) leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability ...

  12. Beta-caryophyllene is a dietary cannabinoid

    Science.gov (United States)

    Gertsch, Jürg; Leonti, Marco; Raduner, Stefan; Racz, Ildiko; Chen, Jian-Zhong; Xie, Xiang-Qun; Altmann, Karl-Heinz; Karsak, Meliha; Zimmer, Andreas

    2008-01-01

    The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB1) and CB2 receptors. Although the CB1 receptor is responsible for the psychomodulatory effects, activation of the CB2 receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-β-caryophyllene [(E)-BCP] selectively binds to the CB2 receptor (Ki = 155 ± 4 nM) and that it is a functional CB2 agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the CB2 receptor, showing ligand π–π stacking interactions with residues F117 and W258. Upon binding to the CB2 receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB2 receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB2 receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis. PMID:18574142

  13. Cannabinoids in the management of difficult to treat pain.

    Science.gov (United States)

    Russo, Ethan B

    2008-02-01

    This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol((R))) and nabilone (Cesamet((R))) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex((R)), a cannabis derived oromucosal spray containing equal proportions of THC (partial CB(1) receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB(1) receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise. PMID:18728714

  14. G-protein coupling of cannabinoid receptors

    International Nuclear Information System (INIS)

    Full text: Since the cloning of the cannabinoid CB1 and CB2 receptors in the early 1990's extensive research has focused on understanding their signal transduction pathways. While it has been known for sometime that both receptors can couple to intracellular signalling via pertussis toxin sensitive G-proteins (Gi/Go), the specificity and kinetics of these interactions have only recently been elucidated. We have developed an in situ reconstitution approach to investigating receptor-G-protein interactions. This approach involves chaotropic extraction of receptor containing membranes in order to inactivate or remove endogenous G-proteins. Recombinant or isolated brain G-proteins can then be added back to the receptors, and their activation monitored through the binding of [35S]-GTPγS. This technique has been utilised for an extensive study of cannabinoid receptor mediated activation of G-proteins. In these studies we have established that CB1 couples with high affinity to both Gi and Go type G-proteins. In contrast, CB2 couples strongly to Gi, but has a very low affinity for Go. This finding correlated well with the previous findings that while CB1 and CB2 both couple to the inhibition of adenylate cyclase, CB1 but not CB2 could also inhibit calcium channels. We then examined the ability of a range of cannabinoid agonists to activate the Gi and Go via CB1. Conventional receptor theory suggests that a receptor is either active or inactive with regard to a G-protein and that the active receptor activates all relevant G-proteins equally. However, in this study we found that agonists could produce different degrees of activation, depending on which G-protein was present. Further studies have compared the ability of the two endocannabinoids to drive the activation of Gi or Go. These studies show that agonists can induce multiple forms of activated receptor that differ in their ability to catalyse the activation of Gi or Go. The ability of an agonist to drive a receptor

  15. Critical appraisal of the potential use of cannabinoids in cancer management

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    Cridge BJ

    2013-08-01

    Full Text Available Belinda J Cridge, Rhonda J Rosengren Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand Abstract: Cannabinoids have been attracting a great deal of interest as potential anticancer agents. Originally derived from the plant Cannabis sativa, there are now a number of endo-, phyto- and synthetic cannabinoids available. This review summarizes the key literature to date around the actions, antitumor activity, and mechanisms of action for this broad range of compounds. Cannabinoids are largely defined by an ability to activate the cannabinoid receptors – CB1 or CB2. The action of the cannabinoids is very dependent on the exact ligand tested, the dose, and the duration of exposure. Some cannabinoids, synthetic or plant-derived, show potential as therapeutic agents, and evidence across a range of cancers and evidence in vitro and in vivo is starting to be accumulated. Studies have now been conducted in a wide range of cell lines, including glioma, breast, prostate, endothelial, liver, and lung. This work is complemented by an increasing body of evidence from in vivo models. However, many of these results remain contradictory, an issue that is not currently able to be resolved through current knowledge of mechanisms of action. While there is a developing understanding of potential mechanisms of action, with the extracellular signal-regulated kinase pathway emerging as a critical signaling juncture in combination with an important role for ceramide and lipid signaling, the relative importance of each pathway is yet to be determined. The interplay between the intracellular pathways of autophagy versus apoptosis is a recent development that is discussed. Overall, there is still a great deal of conflicting evidence around the future utility of the cannabinoids, natural or synthetic, as therapeutic agents. Keywords: cancer, cannabinoid, endocannabinoid, tetrahydrocannabinol, JWH-133, WIN-55,212-2

  16. Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation.

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    Rom, Slava; Persidsky, Yuri

    2013-06-01

    An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB(1), CB(2)) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer's disease to name a few), mainly mediated by CB(2) activation. Development of CB(2) agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB(2) activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection. PMID:23471521

  17. Feeding induced by cannabinoids is mediated independently of the melanocortin system.

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    Puspha Sinnayah

    Full Text Available BACKGROUND: Cannabinoids, the active components of marijuana, stimulate appetite, and cannabinoid receptor-1 (CB1-R antagonists suppress appetite and promote weight loss. Little is known about how CB1-R antagonists affect the central neurocircuitry, specifically the melanocortin system that regulates energy balance. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that peripherally administered CB1-R antagonist (AM251 or agonist equally suppressed or stimulated feeding respectively in A(y , which lack a functional melanocortin system, and wildtype mice, demonstrating that cannabinoid effects on feeding do not require melanocortin circuitry. CB1-R antagonist or agonist administered into the ventral tegmental area (VTA equally suppressed or stimulated feeding respectively, in both genotypes. In addition, peripheral and central cannabinoid administration similarly induced c-Fos activation in brain sites suggesting mediation via motivational dopaminergic circuitry. Amperometry-detected increases in evoked dopamine (DA release by the CB1-R antagonist in nucleus accumbens slices indicates that AM251 modulates DA release from VTA terminals. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that the effects of cannabinoids on energy balance are independent of hypothalamic melanocortin circuitry and is primarily driven by the reward system.

  18. Peripheral cannabinoid receptor, CB2, regulates bone mass

    Science.gov (United States)

    Ofek, Orr; Karsak, Meliha; Leclerc, Nathalie; Fogel, Meirav; Frenkel, Baruch; Wright, Karen; Tam, Joseph; Attar-Namdar, Malka; Kram, Vardit; Shohami, Esther; Mechoulam, Raphael; Zimmer, Andreas; Bab, Itai

    2006-01-01

    The endogenous cannabinoids bind to and activate two G protein-coupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB2–/– phenotype is also characterized by increased activity of trabecular osteoblasts (bone-forming cells), increased osteoclast (the bone-resorbing cell) number, and a markedly decreased number of diaphyseal osteoblast precursors. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist that does not have any psychotropic effects enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis, apparently by inhibiting proliferation of osteoclast precursors and receptor activator of NF-κB ligand expression in bone marrow-derived osteoblasts/stromal cells. The same agonist attenuates ovariectomy-induced bone loss and markedly stimulates cortical thickness through the respective suppression of osteoclast number and stimulation of endocortical bone formation. These results demonstrate that the endocannabinoid system is essential for the maintenance of normal bone mass by osteoblastic and osteoclastic CB2 signaling. Hence, CB2 offers a molecular target for the diagnosis and treatment of osteoporosis, the most prevalent degenerative disease in developed countries. PMID:16407142

  19. MicroRNA let-7d is a target of cannabinoid CB1 receptor and controls cannabinoid signaling.

    Science.gov (United States)

    Chiarlone, Anna; Börner, Christine; Martín-Gómez, Laura; Jiménez-González, Ada; García-Concejo, Adrián; García-Bermejo, María L; Lorente, Mar; Blázquez, Cristina; García-Taboada, Elena; de Haro, Amador; Martella, Elisa; Höllt, Volker; Rodríguez, Raquel; Galve-Roperh, Ismael; Kraus, Jürgen; Guzmán, Manuel

    2016-09-01

    Cannabinoid CB1 receptor, the molecular target of endocannabinoids and cannabis active components, is one of the most abundant metabotropic receptors in the brain. Cannabis is widely used for both recreational and medicinal purposes. Despite the ever-growing fundamental roles of microRNAs in the brain, the possible molecular connections between the CB1 receptor and microRNAs are surprisingly unknown. Here, by using reporter gene constructs that express interaction sequences for microRNAs in human SH-SY5Y neuroblastoma cells, we show that CB1 receptor activation enhances the expression of several microRNAs, including let-7d. This was confirmed by measuring hsa-let-7d expression levels. Accordingly, knocking-down CB1 receptor in zebrafish reduced dre-let-7d levels, and knocking-out CB1 receptor in mice decreased mmu-let-7d levels in the cortex, striatum and hippocampus. Conversely, knocking-down let-7d increased CB1 receptor mRNA expression in zebrafish, SH-SY5Y cells and primary striatal neurons. Likewise, in primary striatal neurons chronically exposed to a cannabinoid or opioid agonist, a let-7d-inhibiting sequence facilitated not only cannabinoid or opioid signaling but also cannabinoid/opioid cross-signaling. Taken together, these findings provide the first evidence for a bidirectional link between the CB1 receptor and a microRNA, namely let-7d, and thus unveil a new player in the complex process of cannabinoid action. PMID:27179908

  20. Cannabinoid-Induced Hyperemesis: A Conundrum—From Clinical Recognition to Basic Science Mechanisms

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    Nissar A. Darmani

    2010-07-01

    Full Text Available Cannabinoids are used clinically on a subacute basis as prophylactic agonist antiemetics for the prevention of nausea and vomiting caused by chemotherapeutics. Cannabinoids prevent vomiting by inhibition of release of emetic neurotransmitters via stimulation of presynaptic cannabinoid CB1 receptors. Cannabis-induced hyperemesis is a recently recognized syndrome associated with chronic cannabis use. It is characterized by repeated cyclical vomiting and learned compulsive hot water bathing behavior. Although considered rare, recent international publications of numerous case reports suggest the contrary. The syndrome appears to be a paradox and the pathophysiological mechanism(s underlying the induced vomiting remains unknown. Although some traditional hypotheses have already been proposed, the present review critically explores the basic science of these explanations in the clinical setting and provides more current mechanisms for the induced hyperemesis. These encompass: (1 pharmacokinetic factors such as long half-life, chronic exposure, lipid solubility, individual variation in metabolism/excretion leading to accumulation of emetogenic cannabinoid metabolites, and/or cannabinoid withdrawal; and (2 pharmacodynamic factors including switching of the efficacy of Δ9-THC from partial agonist to antagonist, differential interaction of Δ9-THC with Gs and Gi signal transduction proteins, CB1 receptor desensitization or downregulation, alterations in tissue concentrations of endocannabinoid agonists/inverse agonists, Δ9-THC-induced mobilization of emetogenic metabolites of the arachidonic acid cascade, brainstem versus enteric actions of Δ9-THC, and/or hypothermic versus hyperthermic actions of Δ9-THC. In addition, human and animal findings suggest that chronic exposure to cannabis may not be a prerequisite for the induction of vomiting but is required for the intensity of emesis.

  1. Cannabinoid receptor localization in brain

    Energy Technology Data Exchange (ETDEWEB)

    Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. (National Institute of Mental Health, Bethesda, MD (USA))

    1990-03-01

    (3H)CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of (3H)CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

  2. [Palliative pain therapy, cannabinoids].

    Science.gov (United States)

    Radbruch, L; Elsner, F

    2005-10-01

    Cancer pain treatment should follow the recommendations of the World Health Organisation. Treatment should be with oral application, regular application times and following the analgesic step-ladder. Non-opioids such as dipyrone or non-steroids are used for slight to moderate pain, step-2 opioids such as tramadol or tilidine/naloxone for moderate pain and step-3 opioids such as morphine, oxycodone or hydromorphone for severe pain. Transdermal application of fentanyl or buprenorphine offer a non-invasive parenteral alternative for patients with stable pain syndromes. Cannabinoids such as tetrahydrocannabinol offer a valuable add-on option for cancer patients with refractory pain, spasticity, nausea or appetite loss. PMID:15965665

  3. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice

    Directory of Open Access Journals (Sweden)

    Martín-Moreno Ana María

    2012-01-01

    Full Text Available Abstract Background Alzheimer's disease (AD brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential. Methods We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose (18FDG uptake by positron emission tomography (PET. Results Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro. Conclusions In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

  4. CB1 cannabinoid receptor stimulation modulates transient receptor potential vanilloid receptor 1 activities in calcium influx and substande P release in cultured rat dorsal root ganglion cells

    OpenAIRE

    Ohshita, Kyoko

    2005-01-01

    Cannabinoids have been reported to have analgesic properties in animals of acute nociception or of inflammatory and neuropathic pain models, but the mechanisms by which they exert such alleviative effects are not yet fully understood. We investigated whether the CB1- cannabinoid-receptor agonist HU210 modulates the capsaicin-induced 45Ca2+ influx and substance P like-immunoreactivity (SPLI) release in cultured rat dorsal root ganglion (DRG) cells. HU210 attenuated the capsaicin-induced 45Ca2+...

  5. Continuous improvement: A win... win process

    International Nuclear Information System (INIS)

    Implementing a continuous improvement (CI) process within PanCanadian's oil and gas production operations might have been a simple assignment if one were not also trying to capture the hearts and imaginations of the people in a changing work environment. Meeting the challenge is resulting in big payoffs to both the organization and its people. The plan used within the Company's Production Division to successfully introduce the CI process is discussed. A brief insight is provided on the process philosophy, with emphasis placed on planning, training and coaching used to launch the process. Also reviewed at length are the impediments to change and the challenges faced when changing an organization's culture. In a CI work environment, the supervisor's traditional role changes from one of monitoring and controlling to one of inspiring, motivating and leading people by communicating a clear vision. Employees at all levels in the work environment are organized into teams and armed with a good working knowledge of the problem solving tools which allow them to pursue and implement improvement initiatives. The outcome of the process is an ongoing 'win-win' situation for both the Company and its people. Employees are gaining more trust, eliminating job irritants and enjoying their work more in a team environment. The Company is winning through increased production, improved safety and reduced operating expenses, thanks to many innovative ideas which the employees have implemented. 4 refs

  6. Constitutive cannabinoid 1 and mu opioid receptor activity in the ventral tegmental area: occurrence, function and therapeutic relevance

    NARCIS (Netherlands)

    Meye, F.J.

    2012-01-01

    Cannabinoid 1 receptors (CB1Rs) play a crucial role in regulating systems dedicated to processing rewards and emotions. It was known that in artificial systems, CB1Rs can exhibit activity that is independent of the typical agonist-driven form. However, it remained largely unclear whether this consti

  7. Plant cannabinoids: a neglected pharmacological treasure trove

    OpenAIRE

    Mechoulam, Raphael

    2005-01-01

    Most of the cannabinoids in Cannabis sativa L. have not been fully evaluated for their pharmacological activity. A publication in this issue presents evidence that a plant cannabinoid, Δ9-tetrahydrocannabivarin is a potent antagonist of anandamide, a major endogenous cannabinoid. It seems possible that many of the non-psychoactive constituents of this plant will be of biological interest.

  8. Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition

    Directory of Open Access Journals (Sweden)

    Flores Juana M

    2010-07-01

    Full Text Available Abstract Background ErbB2-positive breast cancer is characterized by highly aggressive phenotypes and reduced responsiveness to standard therapies. Although specific ErbB2-targeted therapies have been designed, only a small percentage of patients respond to these treatments and most of them eventually relapse. The existence of this population of particularly aggressive and non-responding or relapsing patients urges the search for novel therapies. The purpose of this study was to determine whether cannabinoids might constitute a new therapeutic tool for the treatment of ErbB2-positive breast tumors. We analyzed their antitumor potential in a well established and clinically relevant model of ErbB2-driven metastatic breast cancer: the MMTV-neu mouse. We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors. Results Our results show that both Δ9-tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH-133, a non-psychotropic CB2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu mice. Histological analyses of the tumors revealed that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis. Cannabinoid antitumoral action relies, at least partially, on the inhibition of the pro-tumorigenic Akt pathway. We also found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB2. Conclusions Taken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.

  9. Successful Undergraduate Research: Creating Win-Win-Win

    Science.gov (United States)

    Guswa, A. J.; Rhodes, A. L.

    2003-12-01

    Undergraduate involvement in research has the potential to advance science, enhance education, strengthen the research community, and raise general awareness of the importance and impact of scientific understanding. Rather than being competing objectives, these goals are synergistic. Effective research experiences are those that create win-win-win situations: benefits to the student, benefits to the project, and benefits to the scientific community. When structured appropriately, undergraduate research fits into a learner-centered paradigm that puts emphasis on student learning, rather than instructor teaching. Under such a paradigm the student and professor learn together, constructing knowledge by integrating information with critical-thinking and problem-solving skills, and use this knowledge to address issues in real-life contexts. Creating such a learning environment requires that the professor be vested in the outcome of the research, that the student take a meta-cognitive approach to the project and work at a level appropriate to her abilities, and that the student understand how her contribution fits into the project and the larger field. All of these factors lead to greater independence, confidence, and productivity on the part of the student. By providing undergraduates with these experiences, we introduce not only future scientists but also non-scientists to the excitement of discovery and the value of scientific research. Currently, we involve undergraduates in our research on the hydrology and geochemistry of a tropical montane cloud forest in Monteverde, Costa Rica. At the start of each student's involvement, we provide her with the big picture: our project goals, the relevant social issues, and the importance of watershed research. Each student then articulates her own educational and project objectives. Together, we choose tasks that match her skills and interests with our scholarly work. Specific activities range from literature review to

  10. Intraperirhinal cortex administration of the synthetic cannabinoid, HU210, disrupts object recognition memory in rats.

    Science.gov (United States)

    Sticht, Martin A; Jacklin, Derek L; Mechoulam, Raphael; Parker, Linda A; Winters, Boyer D

    2015-03-25

    Cannabinoids disrupt learning and memory in human and nonhuman participants. Object recognition memory, which is particularly susceptible to the impairing effects of cannabinoids, relies critically on the perirhinal cortex (PRh); however, to date, the effects of cannabinoids within PRh have not been assessed. In the present study, we evaluated the effects of localized administration of the synthetic cannabinoid, HU210 (0.01, 1.0 μg/hemisphere), into PRh on spontaneous object recognition in Long-Evans rats. Animals received intra-PRh infusions of HU210 before the sample phase, and object recognition memory was assessed at various delays in a subsequent retention test. We found that presample intra-PRh HU210 dose dependently (1.0 μg but not 0.01 μg) interfered with spontaneous object recognition performance, exerting an apparently more pronounced effect when memory demands were increased. These novel findings show that cannabinoid agonists in PRh disrupt object recognition memory. PMID:25714419

  11. Cannabinoid receptor activation reverses kainate-induced synchronized population burst firing in rat hippocampus

    Directory of Open Access Journals (Sweden)

    Rob Mason

    2009-06-01

    Full Text Available Cannabinoids have been shown to possess anticonvulsant properties in whole animal models of epilepsy. The present investigation sought to examine the effects of cannabinoid receptor activation on kainic acid (KA-induced epileptiform neuronal excitability. Under urethane anesthesia, acute KA treatment (10 mg/kg, i.p. entrained the spiking mode of simultaneously recorded neurons from random firing to synchronous bursting (% change in burst rate. Injection of the high-affinity cannabinoid agonist (--11-hydroxy-8-tetrahydrocannabinol-dimethyl-heptyl (HU210, 100 µg/kg, i.p. following KA markedly reduced the burst frequency (% decrease in burst frequency and reversed synchronized firing patterns back to baseline levels. Pre-treatment with the central cannabinoid receptor (CB1 antagonist N-piperidino-5-(4-clorophenyl-1-(2,4-dichlorophenyl-4-methyl-3-pyrazole-carboxamide (rimonabant, SR141716A 3 mg/kg, i.p. completely prevented the actions of HU210. The present results indicate that cannabinoids exert their antiepileptic effects by impeding pathological synchronization of neuronal networks in the hippocampus.

  12. Cannabinoid receptor activation reverses kainate-induced synchronized population burst firing in rat hippocampus.

    Science.gov (United States)

    Mason, Rob; Cheer, Joseph F

    2009-01-01

    Cannabinoids have been shown to possess anticonvulsant properties in whole animal models of epilepsy. The present investigation sought to examine the effects of cannabinoid receptor activation on kainic acid (KA)-induced epileptiform neuronal excitability. Under urethane anesthesia, acute KA treatment (10 mg kg(-1), i.p.) entrained the spiking mode of simultaneously recorded neurons from random firing to synchronous bursting (% change in burst rate). Injection of the high-affinity cannabinoid agonist (-)-11-hydroxy-8-tetrahydrocannabinol-dimethyl-heptyl (HU210, 100 mug kg(-1), i.p.) following KA markedly reduced the burst frequency (% decrease in burst frequency) and reversed synchronized firing patterns back to baseline levels. Pre-treatment with the central cannabinoid receptor (CB1) antagonist N-piperidino-5-(4-clorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant, SR141716A 3 mg kg(-1), i.p.) completely prevented the actions of HU210. The present results indicate that cannabinoids exert their antiepileptic effects by impeding pathological synchronization of neuronal networks in the hippocampus. PMID:19562087

  13. Cannabinoid modulation of neuroinflammatory disorders.

    Science.gov (United States)

    Saito, Viviane M; Rezende, Rafael M; Teixeira, Antonio L

    2012-06-01

    In recent years, a growing interest has been dedicated to the study of the endocannabinoid system. The isolation of Cannabis sativa main psychotropic compound, Δ(9)-tetrahydrocannabinol (THC), has led to the discovery of an atypical neurotransmission system that modulates the release of other neurotransmitters and participates in many biological processes, including the cascade of inflammatory responses. In this context, cannabinoids have been studied for their possible therapeutic properties in neuroinflammatory diseases. In this review, historic and biochemical aspects of cannabinoids are discussed, as well as their function as modulators of inflammatory processes and therapeutic perspectives for neurodegenerative disorders, particularly, multiple sclerosis. PMID:23204985

  14. Continuous improvement: A win-win process

    International Nuclear Information System (INIS)

    The strategies used within PanCanadian Petroleum Limited's production division to successfully introduce the continuous improvement (CI) process are discussed. Continuous improvement is an operating philosophy and management style which allows all employees to participate in and improve the way an organization performs its day-to-day business. In the CI work environment the supervisor's traditional role changes from one of monitoring and controlling, to one of inspiring, motivating and leading people by communicating a clear vision. Employees at all levels in the work environment are organized into teams and armed with a good working knowledge of the problem-solving tools which allow them to pursue and implement improvement initiatives. The outcome of the process is an ongoing win-win situation for both PanCanadian and its people. Employees are gaining more trust, eliminating job irritants, and enjoying their work in a team environment. The company is benefiting through increased production, improved safety and reduced operating expenses, thanks to the many innovative ideas introduced by employees. 4 refs

  15. A novel control of human keratin expression: cannabinoid receptor 1-mediated signaling down-regulates the expression of keratins K6 and K16 in human keratinocytes in vitro and in situ

    Directory of Open Access Journals (Sweden)

    Yuval Ramot

    2013-02-01

    Full Text Available Cannabinoid receptors (CB are expressed throughout human skin epithelium. CB1 activation inhibits human hair growth and decreases proliferation of epidermal keratinocytes. Since psoriasis is a chronic hyperproliferative, inflammatory skin disease, it is conceivable that the therapeutic modulation of CB signaling, which can inhibit both proliferation and inflammation, could win a place in future psoriasis management. Given that psoriasis is characterized by up-regulation of keratins K6 and K16, we have investigated whether CB1 stimulation modulates their expression in human epidermis. Treatment of organ-cultured human skin with the CB1-specific agonist, arachidonoyl-chloro-ethanolamide (ACEA, decreased K6 and K16 staining intensity in situ. At the gene and protein levels, ACEA also decreased K6 expression of cultured HaCaT keratinocytes, which show some similarities to psoriatic keratinocytes. These effects were partly antagonized by the CB1-specific antagonist, AM251. While CB1-mediated signaling also significantly inhibited human epidermal keratinocyte proliferation in situ, as shown by K6/Ki-67-double immunofluorescence, the inhibitory effect of ACEA on K6 expression in situ was independent of its anti-proliferative effect. Given recent appreciation of the role of K6 as a functionally important protein that regulates epithelial wound healing in mice, it is conceivable that the novel CB1-mediated regulation of keratin 6/16 revealed here also is relevant to wound healing. Taken together, our results suggest that cannabinoids and their receptors constitute a novel, clinically relevant control element of human K6 and K16 expression.

  16. The effect of cannabinoids on dinitrofluorobenzene-induced experimental asthma in mice.

    Science.gov (United States)

    Bozkurt, Turgut Emrah; Kaya, Yesim; Durlu-Kandilci, Nezahat Tugba; Onder, Sevgen; Sahin-Erdemli, Inci

    2016-09-01

    Cannabinoids have anti-inflammatory effects and can produce bronchodilation in the airways. We have investigated the effects of cannabinoids on tracheal hyperreactivity and airway inflammation in dinitrofluorobenzene (DNFB)-induced experimental non-atopic asthma in mice. 5-hydroxytryptamine (5-HT)-induced contraction response was enhanced while carbachol- and electrical field stimulation-induced contractions, and isoprenaline-induced relaxation responses were remained unchanged in DNFB group. The increased 5-HT-induced contractions were inhibited by incubation with either atropine or tetrodotoxin. DNFB application resulted in increased macrophage number in the bronchoalveolar lavage fluid (BALF). In vivo ACEA (CB1 agonist) treatment prevented the increase in 5-HT contractions, while JWH133 (CB2 agonist) had no effect. However, neither ACEA nor JWH133 prevented the increase in macrophage number in BALF. In vitro ACEA incubation also inhibited the increase in 5-HT contraction in DNFB group. These results show that cannabinoid CB1 receptor agonist can prevent tracheal hyperreactivity to 5-HT in DNFB-induced non-atopic asthma in mice. PMID:27216000

  17. Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease.

    Science.gov (United States)

    O'Sullivan, S E; Kendall, D A

    2010-08-01

    Cannabinoids act via cell surface G protein-coupled receptors (CB(1) and CB(2)) and the ion channel receptor TRPV1. Evidence has now emerged suggesting that an additional target is the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors. There are three PPAR subtypes alpha, delta (also known as beta) and gamma, which regulate cell differentiation, metabolism and immune function. The major endocannabinoids, anandamide and 2-arachidonoylglycerol, and ajulemic acid, a structural analogue of the phytocannabinoid Delta(9)-tetrahydrocannabinol (THC), have anti-inflammatory properties mediated by PPARgamma. Other cannabinoids which activate PPARgamma include N-arachidonoyl-dopamine, THC, cannabidiol, HU210, WIN55212-2 and CP55940. The endogenous acylethanolamines, oleoylethanolamide and palmitoylethanolamide regulate feeding and body weight, stimulate fat utilization and have neuroprotective effects mediated through PPARalpha. Other endocannabinoids that activate PPARalpha include anandamide, virodhamine and noladin ether. There is, as yet, little direct evidence for interactions of cannabinoids with PPARdelta. There is a convergence of effects of cannabinoids, acting via cell surface and nuclear receptors, on immune cell function which provides promise for the targeted therapy of a variety of immune, particularly neuroinflammatory, diseases. PMID:19833407

  18. Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.

    Science.gov (United States)

    Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu; Secci, Maria E; Redhi, Godfrey H; Panlilio, Leigh V; Scherma, Maria; Barnes, Chanel; Parashos, Alexandra; Zara, Tamara; Fratta, Walter; Solinas, Marcello; Pistis, Marco; Bergman, Jack; Kangas, Brian D; Ferré, Sergi; Tanda, Gianluigi; Schwarcz, Robert; Goldberg, Steven R

    2013-11-01

    In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse. PMID:24121737

  19. Involvement of cannabinoid-1 and cannabinoid-2 receptors in septic ileus.

    Science.gov (United States)

    Li, Y-Y; Li, Y-N; Ni, J-B; Chen, C-J; Lv, S; Chai, S-Y; Wu, R-H; Yüce, B; Storr, M

    2010-03-01

    BACKGROUND Cannabinoid (CB) receptors are involved in the regulation of gastrointestinal (GI) motility under physiological and pathophysiological conditions. We aimed to characterize the possible influence of CB(1) and CB(2) receptors on motility impairment in a model of septic ileus. METHODS Lipopolysaccharide (LPS) injections were used to mimic pathophysiological features of septic ileus. Spontaneous jejunal myoelectrical activity was measured in rats in vivo, and upper GI transit was measured in vivo by gavaging of a charcoal marker into the stomach of mice, in absence or presence of LPS, and CB(1) and CB(2) receptor agonists and antagonists. Tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 levels were measured using enzyme-linked immunosorbent assay. Histology was performed with haematoxylin-eosin staining. KEY RESULTS Lipopolysaccharide treatment significantly reduced amplitude and frequency of myoelectric spiking activity and GI transit in vivo in a dose-dependent manner. TNF-alpha and IL-6 were increased in LPS-treated animals and histology showed oedema and cell infiltration. Both, the CB(1) agonist HU210 and the CB(2) agonist JWH133 reduced myoelectrical activity whereas the CB(1) antagonist AM251 caused an increase of myoelectrical activity. Pretreatment with AM251 or AM630 prevented against LPS-induced reduction of myoelectrical activity, and also against the delay of GI transit during septic ileus in vivo. CONCLUSIONS & INFERENCES The LPS model of septic ileus impairs jejunal myoelectrical activity and delays GI transit in vivo. Antagonists at the CB(1) receptor or the CB(2) receptor prevent the delay of GI transit and thus may be powerful tools in the future treatment of septic ileus. PMID:19840270

  20. Basolateral amygdala CB1 cannabinoid receptors are involved in cross state-dependent memory retrieval between morphine and ethanol.

    Science.gov (United States)

    Ofogh, Sattar Norouzi; Rezayof, Ameneh; Sardari, Maryam; Ghasemzadeh, Zahra

    2016-09-01

    Ethanol and morphine are largely co-abused and affect memory formation. The present study intended to investigate the involvement of cannabinoid CB1 receptors of the basolateral amygdala (BLA) in cross state-dependent memory retrieval between morphine and ethanol. Adult male Wistar rats received bilateral cannulation of the BLA, and memory retrieval was measured in step-through type passive avoidance apparatus. Our results showed that post-training intraperitoneal (i.p.) administration of morphine (6mg/kg) induced amnesia. Pre-test administration of ethanol (0.5g/kg, i.p.) significantly improved morphine-induced memory impairment, suggesting that there is cross state-dependent memory retrieval between morphine and ethanol. It should be considered that pre-test administration of ethanol (0.1 and 0.5g/kg, i.p.) by itself had no effect on memory retrieval in the passive avoidance task. Interestingly, pre-test intra-BLA microinjection of different doses of WIN55,212-2 (0.1, 0.2 and 0.3μg/rat), a non-selective CB1/CB2 receptor agonist, plus an ineffective dose of ethanol (0.1g/kg, i.p.) improved morphine-induced memory impairment. Intra-BLA microinjection of AM251 (0.4-0.6ng/rat), a selective CB1 receptor antagonist, inhibited the improved effect of ethanol (0.5g/kg, i.p.) on morphine response. Pre-test intra-BLA microinjection of WIN55,212-2 or AM251 had no effect on memory retrieval or morphine-induced amnesia. Taken together, it can be concluded that morphine and ethanol can induce state-dependent memory retrieval. In addition, the BLA endocannabinoid system mediates via CB1 receptors the functional interaction of morphine and ethanol state-dependent memory retrieval which may depend on the rewarding effects of the drugs. PMID:27327764

  1. HU210-induced downregulation in cannabinoid CB1 receptor binding strongly correlates with body weight loss in the adult rat.

    Science.gov (United States)

    Dalton, Victoria S; Wang, Hongqin; Zavitsanou, Katerina

    2009-07-01

    In vitro autoradiography was used to examine changes in cannabinoid CB1 receptors (targeted with [(3)H] CP55,940) in rats treated with the potent cannabinoid agonist HU210. Animals were administered with HU210 (25, 50, 100 microg/kg) for 4 or 14 days or received a single 100 microg/kg injection of HU210 and sacrificed 24 h later. The acute dose resulted in a decrease in binding in the caudate putamen and hippocampus. A dose dependent, region-specific reduction (P HU210. PMID:19169813

  2. Cannabinoids: novel medicines for the treatment of Huntington's disease.

    Science.gov (United States)

    Sagredo, Onintza; Pazos, M Ruth; Valdeolivas, Sara; Fernandez-Ruiz, Javier

    2012-04-01

    Cannabinoid pharmacology has experienced a notable increase in the last 3 decades which is allowing the development of novel cannabinoid-based medicines for the treatment of different human pathologies, for example, Cesamet® (nabilone) or Marinol® (synthetic Δ9-tetrahydrocannabinol for oral administration) that were approved in 80s for the treatment of nausea and vomiting associated with chemotherapy treatment in cancer patients and in 90s for anorexiacachexia associated with AIDS therapy. Recently, the british company GW Pharmaceuticals plc has developed an oromucosal spray called Sativex®, which is constituted by an equimolecular combination of Δ9-tetrahydrocannabinol- and cannabidiol- enriched botanical extracts. Sativex® has been approved for the treatment of specific symptoms (i.e. spasticity and pain) of multiple sclerosis patients in various countries (i.e. Canada, UK, Spain, New Zealand). However, this cannabis- based medicine has been also proposed to be useful in other neurological disorders given the analgesic, antitumoral, anti-inflammatory, and neuroprotective properties of their components demonstrated in preclinical models. Numerous clinical trials are presently being conducted to confirm this potential in patients. We are particularly interested in the case of Huntington's disease (HD), an autosomal-dominant inherited disorder caused by an excess of CAG repeats in the genomic allele resulting in a polyQ expansion in the encoded protein called huntingtin, and that affects primarily striatal and cortical neurons thus producing motor abnormalities (i.e. chorea) and dementia. Cannabinoids have been studied for alleviation of hyperkinetic symptoms, given their inhibitory effects on movement, and, in particular, as disease-modifying agents due to their anti-inflammatory, neuroprotective and neuroregenerative properties. This potential has been corroborated in different experimental models of HD and using different types of cannabinoid agonists

  3. An update on PPAR activation by cannabinoids.

    Science.gov (United States)

    O'Sullivan, Saoirse Elizabeth

    2016-06-01

    Some cannabinoids activate the different isoforms of PPARs (α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies. Activation of all isoforms, but primarily PPARα and γ, mediates some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumour, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel. PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins. The aims of this review are to update the evidence supporting PPAR activation by cannabinoids and to review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation. PMID:27077495

  4. Acute Immobilization Stress Modulate GABA Release from Rat Olfactory Bulb: Involvement of Endocannabinoids—Cannabinoids and Acute Stress Modulate GABA Release

    OpenAIRE

    Alejandra Delgado; Erica H. Jaffé

    2011-01-01

    We studied the effects of cannabinoids and acute immobilization stress on the regulation of GABA release in the olfactory bulb. Glutamate-stimulated 3H-GABA release was measured in superfused slices. We report that cannabinoids as WIN55, 212-2, methanandamide, and 2-arachidonoylglycerol were able to inhibit glutamate- and KCl-stimulated 3H-GABA release. This effect was blocked by the CB1 antagonist AM281. On the other hand, acute stress was able per se to increase endocannabinoid activity. Th...

  5. Participaci??n del sistema cannabinoide end??geno en los fen??menos de adicci??n. Interacci??n con otros sistemas de neurotransmisi??n

    OpenAIRE

    Casta???? Forn, Anna

    2005-01-01

    Con la finalidad de explorar con profundidad las bases neurobiol??gicas de la adicci??n a cannabinoides hemos llevado a cabo diferentes estudios farmacol??gicos y moleculares. El sustrato neuroanat??mico de la dependencia f??sica de cannabinoides ha sido investigado en ratones que recibieron un tratamiento cr??nico con el agonista WIN55,212-2. En este estudio, se observ?? que el cerebelo y en menor grado el hipocampo y la am??gdala, participan en la manifestaci??n comportamental del s??ndrome...

  6. Cannabinoids Occlude the HIV-1 Tat-Induced Decrease in GABAergic Neurotransmission in Prefrontal Cortex Slices.

    Science.gov (United States)

    Xu, Changqing; Hermes, Douglas J; Mackie, Ken; Lichtman, Aron H; Ignatowska-Jankowska, Bogna M; Fitting, Sylvia

    2016-06-01

    In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is now considered a chronic disease that specifically targets the brain and causes HIV-1-associated neurocognitive disorders (HAND). Endocannabinoids exhibit neuroprotective and anti-inflammatory properties in several central nervous system (CNS) disease models, but their effects in HAND are poorly understood. To address this issue, whole-cell recordings were performed on young (14-24 day old) C57BL/6J mice. We investigated the actions of the synthetic cannabinoid WIN55,212-2 (1 μM) and the endocannabinoid N-arachidonoyl ethanolamine (anandamide; AEA, 1 μM) in the presence of HIV-1 Tat on GABAergic neurotransmission in mouse prefrontal cortex (PFC) slices. We found a Tat concentration-dependent (5-50 nM) decrease in the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). The cannabinoid 1 receptor (CB1R) antagonist rimonabant (1 μM) and zero extracellular calcium prevented the significant Tat-induced decrease in mIPSCs. Further, bath-applied WIN55,212-2 or AEA by itself, significantly decreased the frequency, but not amplitude of mIPSCs and/or spontaneous IPSCs (sIPSCs), and occluded a further downregulation of IPSCs by Tat. Pretreatment with rimonabant but not the CB2R antagonist AM630 (1 μM) prevented the WIN55,212-2- and AEA-induced decrease in IPSCs frequency without any further Tat effect. Results indicated a Tat-induced decrease in GABAergic neurotransmission, which was occluded by cannabinoids via a CB1R-related mechanism. Understanding the relationship between Tat toxicity and endocannabinoid signaling has the potential to identify novel therapeutic interventions to benefit individuals suffering from HAND and other cognitive impairments. PMID:26993829

  7. The role of cannabinoids in adult neurogenesis.

    Science.gov (United States)

    Prenderville, Jack A; Kelly, Áine M; Downer, Eric J

    2015-08-01

    The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, probably through activation of both CB1 and CB2 receptors. In recent years, a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarizes the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall, these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain. PMID:25951750

  8. Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions.

    Science.gov (United States)

    Mendizábal, V E; Adler-Graschinsky, E

    2007-06-01

    In addition to their classical known effects, such as analgesia, impairment of cognition and learning and appetite enhancement, cannabinoids have also been related to the regulation of cardiovascular responses and implicated in cardiovascular pathology. Elevated levels of endocannabinoids have been related to the extreme hypotension associated with various forms of shock as well as to the cardiovascular abnormalities that accompany cirrhosis. In contrast, cannabinoids have also been associated with beneficial effects on the cardiovascular system, such as a protective role in atherosclerosis progression and in cerebral and myocardial ischaemia. In addition, it has also been suggested that the pharmacological manipulation of the endocannabinoid system may offer a novel approach to antihypertensive therapy. During the last decades, the tremendous increase in the understanding of the molecular basis of cannabinoid activity has encouraged many pharmaceutical companies to develop more potent synthetic cannabinoid analogues and antagonists, leading to an explosion of basic research and clinical trials. Consequently. not only the synthetic THC dronabinol (Marinol) and the synthetic THC analogue nabilone (Cesamet) have been approved in the United States, but also the standardized cannabis extract (Sativex) in Canada. At least three strategies can be foreseen in the future clinical use of cannabinoid-based drugs: (a) the use of CB(1) receptor antagonists, such as the recently approved rimonabant (b) the use of CB(2)-selective agonists, and (c) the use of inhibitors of endocannabinoid degradation. In this context, the present review examines the effects of cannabinoids and of the pharmacological manipulation of the endocannabinoid system, in cardiovascular pathophysiology. PMID:17450170

  9. Winning hearts and minds

    International Nuclear Information System (INIS)

    'The greatest problem in communication is the illusion that it has been accomplished' (George Bernard Shaw). Over the past few decades we have seen major shifts in opinion as to what makes a business successful. The 1950's and 1960's saw a production focus whilst the 1970's and 1980's saw progressive change towards quality and 'customer is king' as key business drivers. A popular view now suggests that the next step change will be towards internal marketing, based on the concept that, in the future, winning employee support will be seen as the single biggest contributor to driving business performances. In summary, to win hearts and minds you must understand the needs of your audience, the intent of your communication activity, adopt a suitable style and match your deeds to your words

  10. Cannabinoid Modulation of Neuroinflammatory Disorders

    OpenAIRE

    Saito, Viviane M; Rezende, Rafael M; Teixeira, Antonio L.

    2012-01-01

    In recent years, a growing interest has been dedicated to the study of the endocannabinoid system. The isolation of Cannabis sativa main psychotropic compound, Δ9-tetrahydrocannabinol (THC), has led to the discovery of an atypical neurotransmission system that modulates the release of other neurotransmitters and participates in many biological processes, including the cascade of inflammatory responses. In this context, cannabinoids have been studied for their possible therapeutic properties i...

  11. Therapeutic potential of cannabinoid medicines.

    Science.gov (United States)

    Robson, P J

    2014-01-01

    Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines. The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology. In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders. PMID:24006213

  12. Pharmacokinetics and pharmacodynamics of cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo

    2003-01-01

    Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial

  13. Detecting constitutive activity and protean agonism at cannabinoid-2 receptor.

    Science.gov (United States)

    Beltramo, Massimiliano; Brusa, Rossella; Mancini, Isabella; Scandroglio, Paola

    2010-01-01

    Since the cannabinoid system is involved in regulating several physiological functions such as locomotor activity, cognition, nociception, food intake, and inflammatory reaction, it has been the subject of intense study. Research on the pharmacology of this system has enormously progressed in the last 20years. One intriguing aspect that emerged from this research is that cannabinoid receptors (CBs) express a high level of constitutive activity. Investigation on this particular aspect of receptor pharmacology has largely focused on CB1, the CB subtype highly expressed in several brain regions. More recently, research on constitutive activity on the other CB subtype, CB2, was stimulated by the increasing interest on its potential as target for the treatment of various pathologies (e.g., pain and inflammation). There are several possible implications of constitutive activity on the therapeutic action of both agonists and antagonists, and consequently, it is important to have valuable methods to study this aspect of CB2 pharmacology. In the present chapter, we describe three methods to study constitutive activity at CB2: two classical methods relying on the detection of changes in cAMP level and GTPγS binding and a new one based on cell impedance measurement. In addition, we also included a section on detection of protean agonism, which is an interesting pharmacological phenomenon strictly linked to constitutive activity. PMID:21036225

  14. Identification of essential cannabinoid-binding domains: structural insights into early dynamic events in receptor activation.

    Science.gov (United States)

    Shim, Joong-Youn; Bertalovitz, Alexander C; Kendall, Debra A

    2011-09-23

    The classical cannabinoid agonist HU210, a structural analog of (-)-Δ(9)-tetrahydrocannabinol, binds to brain cannabinoid (CB1) receptors and activates signal transduction pathways. To date, an exact molecular description of the CB1 receptor is not yet available. Utilizing the minor binding pocket of the CB1 receptor as the primary ligand interaction site, we explored HU210 binding using lipid bilayer molecular dynamics (MD) simulations. Among the potential ligand contact residues, we identified residues Phe-174(2.61), Phe-177(2.64), Leu-193(3.29), and Met-363(6.55) as being critical for HU210 binding by mutational analysis. Using these residues to guide the simulations, we determined essential cannabinoid-binding domains in the CB1 receptor, including the highly sought after hydrophobic pocket important for the binding of the C3 alkyl chain of classical and nonclassical cannabinoids. Analyzing the simulations of the HU210-CB1 receptor complex, the CP55940-CB1 receptor complex, and the (-)-Δ(9)-tetrahydrocannabinol-CB1 receptor complex, we found that the positioning of the C3 alkyl chain and the aromatic stacking between Trp-356(6.48) and Trp-279(5.43) is crucial for the Trp-356(6.48) rotamer change toward receptor activation through the rigid-body movement of H6. The functional data for the mutant receptors demonstrated reductions in potency for G protein activation similar to the reductions seen in ligand binding affinity for HU210. PMID:21795705

  15. Khat (Catha edulis F.) and cannabinoids: Parallel and contrasting behavioral effects in preclinical and clinical studies.

    Science.gov (United States)

    Geresu, Berhanu

    2015-11-01

    After a brief outline of Catha edulis F. (khat) and the cannabinoid systems, the interactions between the pharmacological effects of khat and cannabinoids will be reviewed. Khat chewing is a widespread habit that has a deep-rooted sociocultural tradition in Africa and the Middle East. Experimental studies conducted to investigate khat's central and peripheral effects have revealed an amphetamine-like mechanism of action mediated through the dopaminergic system. The endocannabinoid system comprises the receptors, the endogenous agonists and the related biochemical machinery responsible for synthesizing these substances and terminating their actions. Endocannabinoids are synthesized "on demand" from membrane phospholipids and then rapidly cleared by cellular uptake and enzymatic degradation. Khat and cannabinoids produce a body of parallel and contrasting behavioral effects. Concurrent consumption of khat and cannabinoids may increase the risk of getting or precipitating psychosis, has rewarding and motivational effect, increases the threshold of pain perception and impairs learning and memory. On the other hand, the action of cannabis to enhance food intake is likely to reduce khat's appetite suppressant effects. PMID:26469212

  16. When winning is everything.

    Science.gov (United States)

    Malhotra, Deepak; Ku, Gillian; Murnighan, J Keith

    2008-05-01

    In the heat of competition, executives can easily become obsessed with beating their rivals. This adrenaline-fueled emotional state, which the authors call competitive arousal, often leads to bad decisions. Managers can minimize the potential for competitive arousal and the harm it can inflict by avoiding certain types of interaction and targeting the causes of a win-at-all-costs approach to decision making. Through an examination of companies such as Boston Scientific and Paramount, and through research on auctions, the authors identified three principal drivers of competitive arousal: intense rivalry, especially in the form of one-on-one competitions; time pressure, found in auctions and other bidding situations, for example; and being in the spotlight--that is, working in the presence of an audience. Individually, these factors can seriously impair managerial decision making; together, their consequences can be dire, as evidenced by many high-profile business disasters. It's not possible to avoid destructive competitions and bidding wars completely. But managers can help prevent competitive arousal by anticipating potentially harmful competitive dynamics and then restructuring the deal-making process. They can also stop irrational competitive behavior from escalating by addressing the causes of competitive arousal. When rivalry is intense, for instance, managers can limit the roles of those who feel it most. They can reduce time pressure by extending or eliminating arbitrary deadlines. And they can deflect the spotlight by spreading the responsibility for critical competitive decisions among team members. Decision makers will be most successful when they focus on winning contests in which they have a real advantage--and take a step back from those in which winning exacts too high a cost. PMID:18543810

  17. Win Market by Brand

    Institute of Scientific and Technical Information of China (English)

    FENG Zhende

    2002-01-01

    Brand is symbol of product quality and strength of enterprise. As a typical culture in market economy, it has great influences in everyday life. Famous brands attract purchasing, which prospers enterprise. After China' s entry to WTO, Chinese economy has turned into a new page.As the world manufacturing base, China is to win international market with its own brands. Chunsheng Refractory Ltd., which specialized in quality silica bricks, has grown in size and strength. And our experiences proved how important the brand is for an enterprise.

  18. Who Will Win the Game?

    Institute of Scientific and Technical Information of China (English)

    一维

    2007-01-01

    <正>Peter:Do you think Brazil will win? Paul:Could be.Peter:I bet you that Brazil will win the game. Paul:Don’t be so sure.Italy is also one of the best teams in Europe.Peter:But Brazil had won five World Cup Champions.Paul:Things are changing! Peter:It’s

  19. Cannabinoid-receptor expression in human leukocytes.

    Science.gov (United States)

    Bouaboula, M; Rinaldi, M; Carayon, P; Carillon, C; Delpech, B; Shire, D; Le Fur, G; Casellas, P

    1993-05-15

    Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS), probably through the cannabinoid receptor, which has recently been cloned in rat and human. While numerous reports have also described effects of cannabinoids on the immune system, the observation of both mRNA and cannabinoid receptor has hitherto been exclusively confined to the brain, a reported detection in the testis being the sole example of its presence at the periphery. Here we report the expression of the cannabinoid receptor on human immune tissues using a highly sensitive polymerase-chain-reaction-based method for mRNA quantification. We show that, although present in a much lower abundance than in brain, cannabinoid receptor transcripts are found in human spleen, tonsils and peripheral blood leukocytes. The distribution pattern displays important variations of the mRNA level for the cannabinoid receptor among the main human blood cell subpopulations. The rank order of mRNA levels in these cells is B cells > natural killer cells > or = polymorphonuclear neutrophils > or = T8 cells > monocytes > T4 cells. Cannabinoid-receptor mRNA, which is also found in monocytic, as well as T and B leukemia cell lines but not in Jurkat cells, presents a great diversity of expression on these cells as well, B-cell lines expressing a much higher level than T-cell lines. The cannabinoid receptor PCR products from leukocytes and brain are identical both in size and sequence suggesting a strong similarity between central and peripheral cannabinoid receptors. The expression of this receptor was demonstrated on membranes of the myelomonocytic U937 cells using the synthetic cannabinoid [3H]CP-55940 as ligand. The Kd determined from Scatchard analysis was 0.1 nM and the Bmax for membranes was 525 fmol/mg protein. The demonstration of cannabinoid-receptor expression at both mRNA and protein levels on human leukocytes provides a molecular basis for cannabinoid action on these cells. PMID

  20. Anandamide reduces infarct size in rat isolated hearts subjected to ischaemia–reperfusion by a novel cannabinoid mechanism

    OpenAIRE

    Underdown, Nichola J; Hiley, C. Robin; Ford, William R

    2005-01-01

    Although the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide share a similar pharmacology, 2-AG reportedly limits myocardial ischaemia–reperfusion injury whereas anandamide does not. We therefore investigated whether or not anandamide reduces infarct size and which, if any, of the known cannabinoid-signalling pathways are involved.Rat isolated perfused hearts were subjected to global, no-flow ischaemia (30 min) and reperfusion (1 h). Agonists were present from 5 min before ischa...

  1. Lithium attenuates cannabinoid-induced dependence in the animal model: involvement of phosphorylated ERK1/2 and GSK-3β signaling pathways.

    Directory of Open Access Journals (Sweden)

    Hamid Reza Rahimi

    2014-09-01

    Full Text Available Cannabis is one of the most banned drugs in the world. Cannabinoid-induced dependence or withdrawal signs are indicated by the result of complex molecular mechanisms including upstream protein kinases (PKs, such as an extracellular signal regulated kinase1/2 (ERK1/2 and downstream glycogen synthase kinase-3β (GSK-3β, which lead to neuronal plasticity. In this study, we examined the protective effect of lithium (Li as a potent ERK1/2 and GSK-3β modulator to prevent the development of dependence on cannabinoids. For this purpose, rats were treated twice daily with increasing doses of WIN 55,212-2 (WIN, 2-8 mg/kg, intraperitoneally (i.p., for five consecutive days. AM251 (AM, 2 mg/kg, a cannabinoid antagonist, was injected i.p to induce manifestations of abstinence in rat dependency on WIN, and the subsequent withdrawal signs were recorded. To evaluate the preventive effect of Li, the rats were pre-treated with Li (10 mg/kg, i.p. twice daily, 30 minutes before every injection of WIN. SL327, as an ERK1/2 inhibitor, was also injected (SL, 50 mg/kg, i.p. 30 minutes before the last doses of WIN in separate groups. The p-ERK1/2, total ERK1/2, p-GSK-3β and total GSK-3β expressions were determined with Western blot method after 60 minutes, prior to the Li, WIN or AM injections. Li and SL pre-treatment attenuated the global withdrawal signs in regarding their modulation effect on the up-regulation of p-ERK1/2 cascade enhanced by AM injection. Furthermore, the p-GSK-3β expression was up-regulated with SL and Li pre-treatment against AM injection, without alteration on the total contents of ERK1/2 and GSK-3β level. Therefore, p-ERK1/2 and p-GSK-3β pathways are involved in the cannabinoid-induced dependence. However, no crosstalk was indicated between these two pathways. In conclusion, Li neuroprotectionwith regard to cannabinoid abstinence may occur through the regulation of the p-ERK1/2 cascade inconsequent of p-GSK-3β signaling pathways in rats.

  2. 大麻素CB1受体对大鼠视网膜神经节细胞诱发动作电位的作用%Activation of cannabinoid CB1 receptors modulates evoked action potentials in rat retinal ganglion cells

    Institute of Scientific and Technical Information of China (English)

    蒋淑霞; 李倩; 王霄汉; 李芳; 王中峰

    2013-01-01

    Activation of cannabinoid CB1 receptors (CB 1Rs) regulates a variety of physiological functions in the vertebrate retina through modulating various types of ion channels.The aim of the present study was to investigate the effects of this receptor on cell excitability of rat retinal ganglion cells (RGCs) in retinal slices using whole-cell patch-clamp techniques.The results showed that under current-clamped condition perfusing WIN55212-2 (WIN,5 μmol/L),a CB1R agonist,did not significantly change the spontaneous firing frequency and resting membrane potential of RGCs.In the presence of cocktail synaptic blockers,including excitatory postsynaptic receptor blockers CNQX and D-APV,and inhibitory receptor blockers bicuculline and strychnine,perfusion of WIN (5 μmol/L)hardly changed the frequencies of evoked action potentials by a series of positive current injection (from +10 to +100 pA).Phaseplane plot analysis showed that both average threshold voltage for triggering action potential and delay time to reach threshold voltage were not affected by WIN.However,WIN significantly decreased +dV/dtmax and-dV/dtmax of action potentials,suggestive of reduced rising and descending velocities of action potentials.The effects of WIN were reversed by co-application of SR141716,a CB1R selective antagonist.Moreover,WIN did not influence resting membrane potential of RGCs with synaptic inputs being blocked.These results suggest that activation of CB1Rs may regulate intrinsic excitability of rat RGCs through modulating evoked action potentials.%激活大麻素CB1受体(CB1Rs)通过调控多种离子通道,从而调节脊椎动物视网膜的功能.本文旨在利用膜片钳全细胞记录技术,在大鼠视网膜薄片上研究CB1Rs对神经节细胞兴奋性的作用.结果显示,在电流钳制状态下,灌流CB1R激动剂WIN55212-2 (WIN,5μmol/L)对神经节细胞的自发动作电位发放频率和静息膜电位均没有显著影响.在灌流液中加入CNQX,D-APV,bicuculline

  3. Impaired Excitatory Neurotransmission in the Urinary Bladder from the Obese Zucker Rat: Role of Cannabinoid Receptors

    Science.gov (United States)

    Blaha, Igor; Recio, Paz; Martínez, María Pilar; López-Oliva, María Elvira; Ribeiro, Ana S. F.; Agis-Torres, Ángel; Martínez, Ana Cristina; Benedito, Sara; García-Sacristán, Albino; Fernandes, Vítor S.; Hernández, Medardo

    2016-01-01

    Metabolic syndrome (MS) is a known risk factor for lower urinary tract symptoms. This study investigates whether functional and expression changes of cannabinoid CB1 and CB2 receptors are involved in the bladder dysfunction in an obese rat model with insulin resistance. Bladder samples from obese Zucker rat (OZR) and their respective controls lean Zucker rat (LZR) were processed for immunohistochemistry and western blot for studying the cannabinoid receptors expression. Detrusor smooth muscle (DSM) strips from LZR and OZR were also mounted in myographs for isometric force recordings. Neuronal and smooth muscle CB1 and CB2 receptor expression and the nerve fiber density was diminished in the OZR bladder. Electrical field stimulation (EFS) and acetylcholine (ACh) induced frequency- and concentration-dependent contractions of LZR and OZR DSM. ACh contractile responses were similar in LZR and OZR. EFS-elicited contractions, however, were reduced in OZR bladder. Cannabinoid receptor agonists and antagonists failed to modify the DSM basal tension in LZR and OZR In LZR bladder, EFS responses were inhibited by ACEA and SER-601, CB1 and CB2 receptor agonists, respectively, these effects being reversed by ACEA plus the CB1 antagonist, AM-251 or SER-601 plus the CB2 antagonist, AM-630. In OZR bladder, the inhibitory action of ACEA on nerve-evoked contractions was diminished, whereas that SER-601 did not change EFS responses. These results suggest that a diminished function and expression of neuronal cannabinoid CB1 and CB2 receptors, as well as a lower nerve fiber density is involved in the impaired excitatory neurotransmission of the urinary bladder from the OZR. PMID:27285468

  4. Direct Quantification of Cannabinoids and Cannabinoid Glucuronides in Whole Blood by Liquid Chromatography Tandem Mass Spectrometry

    OpenAIRE

    Schwope, David M.; Scheidweiler, Karl B.; Huestis, Marilyn A.

    2011-01-01

    The first method for quantifying cannabinoids and cannabinoid glucuronides in whole blood by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated. Solid-phase extraction followed protein precipitation with acetonitrile. HPLC separation was achieved in 16 min via gradient elution. Electrospray ionization was utilized for cannabinoid detection; both positive (Δ9-tetrahydrocannabinol [THC], cannabinol [CBN]) and negative (11-hydroxy-THC [11-OH-THC], 11-nor-9-carb...

  5. Cannabinoids promote oligodendrocyte progenitor survival: Involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling

    OpenAIRE

    Molina-Holgado, E; Vela, J.M. (José Miguel); Arévalo, Maria Ángeles; Almazán, G.; Molina-Holgado, F.; Borrell, Jose; Guaza, Carmen

    2002-01-01

    Cannabinoids exert pleiotropic actions in the CNS, including the inhibition of inflammatory responses and the enhancement of neuronal survival after injury. Although cannabinoid receptors are distributed widely in brain, their presence has not been investigated previously in oligodendrocytes. This study examined the expression of cannabinoid type 1 (CB1) receptors in rat oligodendrocytes in vivo and in culture and explored their biological function. Expression of CB1 receptors by oligodendroc...

  6. EFFECT OF CANNABINOIDS ON TESTICULAR ISCHEMIA-REPERFUSION INJURY IN RAT

    Directory of Open Access Journals (Sweden)

    H. Sepehri

    2006-11-01

    Full Text Available Anandamide is an endogenous ligand for cannabinoid receptors and has endothelial protective effect against ischemic preconditioning. The purpose of this study was to investigate the effects of cannabinoids on reperfusion injury due to testicular torsion-detorsion (T/D. A total of 36 adult male Sprague-Dawley rats were divided into 6 groups. Testicular ischemia was achieved by twisting the right testes 720◦ counters clockwise for 1 hour and reperfusion was allowed for 4 hours after detorsion. In baseline (normal group, bilateral orchiectomies performed after anesthesia. Sham operated group was served as a control group. Torsion/detorsion group underwent 1 hour testicular torsion and 4 hours of detorsion. Anandamide (cannabinoid agonist group received pretreatment with intraperitoneally anandamide 30 min before torsion. AM251 (CB1 antagonist group, received intraperitoneally injection of AM251 45 min before torsion. Anandamid/AM251 (An/AM group received administrations of AM251 45 min before torsion and anandamide 30 min before torsion. The ipsilateral malondialdehyde (MDA level in T/D group were significantly higher versus control and base line groups. Ipsilateral MDA values in anandamid group were significantly lower than T/D and An/AM groups. There were also significant decreases in catalase activity in T/D group compared with control and base line groups. These values were significantly higher in cannabinoid group versus T/D and An/AM groups. Anandamide increased ipsilateral intratesticular antioxidative markers and decreased free radicals formation during reperfusion phase after unilateral testicular torsion, which was reflected in lesser testicular MDA level. Furthermore, the effects of anandamide were mediated via cannabinoid receptors, since AM251 could abolish these effects.

  7. Country Report WIN Taiwan

    International Nuclear Information System (INIS)

    NPP, nuclear power up-rate for existing NPPs, NPP license renewal related studies, development of D and D technology, development of fuel cells and solar and wind power generation systems, and development and commercialization of radiopharmaceuticals. Among major nuclear regulatory activities during the past year include: establishment of a nuclear knowledge management web site, completion of review for power up-rate for Kuosheng NPP, oversight of the installation of automatic scram systems at NPPs during strong earthquakes, advancement of the electronically oriented radiation protection control operations, strengthening of safety controls of high-risk radiation sources, development of a mammography quality control program, and review and conditional approval of the preliminary safety analysis report (PSAR) of the construction license application for the spent nuclear fuel dry storage facility at the Chinshan NPP. C - WIN Taiwan: Founded in 1994, WIN Taiwan now has 110 national members and 33 global members. 2007-2008 Activities and Achievements: 15. WIN Global Annual Meeting held (21-27 April 2007, Bali, Indonesia); Science Excursions at TPC's Northern Visitors Center and at radwaste volume reduction center (12 July 2007); WIN-Taiwan and ANS Taiwan Joint Annual Meeting at the National Tsing Hua University's newly re-established Institute of Nuclear Engineering and Science (9 August 2007); workshop on 'understanding radiation and radioactive waste' (28 September 2007), Fall Seminar (7 December 2007), Steering and Advisory Committee Meetings (1 June and 1 November 2006, 11 January and 18 March, 2008)

  8. WIN Belarus report 2007

    International Nuclear Information System (INIS)

    national WIN: WIN Belarus was established in December 1998 and at present has 17 members. Highlights of the last year and trends in Belarus: There are some problems with the natural gas supply in Belarus from Russia. Energy policy directed to use the local fuel resources and energy saving, but these resources can not provide for Belarus energy demand. Therefore made a decision of NPP construction. At present the NPP site is selected. WIN activities: Collection and analysis of articles in newspapers and journals on energy problems in Belarus and construction of nuclear power plant in our republic. Publication and distribution of newsletters on nuclear problems for public information and authorities, which are available for the press too. We took part in debates with environmental and other opponents on the ecological, economical and safety problems of nuclear technology. We published articles about nuclear energy (safety problems, environment and climate). Female communication: Collaboration with women organizations in Belarus (Women Alliance, Women group in physics and others). Future plans and goals for WIN: Participation in several international conferences and seminars. Publication and distribution of newsletters on nuclear problems for public information and authorities, which are available for the press too. Collection and analysis of articles in newspapers and journals on energy problems in Belarus and construction of nuclear power plant in our republic. Publication articles in newspapers and 'Industrial Safety' journal about using nuclear technology and radiation and power problems. Investigation problems of radioactive waste handling. Preparation trainings for journalists and public organizations on radiation problems, nuclear power and on un-traditional renewed sources of energy. We shall continue debates with opponents on the ecological, economical and safety problems of NPP. Collaboration with women and ecological organizations in Belarus (Women's Alliance

  9. CB2 Cannabinoid Receptor As Potential Target against Alzheimer's Disease

    Science.gov (United States)

    Aso, Ester; Ferrer, Isidro

    2016-01-01

    The CB2 receptor is one of the components of the endogenous cannabinoid system, a complex network of signaling molecules and receptors involved in the homeostatic control of several physiological functions. Accumulated evidence suggests a role for CB2 receptors in Alzheimer's disease (AD) and indicates their potential as a therapeutic target against this neurodegenerative disease. Levels of CB2 receptors are significantly increased in post-mortem AD brains, mainly in microglia surrounding senile plaques, and their expression levels correlate with the amounts of Aβ42 and β-amyloid plaque deposition. Moreover, several studies on animal models of AD have demonstrated that specific CB2 receptor agonists, which are devoid of psychoactive effects, reduce AD-like pathology, resulting in attenuation of the inflammation associated with the disease but also modulating Aβ and tau aberrant processing, among other effects. CB2 receptor activation also improves cognitive impairment in animal models of AD. This review discusses available data regarding the role of CB2 receptors in AD and the potential usefulness of specific agonists of these receptors against AD. PMID:27303261

  10. [Cannabinoids for symptomatic therapy of multiple sclerosis].

    Science.gov (United States)

    Husseini, L; Leussink, V I; Warnke, C; Hartung, H-P; Kieseier, B C

    2012-06-01

    Spasticity represents a common troublesome symptom in patients with multiple sclerosis (MS). Treatment of spasticity remains difficult, which has prompted some patients to self-medicate with and perceive benefits from cannabis. Advances in the understanding of cannabinoid biology support these anecdotal observations. Various clinical reports as well as randomized, double-blind, placebo-controlled studies have now demonstrated clinical efficacy of cannabinoids for the treatment of spasticity in MS patients. Sativex is a 1:1 mix of delta-9-tetrahydocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, which recently received a label for treating MS-related spasticity in Germany. The present article reviews the current understanding of cannabinoid biology and the value of cannabinoids as a symptomatic treatment option in MS. PMID:22080198

  11. Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity.

    Directory of Open Access Journals (Sweden)

    Lisa K Brents

    Full Text Available BACKGROUND: K2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ(9-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R. METHODS/PRINCIPAL FINDINGS: JWH-018, five potential monohydroxylated metabolites (M1-M5, and one carboxy metabolite (M6 were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [(3H]CP-55,940, and then for CB1R intrinsic efficacy using an [(35S]GTPγS binding assay. JWH-018 and M1-M5 bound CB1Rs with high affinity, exhibiting K(i values that were lower than or equivalent to Δ(9-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ(9-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ(9-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251. CONCLUSIONS/SIGNIFICANCE: Unlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations

  12. Win-Win transportation solutions price reforms with multiple benefits

    International Nuclear Information System (INIS)

    Reform strategies in the transportation market, such as the Win-Win Transportation Solutions, can provide several economic, social and environmental benefits. The strategies are cost effective, technically feasible reforms based on market principles which help create a more equitable and efficient transportation system that supports sustainable economic development. The benefits they provide include reduced traffic congestion, road and parking facility savings, consumer savings, equity, safety and environmental protection. They also increase economic productivity. If fully implemented, they could reduce motor vehicle impacts by 15 to 30 per cent and could help achieve the Kyoto emission reduction targets. Examples of Win-Win strategies at the federal level include: (1) removal of subsidies to oil production and internalized costs, and (2) tax exempt employer provided transfer benefits. Examples of Win-Win strategies at the state/provincial level include: (1) distance-based vehicle insurance and registration fees, (2) least-coast transportation planning and funding, (3) revenue-neutral tax shifting, (4) road pricing, (5) reform motor carrier regulations for competition and efficiency, (6) local and regional transportation demand management programs, (7) more efficient land use, (8) more flexible zoning requirements, (9) parking cash out, (10) transportation management associations, (11) location-efficient housing and mortgages, (12) school and campus trip management, (13) car sharing, (14) non-motorized transport improvements, and (15) traffic calming. It was noted that any market reform that leads to more efficient use of existing transportation systems can provide better economic development benefits. 9 refs., 1 tab., 1 fig

  13. Regulation of nausea and vomiting by cannabinoids

    OpenAIRE

    Parker, Linda A; Rock, Erin M; Limebeer, Cheryl L

    2011-01-01

    Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti-emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB1 agonism suppresses vomiting, which is reversed by CB1 antagonism, and CB1 inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially usef...

  14. Ligand Binding Sensitivity of the Extracellular Loop Two of the Cannabinoid Receptor 1

    OpenAIRE

    Bertalovitz, Alexander C.; Ahn, Kwang H.; Kendall, Debra A.

    2010-01-01

    The cannabinoid receptor one (CB1) is a class A G-protein-coupled receptor thought to bind ligands primarily within its helical bundle. Evidence suggests, however, that the extracellular domain may also play a role. We have previously shown that the C-terminus of the extracellular loop 2 of CB1 is important in binding some compounds; receptors with mutations in this region (F268W, P269A, H270A, and I271A) bound some agonists with severely reduced affinity relative to the wild-type receptor. I...

  15. QIN Dahe wins IMO prize

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ Prof.QIN Dahe,a glaciologist and climatologist from the CAS Cold and Arid Regions Environmental and Engineering Research,has been elected to win the prestigious Prize of the International Meteorology Organization (IMO) in 2008.

  16. Participación del sistema cannabinoide endógeno en los fenómenos de adicción. Interacción con otros sistemas de neurotransmisión

    OpenAIRE

    Castañé Forn, Anna

    2005-01-01

    Con la finalidad de explorar con profundidad las bases neurobiológicas de la adicción a cannabinoides hemos llevado a cabo diferentes estudios farmacológicos y moleculares. El sustrato neuroanatómico de la dependencia física de cannabinoides ha sido investigado en ratones que recibieron un tratamiento crónico con el agonista WIN55,212-2. En este estudio, se observó que el cerebelo y en menor grado el hipocampo y la amígdala, participan en la manifestación comportamental del síndrome de abstin...

  17. Cannabinoid 1 and transient receptor potential vanilloid 1 receptors discretely modulate evoked glutamate separately from spontaneous glutamate transmission.

    Science.gov (United States)

    Fawley, Jessica A; Hofmann, Mackenzie E; Andresen, Michael C

    2014-06-11

    Action potentials trigger synaptic terminals to synchronously release vesicles, but some vesicles release spontaneously. G-protein-coupled receptors (GPCRs) can modulate both of these processes. At cranial primary afferent terminals, the GPCR cannabinoid 1 (CB1) is often coexpressed with transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel present on most afferents. Here we tested whether CB1 activation modulates synchronous, action potential-evoked (eEPSCs) and/or spontaneous (sEPSCs) EPSCs at solitary tract nucleus neurons. In rat horizontal brainstem slices, activation of solitary tract (ST) primary afferents generated ST-eEPSCs that were rapidly and reversibly inhibited from most afferents by activation of CB1 with arachidonyl-2'-chloroethylamide (ACEA) or WIN 55,212-2 [R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate]. The CB1 antagonist/inverse agonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] blocked these responses. Despite profound depression of ST-eEPSCs during CB1 activation, sEPSCs in these same neurons were unaltered. Changes in temperature changed sEPSC frequency only from TRPV1(+) afferents (i.e., thermal sEPSC responses only occurred in TRPV1(+) afferents). CB1 activation failed to alter these thermal sEPSC responses. However, the endogenous arachidonate metabolite N-arachidonyldopamine (NADA) promiscuously activated both CB1 and TRPV1 receptors. NADA inhibited ST-eEPSCs while simultaneously increasing sEPSC frequency, and thermally triggered sEPSC increases in neurons with TRPV1(+) afferents. We found no evidence for CB1/TRPV1 interactions suggesting independent regulation of two separate vesicle pools. Together, these data demonstrate that action potential-evoked synchronous glutamate release is modulated separately from TRPV1-mediated glutamate release despite coexistence

  18. In the winning mood

    Directory of Open Access Journals (Sweden)

    Marieke de Vries

    2008-01-01

    Full Text Available The present research aimed to test the role of mood in the Iowa Gambling Task (IGT; Bechara et al., 1994. In the IGT, participants can win or lose money by picking cards from four different decks. They have to learn by experience that two decks are overall advantageous and two decks are overall disadvantageous. Previous studies have shown that at an early stage in this card-game, players begin to display a tendency towards the advantageous decks. Subsequent research suggested that at this stage, people base their decisions on conscious gut feelings (Wagar and Dixon, 2006. Based on empirical evidence for the relation between mood and cognitive processing-styles, we expected and consistently found that, compared to a negative mood state, reported and induced positive mood states increased this early tendency towards advantageous decks. Our results provide support for the idea that a positive mood causes stronger reliance on affective signals in decision-making than a negative mood.

  19. Cannabinoid facilitation of fear extinction memory recall in humans.

    Science.gov (United States)

    Rabinak, Christine A; Angstadt, Mike; Sripada, Chandra S; Abelson, James L; Liberzon, Israel; Milad, Mohammed R; Phan, K Luan

    2013-01-01

    A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 h prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 h after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 h after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID:22796109

  20. Emerging drugs of abuse: current perspectives on synthetic cannabinoids

    Directory of Open Access Journals (Sweden)

    Debruyne D

    2015-10-01

    Full Text Available Danièle Debruyne,1,2 Reynald Le Boisselier1 1Centre for Evaluation and Information on Pharmacodependence - Addictovigilance (CEIP-A, 2Toxicology and Pharmacology Laboratory, Department of Pharmacology, University Hospital Centre Côte de Nacre, Caen, France Abstract: New psychoactive drugs that have appeared over the last decade are typically dominated by cathinones and synthetic cannabinoids (SCs. SCs have been emerging as recreational drugs because they mimic the euphoria effect of cannabis while still being legal. Sprayed on natural herb mixtures, SCs have been primarily sold as “herbal smoking blends” or “herbal incense” under brand names like “Spice” or “K2”. Currently, SCs pure compounds are available from websites for the combination with herbal materials or for the use in e-cigarettes. For the past 5 years, an ever increasing number of compounds, representative of different chemical classes, have been promoted and now represent a large assortment of new popular drugs of abuse, which are difficult to properly identify. Their legal status varies by country with many government institutions currently pushing for their control. The in vitro binding to CB1/CB2 receptors is usually well-known and considerable differences have been found in the CB1 versus CB2 selectivity and potency within the different SCs, with several structure-activity relations being evident. Desired effects by CB1 agonist users are relaxation/recreative, however, cardiovascular, gastrointestinal, or psychiatric/neurological side effects are commonly reported. At present there is no specific antidote existing if an overdose of designer drugs was to occur, and no curative treatment has been approved by health authorities. Management of acute toxic effects is mainly symptomatic and extrapolated from experience with cannabis. Keywords: synthetic cannabinoids, chemistry, analysis, pharmacology, toxicology, dependence, medical care

  1. Functional role of cannabinoid receptors in urinary bladder

    OpenAIRE

    Tyagi, Pradeep; Tyagi, Vikas; Yoshimura, Naoki; Chancellor, Michael

    2010-01-01

    Cannabinoids, the active components of Cannabis sativa (maijuana), and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical applications. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to the general cannabinoid pharmacology. In recent years, studies on the functional role of cannabinoid receptors in bladder have been motivated by the therapeutic effects ...

  2. Dissimilar cannabinoid substitution patterns in mice trained to discriminate Δ(9)-tetrahydrocannabinol or methanandamide from vehicle.

    Science.gov (United States)

    Wiley, Jenny L; Matthew Walentiny, D; Vann, Robert E; Baskfield, Cassandra Y

    2011-09-01

    Δ(9)-Tetrahydrocannabinol (THC) discrimination in rodents is a behavioral assay that has been used to probe differences among classes of cannabinoids in rats. The purpose of this study was to determine whether traditional and anandamide-like cannabinoids were distinguishable in cannabinoid discrimination procedures in mice. Male mice were trained to discriminate 30 mg/kg THC or 70 mg/kg methanandamide from vehicle in a two-lever milk-reinforced drug discrimination procedure. After acquisition, agonist tests with THC, methanandamide, CP 55940, and anandamide were conducted, as were antagonism tests with rimonabant. Substitution (agonism) and antagonism tests were also carried out in female mice trained to discriminate THC. THC and CP 55940 fully substituted in THC-trained mice of both sexes. Further, THC substitution was rimonabant reversible. In contrast, mice injected with methanandamide or anandamide failed to respond substantially on the THC lever, even up to doses that decreased overall responding. In methanandamide-trained mice, methanandamide fully generalized to the methanandamide training dose. Rimonabant did not reverse this generalization. Although THC, CP 55940, and anandamide also increased responding on the methanandamide lever, the magnitude of substitution was less than for methanandamide. These results suggest incomplete overlap in the underlying mechanisms mediating endocannabinoid pharmacology and marijuana intoxication. Further, they suggest that methanandamide discrimination may involve a non-CB(1) receptor mechanism that is particularly prominent at higher doses. PMID:21712709

  3. Creating a winning organizational culture.

    Science.gov (United States)

    Campbell, Robert James

    2009-01-01

    This article explores the idea of how to create a winning organizational culture. By definition, a winning organizational culture is one that is able to make current innovations stick, while continuously changing based on the demands of the marketplace. More importantly, the article explores the notion that a winning organizational culture can have a profound impact on the conscious of the workforce, helping each individual to become a better, more productive person, who provides important services and products to the community. To form a basis toward defining the structure of what a winning organization culture looks like, 4 experts were asked 12 questions related to the development of an organizational culture. Three of the experts have worked intimately within the health care industry, while a fourth has been charged with turning around an organization that has had a losing culture for 17 years. The article provides insight into the role that values, norms, goals, leadership style, familiarity, and hiring practices play in developing a winning organizational culture. The article also emphasizes the important role that leaders perform in developing an organizational culture. PMID:19910709

  4. Eastern countries - WIN activity review

    International Nuclear Information System (INIS)

    Women can play this important role in informing people about nuclear energy. WIN is a world-wide association of women working professionally in the fields of nuclear energy and radiation application who want to devote their time to public information. The main goal of the WIN is to establish an objective and effective communication with the public through educational programmes, information exchange and arranging study visits. The membership includes women working in medicine and health care, in regulatory authorities, in industry and as independent researches at Universities. They want to contribute to objectively informing the public by making presentation, discussing and giving information materials on subjects such as; radiation, radioactivity and health effects medical applications nuclear energy nuclear power plants and their safety nuclear and environment uranium mining radiation protection energy sustainable development WIN is also open to men, supporting the goals of WIN. The intention of this paper was to underline the main aspects which reflect WIN activity in some Eastern and Central countries. There are common features and also specific elements for each country. But the goal is the same: to assure an effective and a real information of the public related to the nuclear field

  5. Win at Work! The Everybody Wins Approach to Conflict Resolution

    CERN Document Server

    Katz, Diane

    2010-01-01

    Proven techniques for resolving workplace conflicts. After years of seeing clients struggling and their businesses suffering with destructive conflicts, Diane Katz developed The Working Circle, a step-by-step process that helps everyone in business resolve conflict in a non-confrontational, creative, collaborative way. Win at Work! provides you with a no-nonsense guide based on real-life examples of people at pivotal points in their careers. Filled with practical wisdom, it reveals how you can move around the roadblocks that, if left unattanded, can stop you in your tracks. Win at Work! also h

  6. Win-win imageries in a soap bubble world

    DEFF Research Database (Denmark)

    Ekman, Susanne

    2015-01-01

    , ranging from New Public Management, over corporate culture, to project work. Each of these trends claims to transcend paradoxes by making contradictory extremes enhance each other rather than hamper each other. This is partly made possible by an increasing immateriality of both money and labor, I argue......This article explores the imagery and notions of personhood underlying the willingness to undertake extreme work among creative knowledge workers. The core argument is that extreme work is informed by pervasive win-win fantasies which can be recognized in a number of current organizational trends...

  7. Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans.

    Science.gov (United States)

    Rabinak, Christine A; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R; Liberzon, Israel; Phan, K Luan

    2014-09-01

    Pre-extinction administration of Δ9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely occurs via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24 h after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders. PMID:24055595

  8. Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington's disease transgenic mice.

    Science.gov (United States)

    Dowie, M J; Howard, M L; Nicholson, L F B; Faull, R L M; Hannan, A J; Glass, M

    2010-09-29

    Early loss of CB1 receptors is a hallmark of human Huntington's disease. Data from rodent studies suggest that preservation and activation of CB1 receptors may be protective against disease progression. R6/1 transgenic mice are considered to be a model of early pathogenic changes in Huntington's disease. We have shown previously that levels of CB1 in R6/1 mice prior to the onset of motor symptoms (12 weeks of age) remain high enough to justify commencement of cannabinoid drug treatment. Eight weeks of daily treatment with the cannabinoid agonists HU210 (0.01 mg/kg) and Delta(9)-tetrahydrocannabinol (THC, 10.00 mg/kg), or the inhibitor of endocannabinoid metabolism URB597 (0.30 mg/kg), did not alter the progressive deterioration of performance observed in motor behavioural testing. HU210-treated R6/1 mice experienced a significant increase in seizure events suggesting that this therapy may lower the seizure threshold and cautioning against highly efficacious agonists as potential therapy in this disease. Molecular characterisation of brains at the end of the study showed that there were no significant effects of HU210 or THC treatment on the ligand binding of cannabinoid CB1, dopamine D1, D2, serotonin 5HT2A or GABA(A) receptors, nor CB1 or fatty acid amide hydrolase (FAAH) mRNA expression in R6/1 mice. Intriguingly, a significant increase in the number of ubiquitinated aggregates was observed in the striatum with HU210 treatment, indicating an influence of CB1 on the disease process. Chronic URB597 treatment preserved CB1 receptors in the R6/1 striatum, suggesting that the manipulation of endocannabinoid levels warrants further exploration. PMID:20600638

  9. Cannabinoids and autoimmune diseases: A systematic review.

    Science.gov (United States)

    Katchan, Valeria; David, Paula; Shoenfeld, Yehuda

    2016-06-01

    Cannabinoids have shown to have a variety effects on body systems. Through CB1 and CB2 receptors, amongst other, they exert an effect by modulating neurotransmitter and cytokine release. Current research in the role of cannabinoids in the immune system shows that they possess immunosuppressive properties. They can inhibit proliferation of leucocytes, induce apoptosis of T cells and macrophages and reduce secretion of pro-inflammatory cytokines. In mice models, they are effective in reducing inflammation in arthritis, multiple sclerosis, have a positive effect on neuropathic pain and in type 1 diabetes mellitus. They are effective as treatment for fibromyalgia and have shown to have anti-fibrotic effect in scleroderma. Studies in human models are scarce and not conclusive and more research is required in this field. Cannabinoids can be therefore promising immunosuppressive and anti-fibrotic agents in the therapy of autoimmune disorders. PMID:26876387

  10. Cannabinoid hyper-emesis syndrome: An enigma

    Directory of Open Access Journals (Sweden)

    Neeraj Gupta

    2013-01-01

    Full Text Available Marijuana is one of the most frequently abused illicit substances in the world especially Australia. Cannabinoid Hyperemesis Syndrome (CHS is characterized by a triad of symptoms: Cyclic vomiting, chronic marijuana use, and compulsive bathing. It involves recurrent episodes of self-limited nausea and vomiting lasting several days and patients are asymptomatic between episodes. We believe that Cannabinoid Hyper emesis Syndrome is much more common than currently recognized. We present a unique case with an apparent positive family history of the same clinical entity.

  11. Cannabinoids prevent lipopolysaccharide-induced neurodegeneration in the rat substantia nigra in vivo through inhibition of microglial activation and NADPH oxidase.

    Science.gov (United States)

    Chung, Eun Sook; Bok, Eugene; Chung, Young Cheul; Baik, Hyung Hwan; Jin, Byung Kwan

    2012-04-27

    We investigated the effects of synthetic cannabinoids, WIN55,212-2 and HU210, on LPS-injected rat substantia nigra in vivo. Intranigral injection of LPS resulted in a significant loss of nigral dopaminergic (DA) neurons, as determined by Nissl staining and TH immunohistochemistry. LPS-induced neurotoxicity was accompanied by microglial activation, as demonstrated by OX-42 immunohistochemistry. In parallel, Western blot analysis, ELISA assay and hydroethidine histochemistry revealed activation of NADPH oxidase, as demonstrated by increased translocation of the cytosolic proteins p47(phox) and p67(phox), generation of reactive oxygen species (ROS) and increased level of proinflammatory cytokines (TNF-α and IL-1β), where degeneration of nigral DA neurons was evident. Interestingly, WIN55,212-2 and HU210 increased the survival of nigral DA neurons at 7days post-LPS treatment. Consistent with these results, cannabinoids inhibited activation of NADPH oxidase, ROS production and production of proinflammatory cytokines in the rat SN. The present data suggest that cannabinoids may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with microglial activation. PMID:22436849

  12. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    Science.gov (United States)

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists. PMID:19832688

  13. IRA Award-Winning Research.

    Science.gov (United States)

    Seifert, Mary

    1984-01-01

    Summarizes award-winning research produced by Andrew M.Hess, Sirkka-Liisa Rauramo, Richard L. Allington, Donna E. Alvermann and David A. Hayes, Lesley M. Morrow and Carol S. Weinstein, Taffy E. Raphael and Bonnie B. Armbruster, Nancy Nelson Spivey, and Courtney B. Cazden. (FL)

  14. Do quantum strategies always win?

    Science.gov (United States)

    Anand, Namit; Benjamin, Colin

    2015-11-01

    In a seminal paper, Meyer (Phys Rev Lett 82:1052, 1999) described the advantages of quantum game theory by looking at the classical penny flip game. A player using a quantum strategy can win against a classical player almost 100 % of the time. Here we make a slight modification to the quantum game, with the two players sharing an entangled state to begin with. We then analyze two different scenarios: First in which quantum player makes unitary transformations to his qubit, while the classical player uses a pure strategy of either flipping or not flipping the state of his qubit. In this case, the quantum player always wins against the classical player. In the second scenario, we have the quantum player making similar unitary transformations, while the classical player makes use of a mixed strategy wherein he either flips or not with some probability " p." We show that in the second scenario, 100 % win record of a quantum player is drastically reduced and for a particular probability " p" the classical player can even win against the quantum player. This is of possible relevance to the field of quantum computation as we show that in this quantum game of preserving versus destroying entanglement a particular classical algorithm can beat the quantum algorithm.

  15. Tips for Writing Winning Resumes

    Science.gov (United States)

    Beale, Andrew V.

    2004-01-01

    With double-digit unemployment rates facing teenage job seekers, adolescents need all the help they can get in securing employment. One step in the job seeking process is the development of resumes that will win employment interviews. Whether they are looking for an after-school job, a summer job, or their first "real" job, this article provides…

  16. Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making.

    Science.gov (United States)

    Khani, Abbas; Kermani, Mojtaba; Hesam, Soghra; Haghparast, Abbas; Argandoña, Enrike G; Rainer, Gregor

    2015-06-01

    Despite the evidence for altered decision making in cannabis abusers, the role of the cannabinoid system in decision-making circuits has not been studied. Here, we examined the effects of cannabinoid modulation during cost-benefit decision making in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), key brain areas involved in decision making. We trained different groups of rats in a delay-based and an effort-based form of cost-benefit T-maze decision-making task. During test days, the rats received local injections of either vehicle or ACEA, a cannabinoid type-1 receptor (CB1R) agonist in the ACC or OFC. We measured spontaneous locomotor activity following the same treatments and characterized CB1Rs localization on different neuronal populations within these regions using immunohistochemistry. We showed that CB1R activation in the ACC impaired decision making such that rats were less willing to invest physical effort to gain high reward. Similarly, CB1R activation in the OFC induced impulsive pattern of choice such that rats preferred small immediate rewards to large delayed rewards. Control tasks ensured that the effects were specific for differential cost-benefit tasks. Furthermore, we characterized widespread colocalizations of CB1Rs on GABAergic axonal ends but few colocalizations on glutamatergic, dopaminergic, and serotonergic neuronal ends. These results provide first direct evidence that the cannabinoid system plays a critical role in regulating cost-benefit decision making in the ACC and OFC and implicate cannabinoid modulation of synaptic ends of predominantly interneurons and to a lesser degree other neuronal populations in these two frontal regions. PMID:25529106

  17. Augmented inhibition from cannabinoid sensitive interneurons diminishes CA1 output after traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Brian Neal Johnson

    2014-12-01

    Full Text Available The neurological impairments associated with traumatic brain injury include learning and memory deficits and increased risk of seizures. The hippocampus is critically involved in both of these phenomena and highly susceptible to damage by traumatic brain injury. To examine network activity in the hippocampal CA1 region after lateral fluid percussion injury, we used a combination of voltage sensitive dye, field potential and patch clamp recording in mouse hippocampal brain slices. When the stratum radiatum was stimulated in slices from injured mice we found decreased depolarization in stratum radiatum and increased hyperpolarization in stratum oriens, together with a decrease in the percentage of pyramidal neurons firing stimulus-evoked action potentials. Increased hyperpolarization in stratum oriens persisted when glutamatergic transmission was blocked. However, we found no changes in stratum oriens responses when the alveus was stimulated to directly activate stratum oriens. These results suggest that the increased stratum oriens hyperpolarization evoked by stratum radiatum stimulation was mediated by interneurons that have cell bodies and/or axons in stratum radiatum, and form synapses in stratum pyramidale and stratum oriens. A low concentration (100 nM of the synthetic cannabinoid WIN55,212-2,restored CA1 output in slices from injured animals. These findings support the hypothesis that increased GABAergic signaling by cannabinoid sensitive interneurons contributes to the reduced CA1 output following traumatic brain injury.

  18. Combined cannabinoid therapy via an oromucosal spray.

    Science.gov (United States)

    Perez, Jordi

    2006-08-01

    Extensive basic science research has identified the potential therapeutic benefits of active compounds extracted from the Cannabis sativa L. plant (the cannabinoids). It is recognized that a significant proportion of patients suffering with the debilitating symptoms of pain and spasticity in multiple sclerosis or other conditions smoke cannabis despite the legal implications and stigma associated with this controlled substance. GW Pharmaceuticals have developed Sativex (GW- 1,000-02), a combined cannabinoid medicine that delivers and maintains therapeutic levels of two principal cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), via an oromucosal pump spray, that aims to minimize psychotropic side effects. Sativex has proved to be well tolerated and successfully self-administered and self-titrated in both healthy volunteers and patient cohorts. Clinical assessment of this combined cannabinoid medicine has demonstrated efficacy in patients with intractable pain (chronic neuropathic pain, pain due to brachial plexus nerve injury, allodynic peripheral neuropathic pain and advanced cancer pain), rheumatoid arthritis and multiple sclerosis (bladder problems, spasticity and central pain), with no significant intoxication-like symptoms, tolerance or withdrawal syndrome. PMID:16969427

  19. Cannabinoid receptor CB2 modulates axon guidance

    DEFF Research Database (Denmark)

    Duff, Gabriel; Argaw, Anteneh; Cecyre, Bruno; Cherif, Hosni; Tea, Nicolas; Zabouri, Nawal; Casanova, Christian; Ptito, Maurice; Bouchard, Jean-François

    2013-01-01

    Navigation of retinal projections towards their targets is regulated by guidance molecules and growth cone transduction mechanisms. Here, we present in vitro and in vivo evidences that the cannabinoid receptor 2 (CB2R) is expressed along the retino-thalamic pathway and exerts a modulatory action ...

  20. The Effect of Dorsal Hippocampal α2-Adrenegic Receptors on WIN55,212-2 State-Dependent Memory of Passive Avoidance

    Directory of Open Access Journals (Sweden)

    Zarrindast M.R.

    2010-09-01

    Full Text Available Background and Objectives: Cannabinoids are a class of psychoactive compounds that produce a wide array of effects in a large number of species. In the present study, the effects of bilateral intra-CA1 injections of an α2-adrenergic receptor agents, on WIN55,212-2 state-dependent learning were examined in adult male Wistar rats. Methods: The animals were bilaterally implanted with chronic cannulae in the CA1 regions of the dorsal hippocampus, trained in a step-down type inhibitory avoidance task, and tested 24h after training to measure step-down latency.Results: Post-training intra-CA1 injection of WIN55,212-2 (0.25 and 0.5µg/rat induced impairment of memory retention. Amnesia produced by post-training WIN55,212-2 (0.5µg/rat was reversed by pre-test administration of the same dose of WIN55,212-2 that is due to a state-dependent effect. Pre-test intra-CA1 injection of clonidine (0.5 and 0.75µg/rat, intra-CA1 improved post-training WIN55,212-2 (0.5µg/rat, intra-CA1-induced retrieval impairment, while pre-test intra-CA1 injection of yohimbine (1µg/rat, intra-CA1 2min before the administration of WIN55,212-2 (0.5µg/rat, intra-CA1 inhibited WIN55,212-2 state-dependent memory. Conclusion: These results suggest that α2-adrenergic receptors of the dorsal hippocampal CA1 regions may play an important role in Win55,212-2-induced amnesia and WIN55,212-2 state-dependent memory.

  1. Cannabinoids for Symptom Management and Cancer Therapy: The Evidence.

    Science.gov (United States)

    Davis, Mellar P

    2016-07-01

    Cannabinoids bind not only to classical receptors (CB1 and CB2) but also to certain orphan receptors (GPR55 and GPR119), ion channels (transient receptor potential vanilloid), and peroxisome proliferator-activated receptors. Cannabinoids are known to modulate a multitude of monoamine receptors. Structurally, there are 3 groups of cannabinoids. Multiple studies, most of which are of moderate to low quality, demonstrate that tetrahydrocannabinol (THC) and oromucosal cannabinoid combinations of THC and cannabidiol (CBD) modestly reduce cancer pain. Dronabinol and nabilone are better antiemetics for chemotherapy-induced nausea and vomiting (CINV) than certain neuroleptics, but are not better than serotonin receptor antagonists in reducing delayed emesis, and cannabinoids have largely been superseded by neurokinin-1 receptor antagonists and olanzapine; both cannabinoids have been recommended for breakthrough nausea and vomiting among other antiemetics. Dronabinol is ineffective in ameliorating cancer anorexia but does improve associated cancer-related dysgeusia. Multiple cancers express cannabinoid receptors directly related to the degree of anaplasia and grade of tumor. Preclinical in vitro and in vivo studies suggest that cannabinoids may have anticancer activity. Paradoxically, cannabinoid receptor antagonists also have antitumor activity. There are few randomized smoked or vaporized cannabis trials in cancer on which to judge the benefits of these forms of cannabinoids on symptoms and the clinical course of cancer. Smoked cannabis has been found to contain Aspergillosis. Immunosuppressed patients should be advised of the risks of using "medical marijuana" in this regard. PMID:27407130

  2. Winning fights induces hyperaggression via the action of the biogenic amine octopamine in crickets.

    Directory of Open Access Journals (Sweden)

    Jan Rillich

    Full Text Available Winning an agonistic interaction against a conspecific is known to heighten aggressiveness, but the underlying events and mechanism are poorly understood. We quantified the effect of experiencing successive wins on aggression in adult male crickets (Gryllus bimaculatus by staging knockout tournaments and investigated its dependence on biogenic amines by treatment with amine receptor antagonists. For an inter-fight interval of 5 min, fights between winners escalated to higher levels of aggression and lasted significantly longer than the preceding round. This winner effect is transient, and no longer evident for an inter-fight interval of 20 min, indicating that it does not result from selecting individuals that were hyper-aggressive from the outset. A winner effect was also evident in crickets that experienced wins without physical exertion, or that engaged in fights that were interrupted before a win was experienced. Finally, the winner effect was abolished by prior treatment with epinastine, a highly selective octopamine receptor blocker, but not by propranolol, a ß-adrenergic receptor antagonist, nor by yohimbine, an insect tyramine receptor blocker nor by fluphenazine an insect dopamine-receptor blocker. Taken together our study in the cricket indicates that the physical exertion of fighting, together with some rewarding aspect of the actual winning experience, leads to a transient increase in aggressive motivation via activation of the octopaminergic system, the invertebrate equivalent to the adrenergic system of vertebrates.

  3. Does a win bonus help to increase profit or wins in professional team sports?

    OpenAIRE

    Késenne, Stefan

    2007-01-01

    In a sports league, team owners can expect to increase player performance, and the team’s winning percentage or profits, by providing a win bonus on top of the players’ fixed salary level. In some clubs, the guaranteed player salary is relatively low and the premium, in case of a winning game, relatively high, whereas in other clubs, hardly any win bonus is paid. In this theoretical paper, we investigate what the impact of a win bonus is on the winning percentage, the competitive balance, the...

  4. Effects of cannabinoids and their receptors on viral infections.

    Science.gov (United States)

    Tahamtan, Alireza; Tavakoli-Yaraki, Masoumeh; Rygiel, Tomasz P; Mokhtari-Azad, Talat; Salimi, Vahid

    2016-01-01

    Cannabinoids, the active ingredient in marijuana, and their derivatives have received remarkable attention in the last two decades because they can affect tumor growth and metastasis. There is a large body of evidence from in vivo and in vitro models showing that cannabinoids and their receptors influence the immune system, viral pathogenesis, and viral replication. The present study reviews current insights into the role of cannabinoids and their receptors on viral infections. The results reported here indicate that cannabinoids and their receptors have different sequels for viral infection. Although activation or inhibition of cannabinoid receptors in the majority of viral infections are proper targets for development of safe and effective treatments, caution is required before using pharmaceutical cannabinoids as a treatment agent for patients with viral infections. PMID:26059175

  5. Cannabinoid-induced autophagy: Protective or death role?

    Science.gov (United States)

    Costa, Lia; Amaral, Cristina; Teixeira, Natércia; Correia-da-Silva, Georgina; Fonseca, Bruno M

    2016-01-01

    Autophagy, the "self-digestion" mechanism of the cells, is an evolutionary conserved catabolic process that targets portions of cytoplasm, damaged organelles and proteins for lysosomal degradation, which plays a crucial role in development and disease. Cannabinoids are active compounds of Cannabis sativa and the most prevalent psychoactive substance is Δ(9)-tetrahydrocannabinol (THC). Cannabinoid compounds can be divided in three types: the plant-derived natural products (phytocannabinoids), the cannabinoids produced endogenously (endocannabinoids) and the synthesized compounds (synthetic cannabinoids). Various studies reported a cannabinoid-induced autophagy mechanism in cancer and non-cancer cells. In this review we focus on the recent advances in the cannabinoid-induced autophagy and highlight the molecular mechanisms involved in these processes. PMID:26732541

  6. Constitutive cannabinoid 1 and mu opioid receptor activity in the ventral tegmental area: occurrence, function and therapeutic relevance

    OpenAIRE

    Meye, F J

    2012-01-01

    Cannabinoid 1 receptors (CB1Rs) play a crucial role in regulating systems dedicated to processing rewards and emotions. It was known that in artificial systems, CB1Rs can exhibit activity that is independent of the typical agonist-driven form. However, it remained largely unclear whether this constitutive activity also occurred in native tissue (e.g. the brain), and if so, what role it plays in neurotransmission and behavior. In this thesis we have taken a multi-disciplinary approach to show ...

  7. The Methods Behind PH WINS.

    Science.gov (United States)

    Leider, Jonathon P; Bharthapudi, Kiran; Pineau, Vicki; Liu, Lin; Harper, Elizabeth

    2015-01-01

    The Public Health Workforce Interests and Needs Survey (PH WINS) has yielded the first-ever nationally representative sample of state health agency central office employees. The survey represents a step forward in rigorous, systematic data collection to inform the public health workforce development agenda in the United States. PH WINS is a Web-based survey and was developed with guidance from a panel of public health workforce experts including practitioners and researchers. It draws heavily from existing and validated items and focuses on 4 main areas: workforce perceptions about training needs, workplace environment and job satisfaction, perceptions about national trends, and demographics. This article outlines the conceptualization, development, and implementation of PH WINS, as well as considerations and limitations. It also describes the creation of 2 new data sets that will be available in public use for public health officials and researchers--a nationally representative data set for permanently employed state health agency central office employees comprising over 10,000 responses, and a pilot data set with approximately 12,000 local and regional health department staff responses. PMID:26422490

  8. Cannabinoids in the management of difficult to treat pain

    OpenAIRE

    Russo, Ethan

    2008-01-01

    Ethan B RussoGW Pharmaceuticals, Vashon, WA, USAAbstract: This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol®) and nabilone (Cesamet®) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in devel...

  9. Cannabinoids in the management of difficult to treat pain

    OpenAIRE

    Russo, Ethan B

    2008-01-01

    This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol®) and nabilone (Cesamet®) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is...

  10. GPR55: a new member of the cannabinoid receptor clan?

    OpenAIRE

    Pertwee, R. G.

    2007-01-01

    In this issue of the British Journal of Pharmacology, Ryberg et al. present convincing in vitro evidence that the orphan GPCR, GPR55, is a cannabinoid receptor. GPR55 was activated by a range of plant, synthetic and endogenous cannabinoids and blocked by the non-psychoactive phytocannabinoid, cannabidiol. Their experiments have revealed several differences between the pharmacology of GPR55 and the established cannabinoid CB1 and CB2 receptors. For example, the CB1 receptor antagonist, AM251, ...

  11. Discussion of "Win-Win concession period determination methodology" by Xueqing Zhang

    OpenAIRE

    Wu, M; Chau, KW; Shen, QP

    2011-01-01

    'Win-win concession period determination methodology' By: Zhang, Xueqing. Journal of Construction Engineering & Management, Jun2009, Vol. 135 Issue 6, p550-558, 9 p; DOI: 10.1061/(ASCE)CO.1943-7862.0000012; (AN 39786304)

  12. Identification of a Functionally Relevant Cannabinoid Receptor on Mouse Spleen Cells that Is Involved in Cannabinoid-Mediated Immune Modulation

    OpenAIRE

    Kaminski, Norbert E.; Abood, Mary E.; Kessler, Fay K.; Martin, Billy R.; Schatz, Anthony R.

    1992-01-01

    Extensive behavioral and biochemical characterization of cannabinoid-mediated effects on the central nervous system has revealed at least three lines of evidence supporting the role of a putative guanine nucleotide-binding protein-coupled cannabinoid receptor for cannabimimetic effects, (i) stereoselectivity, (ii) inhibition of the adenylate cyclase/cAMP second messenger system, and (iii) radioligand-binding studies with the synthetic cannabinoid [3H]CP-55,940 indicating a high degree of spec...

  13. Synthetic Cannabinoid 'Bonzai' Intoxication: Six Case Series.

    Science.gov (United States)

    Ergül, Dursun Fırat; Ekemen, Serdar; Yelken, Birgül Büyükkıdan

    2015-10-01

    In the language of the streets, 'bonzai', known as '1-naphthalenyl of methanol', also known as JWH-18 group, is a drug belonging to the group of synthetic cannabinoids. At the beginning of 2004, it started to be sold on the internet and it is seen that private markets. It has structurally similar chemical characteristics as delta 9-tetrahydrocannabinol (THC), the active substance in marijuana. In 2013, in a study conducted by the European Monitoring Centre of Drugs and Drug Addiction (EMCDDA), 102 varieties of synthetic cannabinoids were identified; however, more than 200 substances have been reported since 1997. In this study, we report the difficulties in the clinical course, treatment and management of six patients that had a use history of bonzai although it was not detected in blood in a short period of time in the intensive care unit. PMID:27366526

  14. Cannabinoid Hyperemesis Syndrome: A Paradoxical Cannabis Effect

    Directory of Open Access Journals (Sweden)

    Ivonne Marie Figueroa-Rivera

    2015-01-01

    Full Text Available Despite well-established antiemetic properties of marijuana, there has been increasing evidence of a paradoxical effect in the gastrointestinal tract and central nervous system, given rise to a new and underrecognized clinical entity called the Cannabinoid Hyperemesis Syndrome. Reported cases in the medical literature have established a series of patients exhibiting a classical triad of symptoms: cyclic vomiting, chronic marijuana use, and compulsive bathing. We present a case of a 29-year-old man whose clinical presentation strongly correlates with cannabinoid hyperemesis syndrome. Despite a diagnosis of exclusion, this syndrome should be considered plausible in the setting of a patient with recurrent intractable vomiting and a strong history of cannabis use as presented in this case.

  15. Cannabinoid Hyperemesis Syndrome: A Paradoxical Cannabis Effect.

    Science.gov (United States)

    Figueroa-Rivera, Ivonne Marie; Estremera-Marcial, Rodolfo; Sierra-Mercado, Marielly; Gutiérrez-Núñez, José; Toro, Doris H

    2015-01-01

    Despite well-established antiemetic properties of marijuana, there has been increasing evidence of a paradoxical effect in the gastrointestinal tract and central nervous system, given rise to a new and underrecognized clinical entity called the Cannabinoid Hyperemesis Syndrome. Reported cases in the medical literature have established a series of patients exhibiting a classical triad of symptoms: cyclic vomiting, chronic marijuana use, and compulsive bathing. We present a case of a 29-year-old man whose clinical presentation strongly correlates with cannabinoid hyperemesis syndrome. Despite a diagnosis of exclusion, this syndrome should be considered plausible in the setting of a patient with recurrent intractable vomiting and a strong history of cannabis use as presented in this case. PMID:26266060

  16. Treatment of Tourette Syndrome with Cannabinoids

    Directory of Open Access Journals (Sweden)

    Kirsten R. Müller-Vahl

    2013-01-01

    Full Text Available Cannabinoids have been used for hundred of years for medical purposes. To day, the cannabinoid delta-9-tetrahydrocannabinol (THC and the cannabis extract nabiximols are approved for the treatment of nausea, anorexia and spasticity, respectively. In Tourette syndrome (TS several anecdotal reports provided evidence that marijuana might be effective not only in the suppression of tics, but also in the treatment of associated behavioural problems. At the present time there are only two controlled trials available investigating the effect of THC in the treatment of TS. Using both self and examiner rating scales, in both studies a significant tic reduction could be observed after treatment with THC compared to placebo, without causing significant adverse effects. Available data about the effect of THC on obsessive-compulsive symptoms are inconsistent. According to a recent Cochrane review on the efficacy of cannabinoids in TS, definite conclusions cannot be drawn, because longer trials including a larger number of patients are missing. Notwithstanding this appraisal, by many experts THC is recommended for the treatment of TS in adult patients, when first line treatments failed to improve the tics. In treatment resistant adult patients, therefore, treatment with THC should be taken into consideration.

  17. Cannabinoid receptor type-1: breaking the dogmas

    Science.gov (United States)

    Busquets Garcia, Arnau; Soria-Gomez, Edgar; Bellocchio, Luigi; Marsicano, Giovanni

    2016-01-01

    The endocannabinoid system (ECS) is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB 1). In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB 1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons). Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB 1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB 1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.

  18. Quantification of Cannabinoid Content in Cannabis

    Science.gov (United States)

    Tian, Y.; Zhang, F.; Jia, K.; Wen, M.; Yuan, Ch.

    2015-09-01

    Cannabis is an economically important plant that is used in many fields, in addition to being the most commonly consumed illicit drug worldwide. Monitoring the spatial distribution of cannabis cultivation and judging whether it is drug- or fiber-type cannabis is critical for governments and international communities to understand the scale of the illegal drug trade. The aim of this study was to investigate whether the cannabinoids content in cannabis could be spectrally quantified using a spectrometer and to identify the optimal wavebands for quantifying the cannabinoid content. Spectral reflectance data of dried cannabis leaf samples and the cannabis canopy were measured in the laboratory and in the field, respectively. Correlation analysis and the stepwise multivariate regression method were used to select the optimal wavebands for cannabinoid content quantification based on the laboratory-measured spectral data. The results indicated that the delta-9-tetrahydrocannabinol (THC) content in cannabis leaves could be quantified using laboratory-measured spectral reflectance data and that the 695 nm band is the optimal band for THC content quantification. This study provides prerequisite information for designing spectral equipment to enable immediate quantification of THC content in cannabis and to discriminate drug- from fiber-type cannabis based on THC content quantification in the field.

  19. Role of cannabinoids in chronic liver diseases

    Institute of Scientific and Technical Information of China (English)

    Anna Parfieniuk; Robert Flisiak

    2008-01-01

    Cannabinoids are a group of compounds acting primarily via CB1 and CB2 receptors. The expression of cannabinoid receptors in normal liver is low or absent. However, many reports have proven up-regulation of the expression of CB1 and CB2 receptors in hepatic myofibroblasts and vascular endothelial cells, as well as increased concentration of endocannabinoids in liver in the course of chronic progressive liver diseases. It has been shown that CB1 receptor signalling exerts profibrogenic and proinflammatory effects in liver tissue, primarily due to the stimulation of hepatic stellate cells, whereas the activation of CB2 receptors inhibits or even reverses liver fibrogenesis. Similarly, CB1 receptor stimulation contributes to progression of liver steatosis. In end-stage liver disease, the endocannabi-noid system has been shown to contribute to hepatic encephalopathy and vascular effects, such as portal hypertension, splanchnic vasodilatation, relative pe-ripheral hypotension and probably cirrhotic cardiomy-opathy. So far, available evidence is based on cellular cultures or animal models. Clinical data on the effects of cannabinoids in chronic liver diseases are limited. However, recent studies have shown the contribution of cannabis smoking to the progression of liver fibrosis and steatosis. Moreover, controlling CB1 or CB2 signal-ling appears to be an attractive target in managing liver diseases.

  20. The discovery of a cannabinoid receptor

    Energy Technology Data Exchange (ETDEWEB)

    Devane, W.A.

    1989-01-01

    A tritiated form of CP-55,940, a Pfizer cannabinoid analog that is 20- to 100-fold more potent than {Delta}{sup 9}-tetrahydrocannabinol in various in vivo and in vitro models of cannabimimetric activity, was used as the tool with which to probe for a cannabinoid receptor in rat cortical membranes. The bound and free ligand were successfully separated using a centrifugation assay. Specific binding was saturable, rapidly attained, and completely reversible. The K{sub D}'s derived from kinetic analysis of binding agreed well with the K{sub D}'s derived from saturation and displacement analysis. The ({sup 3}H)CP-55,940 binding site exhibited high affinity with a K{sub D} of 68 pM as determined by LIGAND analysis of homologous displacement studies. The ability of other cannabinoid drugs to displace ({sup 3}H)CP-55,940 binding correlated well with the potency of these drugs in in vivo and in vitro models of cannabimimetic activity. The K{sub i} of {Delta}{sup 9}-THC was 1.6 nM. Cannabidiol and cannabigerol, which both lack psychoactivity in man, displaced specific binding by less than 50% at 1 {mu}M.

  1. Opportunistic Cognitive Relaying: A Win-Win Spectrum Sharing Scheme

    Directory of Open Access Journals (Sweden)

    Luo Haiyan

    2010-01-01

    Full Text Available A cost-effective spectrum sharing architecture is proposed to enable the legacy noncognitive secondary system to coexist with the primary system. Specifically, we suggest to install a few intermediate nodes, namely, the cognitive relays, to conduct the spectrum sensing and coordinate the spectrum access. To achieve the goal of win-win between primary and secondary systems, the cognitive relay may act as a cooperator for both of them, and an Opportunistic Cognitive Relaying (OCR scheme is specially devised. In this scheme, the cognitive relay opportunistically switches among three different working modes, that is, Relay for Primary Link (RPL, Relay for Secondary Link (RSL, or Relay for Neither of the Links (RNL, respectively, based on the channel-dependent observation of both systems. In addition, the transmit power for cognitive relay and secondary transmitter in each mode are optimally determined by maximizing the transmission rate of secondary system while keeping or even reducing the outage probability of primary system. Simulation results validate the efficiency of the proposed spectrum sharing scheme.

  2. GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils

    Institute of Scientific and Technical Information of China (English)

    Nariman A B Balenga; Maria Waldhoer; Elma Aflaki; Julia Kargl; Wolfgang Platzer; Ralf Schr(o)der; Stefanie Bl(a)ttermann; Evi Kostenis; Andrew J Brown; Akos Heinemann

    2011-01-01

    The directional migration of neutrophils towards inflammatory mediators,such as chemokines and cannabinoids,occurs via the activation of seven transmembrane G protein coupled receptors (7TM/GPCRs) and is a highly organized process.A crucial role for controlling neutrophil migration has been ascribed to the cannabinoid CB2 receptor (CB2R),but additional modulatory sites distinct from CB2R have recently been suggested to impact CB2R-mediated effector functions in neutrophils.Here,we provide evidence that the recently de-orphanized 7TM/GPCR GPR55potently modulates CB2R-mediated responses.We show that GPR55 is expressed in human blood neutrophils and its activation augments the migratory response towards the CB2R agonist 2-arachidonoylglycerol (2-AG),while inhibiting neutrophil degranulation and reactive oxygen species (ROS) production.Using HEK293 and HL60 cell lines,along with primary neutrophils,we show that GPR55 and CB2R interfere with each other's signaling pathways at the level of small GTPases,such as Rac2 and Cdc42.This ultimately leads to cellular polarization and efficient migration as well as abrogation of degranulation and ROS formation in neutrophils.Therefore,GPR55 limits the tissueinjuring inflammatory responses mediated by CB2R,while it synergizes with CB2R in recruiting neutrophils to sites of inflammation.

  3. Neurophysiological evidence for the presence of cannabinoid CB1 receptors in the laterodorsal tegmental nucleus

    DEFF Research Database (Denmark)

    Soni, Neeraj; Satpathy, Shankha; Kohlmeier, Kristi Anne

    2014-01-01

    Marijuana, which acts within the endocannabinoid (eCB) system as an agonist of the cannabinoid type 1 receptor (CB1R), exhibits addictive properties and has powerful actions on the state of arousal of an organism. The laterodorsal tegmental nucleus (LDT), as a component of the reticular activating...... system, is involved in cortical activation and is important in the development of drug addiction-associated behaviours. Therefore, eCBs might exert behavioural effects by actions on the LDT; however, it is unknown whether eCBs have actions on neurons in this nucleus. Accordingly, whole-cell voltage- and...... changes the firing frequency and synaptic activity of neurons in this nucleus. Therefore, endogenous eCB transmission could play a role in processes involving the LDT, such as cortical activation and motivated behaviours and, further, behavioural actions of marijuana are probably mediated, in part, via...

  4. Cannabinoids in the management of spasticity associated with multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Anna Maria Malfitano

    2008-08-01

    Full Text Available Anna Maria Malfitano, Maria Chiara Proto, Maurizio BifulcoDipartimento di Scienze Farmaceutiche, Università degli Studi di SalernoAbstract: The endocannabinoid system and cannabinoid-based treatments have been involved in a wide number of diseases. In particular, several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis (MS. In this study we highlight the main findings reported in literature about the relevance of cannabinoid drugs in the management and treatment of MS. An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of MS, including spasticity and pain. In this report we focus on the effects of cannabinoids in the relief of spasticity describing the main findings in vivo, in the mouse experimental allergic encephalomyelitis model of MS. We report on the current treatments used to control MS symptoms and the most recent clinical studies based on cannabinoid treatments, although long-term studies are required to establish whether cannabinoids may have a role beyond symptom amelioration in MS.Keywords: cannabinoids, multiple sclerosis, spasticity

  5. The effects of cannabinoid drugs on abnormal involuntary movements in dyskinetic and non-dyskinetic 6-hydroxydopamine lesioned rats.

    Science.gov (United States)

    Walsh, Sinéad; Gorman, Adrienne M; Finn, David P; Dowd, Eilís

    2010-12-01

    The long-term use of levodopa as a pharmacotherapy for Parkinson's disease is limited by the development of levodopa-induced dyskinesias. However, recent studies have suggested that pharmacological targeting of the endocannabinoid system may provide a viable adjunct to suppress these motor side effects. Thus, this study sought to determine the effect of pharmacologically activating or blocking endocannabinoid signalling on levodopa-induced dyskinesias in a rat model. Male Sprague-Dawley rats with 6-hydroxydopamine lesions were made dyskinetic by 6 weeks of daily levodopa injections (10mg/kg s.c.). Rats that developed stable abnormal involuntary movements (AIMs) received acute injections of the cannabinoid receptor agonist, HU210 (0.0, 0.5, 5.0, and 50.0 μg/kg i.p.), or the CB(1) receptor antagonist/inverse agonist, AM251 (0.0 and 3.0mg/kg i.p.), whereas rats that did not develop stable AIMs received injections of the CB(1) receptor antagonist/inverse agonist, rimonabant (0.0 and 3.0mg/kg i.p.), for 18 days. In the dyskinetic rats, the highest dose of HU210 significantly reduced certain subtypes of AIMs but it also impaired normal motor functioning, while AM251 had no effect on AIMs. In the non-dyskinetic rats, rimonabant precipitated certain subtypes of AIMs. Overall, this study demonstrates that the anti-dyskinetic effects of cannabinoid receptor agonists may not be dissociable from their motor suppressant effects thereby limiting their potential usefulness for treating established dyskinesias in parkinsonism. However, it is intriguing that blockade of endocannabinoid-CB(1) signalling can unmask levodopa-induced AIMs, and this finding suggests that endocannabinoid tone may confer protection against the development of levodopa-induced dyskinesias. PMID:20888328

  6. Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol.

    Science.gov (United States)

    Wiley, J L; Compton, D R; Gordon, P M; Siegel, C; Singer, M; Dutta, A; Lichtman, A H; Balster, R L; Razdan, R K; Martin, B R

    1996-01-01

    delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects. PMID:9076759

  7. Synthetic cannabinoid hyperemesis resulting in rhabdomyolysis and acute renal failure.

    Science.gov (United States)

    Argamany, Jacqueline R; Reveles, Kelly R; Duhon, Bryson

    2016-04-01

    Synthetic cannabinoid usage has increased in the past decade. Concurrently, emergency management of associated adverse effects due to synthetic cannabinoid usage has also risen. Reported toxicities include psychosis, seizures, cardiotoxicity, acute kidney injury, and death. While cannabis was first described as a cause of acute hyperemesis in 2004, a more recent case series also describes the association between cannabinoid hyperemesis and risk of acute renal failure. Synthetic cannabinoids have also been reported to cause acute hyperemesis and acute renal failure; however, the risk of rhabdomyolysis-induced renal failure has yet to be elucidated. In this article, we report the first known case of synthetic cannabinoid hyperemesis leading to rhabdomyolysis and acute renal failure. PMID:26422191

  8. Bayesian modeling using WinBUGS

    CERN Document Server

    Ntzoufras, Ioannis

    2009-01-01

    A hands-on introduction to the principles of Bayesian modeling using WinBUGS Bayesian Modeling Using WinBUGS provides an easily accessible introduction to the use of WinBUGS programming techniques in a variety of Bayesian modeling settings. The author provides an accessible treatment of the topic, offering readers a smooth introduction to the principles of Bayesian modeling with detailed guidance on the practical implementation of key principles. The book begins with a basic introduction to Bayesian inference and the WinBUGS software and goes on to cover key topics, including: Markov Chain Monte Carlo algorithms in Bayesian inference Generalized linear models Bayesian hierarchical models Predictive distribution and model checking Bayesian model and variable evaluation Computational notes and screen captures illustrate the use of both WinBUGS as well as R software to apply the discussed techniques. Exercises at the end of each chapter allow readers to test their understanding of the presented concepts and all ...

  9. Cannabinoid hyperemesis syndrome with extreme hydrophilia

    Directory of Open Access Journals (Sweden)

    Enuh HA

    2013-08-01

    Full Text Available Hilary A Enuh,1 Julia Chin,1 Jay Nfonoyim21Department of Medicine, 2Critical Care Unit, Richmond University Medical Center, Staten Island, NY, USAAbstract: Marijuana is the most widely used recreational drug in the US. Hyperemetic hydrophilic syndrome is a previously described but infrequently recognized condition of cannabinoid abuse with hyperemesis and obsessive hot showering. We present a 47-year-old male known marijuana addict with intractable abdominal pain who could not wait for physical examination, meal, or medication, because of obsessive compulsive warm baths. He had a history of epilepsy and addiction to marijuana, which he took on the day of admission. He presented to the hospital with a seizure, complicated by nausea, vomiting, and severe abdominal pain. His examination was unremarkable, except for mild epigastric tenderness. His laboratory and radiological tests were within normal limits, except for a positive urine drug screen for marijuana and opiates. He took himself immediately to the bathroom and remained under a hot shower with the exception of two 15-minute breaks for the rest of the day. He stated that it made him feel better than medication. Receiving medication and even eating was a problem because of this compulsive showering. Abstinence from marijuana during the hospital stay made the patient's nausea and vomiting resolve significantly. Cannabinoid hyperemesis is a differential diagnosis among patients with intractable nausea, vomiting, and obsessive hot bathing. The syndrome is an unmistakable indication of marijuana addiction. A thorough history and observation is very valuable. Recognition of this entity will reduce unnecessary testing and utilization of health care resources.Keywords: cannabinoid, compulsive bathing, cyclic vomiting, hyperemesis, hydrophilia, marijuana

  10. Winning Faces Vary By Ideology

    DEFF Research Database (Denmark)

    Laustsen, Lasse; Petersen, Michael Bang

    2016-01-01

    Not just the content of a communication but also the source of the communication shapes its persuasiveness. Recent research in political communication suggests that important source cues are nonverbal and relate to the physical traits of the source such that attractive- and competent-looking sour......Not just the content of a communication but also the source of the communication shapes its persuasiveness. Recent research in political communication suggests that important source cues are nonverbal and relate to the physical traits of the source such that attractive- and competent...... conservative but backfires and decreases success when the audience is liberal. On the other hand, a non-dominant face constitutes a winning face among liberal audiences but backfires among conservatives. These effects seemingly stem from deep-seated psychological responses and shape both the election and...

  11. Cannabinoid-based medicines for neurological disorders--clinical evidence.

    Science.gov (United States)

    Wright, Stephen

    2007-08-01

    Whereas the cannabis plant has a long history of medicinal use, it is only in recent years that a sufficient understanding of the pharmacology of the main plant constituents has allowed for a better understanding of the most rational therapeutic targets. The distribution of cannabinoid receptors, both within the nervous system and without, and the development of pharmacological tools to investigate their function has lead to a substantial increase in efforts to develop cannabinoids as therapeutic agents. Concomitant with these efforts, the understanding of the pharmacology of plant cannabinoids at receptor and other systems distinct from the cannabinoid receptors suggests that the therapeutic applications of plant-derived cannabinoids (and presumably their synthetic derivatives also) may be diverse. This review aims to discuss the clinical evidence investigating the use of medicines derived, directly or indirectly, from plant cannabinoids with special reference to neurological disorders. Published studies suggest that the oral administration of cannabinoids may not be the preferred route of administration and that plant extracts show greater evidence of efficacy than synthetic compounds. One of these, Sativex (GW Pharmaceuticals), was approved as a prescription medicine in Canada in 2005 and is currently under regulatory review in the EU. PMID:17952657

  12. Asymmetric warfare and the will to win

    OpenAIRE

    Quinn, Matthew D.

    2001-01-01

    This thesis explores the will to win in asymmetric war. Asymmetric war, in which one side has an overwhelming advantage over its opponent, will likely be the war of the future for the United States in the post-Cold War uni-polar world. To win an asymmetric war, the individual and then the masses must be motivated to fight and, ultimately, the will to win must be cultivated and sustained for victory. Religion is a highly effective motivat or for both the individual and the masses. This motiva...

  13. Inhibition of leukocyte function and interleukin-2 gene expression by 2-methylarachidonyl-(2'-fluoroethyl)amide, a stable congener of the endogenous cannabinoid receptor ligand anandamide

    International Nuclear Information System (INIS)

    Arachidonylethanolamide (anandamide, AEA) has been identified as an endogenous ligand for cannabinoid receptors CB1 and CB2. Characterization of the direct cannabimimetic actions of anandamide has been hampered by its short duration of action and rapid degradation in in vivo and in vitro systems to arachidonic acid, a precursor in the biosynthesis of a broad range of biologically active molecules. In the present studies, we utilized 2-methylarachidonyl-(2'-fluoroethyl)amide (F-Me-AEA), an analog of anandamide resistant to enzymatic degradation, to determine whether F-Me-AEA modulated T cell function similar to that of plant-derived cannabinoids. Indeed, F-Me-AEA at low micromolar concentrations exhibited a marked inhibition of phorbol ester plus calcium ionophore (PMA/Io)-induced IL-2 protein secretion and steady state mRNA expression. Likewise, a modest suppression of the mixed lymphocyte response was observed in the presence of F-Me-AEA indicating an alteration in T cell responsiveness to allogeneic MHC class II antigens. F-Me-AEA was also found to modestly inhibit forskolin-stimulated adenylate cyclase activity in thymocytes and splenocytes, a hallmark of cannabinoid receptor agonists. Further characterization of the influence of F-Me-AEA on the cAMP signaling cascade revealed an inhibition of CREB-1/ATF-1 phosphorylation and subsequently, an inhibition of CRE DNA binding activity. Characterization of nuclear binding proteins further revealed that NF-AT and, to a lesser extent, NF-κB DNA binding activities were also suppressed. These studies demonstrate that F-Me-AEA modulates T cell function in a similar manner to plant-derived and endogenous cannabinoids and therefore can be utilized as an amidase- and hydrolysis-resistant endogenous cannabinoid

  14. Can a near win kindle motivation? The impact of nearly winning on motivation for unrelated rewards.

    Science.gov (United States)

    Wadhwa, Monica; Kim, JeeHye Christine

    2015-06-01

    Common intuition and research suggest that winning is more motivating than losing. However, we propose that just failing to obtain a reward (i.e., nearly winning it) in one task leads to broader, positive motivational effects on subsequent unrelated tasks relative to clearly losing or actually obtaining the reward. We manipulated a near-win experience using a game app in Experiments 1 through 3 and a lottery in Experiment 4. Our findings showed that nearly winning in one task subsequently led participants to walk faster to get to a chocolate bar (Experiment 1), salivate more for money (Experiment 2), and increase their effort to earn money in a card-sorting task (Experiment 3). A field study (Experiment 4) demonstrated that nearly winning led people to subsequently spend more money on desirable consumer products. Finally, our findings showed that when the activated motivational state was dampened in an intervening task, the nearly-winning effect was attenuated. PMID:25940671

  15. Case Series of Synthetic Cannabinoid Intoxication from One Toxicology Center

    Directory of Open Access Journals (Sweden)

    Kenneth D. Katz

    2016-05-01

    Full Text Available Synthetic cannabinoid use has risen at alarming rates. This case series describes 11 patients exposed to the synthetic cannabinoid, MAB-CHMINACA who presented to an emergency department with life-threatening toxicity including obtundation, severe agitation, seizures and death. All patients required sedatives for agitation, nine required endotracheal intubation, three experienced seizures, and one developed hyperthermia. One developed anoxic brain injury, rhabdomyolysis and died. A significant number were pediatric patients. The mainstay of treatment was aggressive sedation and respiratory support. Synthetic cannabinoids pose a major public health risk. Emergency physicians must be aware of their clinical presentation, diagnosis and treatment.

  16. The Endocannabinoid System, Cannabinoids, and Pain

    Directory of Open Access Journals (Sweden)

    Perry G. Fine

    2013-10-01

    Full Text Available The endocannabinoid system is involved in a host of homeostatic and physiologic functions, including modulation of pain and inflammation. The specific roles of currently identified endocannabinoids that act as ligands at endogenous cannabinoid receptors within the central nervous system (primarily but not exclusively CB1 receptors and in the periphery (primarily but not exclusively CB2 receptors are only partially elucidated, but they do exert an influence on nociception. Exogenous plant-based cannabinoids (phytocannabinoids and chemically related compounds, like the terpenes, commonly found in many foods, have been found to exert significant analgesic effects in various chronic pain conditions. Currently, the use of Δ9-tetrahydrocannabinol is limited by its psychoactive effects and predominant delivery route (smoking, as well as regulatory or legal constraints. However, other phytocannabinoids in combination, especially cannabidiol and β-caryophyllene, delivered by the oral route appear to be promising candidates for the treatment of chronic pain due to their high safety and low adverse effects profiles. This review will provide the reader with the foundational basic and clinical science linking the endocannabinoid system and the phytocannabinoids with their potentially therapeutic role in the management of chronic pain.

  17. Lion and Man -- Can Both Win?

    CERN Document Server

    Bollobás, B; Walters, M

    2009-01-01

    This paper is concerned with continuous-time pursuit and evasion games. Typically, we have a lion and a man in a metric space: they have the same speed, and the lion wishes to catch the man while the man tries to evade capture. We are interested in questions of the following form: is it the case that exactly one of the man and the lion has a winning strategy? As we shall see, in a compact metric space at least one of the players has a winning strategy. We show that, perhaps surprisingly, there are examples in which both players have winning strategies. We also construct a metric space in which, for the game with two lions versus one man, neither player has a winning strategy. We prove various other (positive and negative) related results, and pose some open problems.

  18. Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists.

    Science.gov (United States)

    Altun, Ahmet; Yildirim, Kemal; Ozdemir, Ercan; Bagcivan, Ihsan; Gursoy, Sinan; Durmus, Nedim

    2015-09-01

    Cannabinoid CB1 and CB2 receptor antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance. The aim of this study was to investigate the effects of AM251 (a selective CB1 antagonist) and JTE907 (a selective CB2 antagonist) on morphine analgesia and tolerance in rats. Adult male Wistar albino rats weighing 205-225 g were used in these experiments. To constitute morphine tolerance, we used a 3 day cumulative dosing regimen. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated by analgesia tests. The analgesic effects of morphine (5 mg/kg), ACEA (a CB1 receptor agonist, 5 mg/kg), JWH-015 (a CB2 receptor agonist, 5 mg/kg), AM251 (1 mg/kg) and JTE907 (5 mg/kg) were considered at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. Our findings indicate that ACEA and JWH907 significantly increased morphine analgesia and morphine antinociceptive tolerance in the analgesia tests. In contrast, the data suggested that AM251 and JTE907 significantly attenuated the expression of morphine tolerance. In conclusion, we observed that co-injection of AM251 and JTE907 with morphine attenuated expression of tolerance to morphine analgesic effects and decreased the morphine analgesia. PMID:25894754

  19. Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced β-Endorphin Release.

    Science.gov (United States)

    Gao, Fang; Zhang, Ling-Hong; Su, Tang-Feng; Li, Lin; Zhou, Rui; Peng, Miao; Wu, Cai-Hua; Yuan, Xiao-Cui; Sun, Ning; Meng, Xian-Fang; Tian, Bo; Shi, Jing; Pan, Hui-Lin; Li, Man

    2016-08-01

    Activation of cannabinoid receptor-2 (CB2) results in β-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception. However, the underlying mechanism is still unknown. The CB2 receptor is generally thought to couple to Gi/o to inhibit cAMP production, which cannot explain the peripheral stimulatory effects of CB2 receptor activation. In this study, we found that in a keratinocyte cell line, the Gβγ subunits from Gi/o, but not Gαs, were involved in CB2 receptor activation-induced β-endorphin release. Inhibition of MAPK kinase, but not PLC, abolished CB2 receptor activation-induced β-endorphin release. Also, CB2 receptor activation significantly increased intracellular Ca(2+). Treatment with BAPTA-AM or thapsigargin blocked CB2 receptor activation-induced β-endorphin release. Using a rat model of inflammatory pain, we showed that the MAPK kinase inhibitor PD98059 abolished the peripheral effect of the CB2 receptor agonist on nociception. We thus present a novel mechanism of CB2 receptor activation-induced β-endorphin release through Gi/o-Gβγ-MAPK-Ca(2+) signaling pathway. Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists. PMID:26108183

  20. Who will win the Nobel Prize?

    OpenAIRE

    Terence tai-leung Chong; Cally Choi; Benjamin Everard

    2009-01-01

    This paper identifies the determinants of the Nobel Prize Award. The analysis is analogous in spirit to Hamermesh and Schmidt (Econometrica, 2003) on the election of Econometric Society fellows. It is found that the number of citations, age and nationality have significant impacts on the odds of winning the Nobel. We provide the first statistical evidence that John Bates Clark medalists and individuals affiliated with the University of Chicago have a higher chance of winning the Prize.

  1. Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms.

    Science.gov (United States)

    Michler, Thomas; Storr, Martin; Kramer, Johannes; Ochs, Stefanie; Malo, Antje; Reu, Simone; Göke, Burkhard; Schäfer, Claus

    2013-01-15

    The endocannabinoid system has been shown to mediate beneficial effects on gastrointestinal inflammation via cannabinoid receptors 1 (CB(1)) and 2 (CB(2)). These receptors have also been reported to activate the MAP kinases p38 and c-Jun NH(2)-terminal kinase (JNK), which are involved in early acinar events leading to acute pancreatitis and induction of proinflammatory cytokines. Our aim was to examine the role of cannabinoid receptor activation in an experimental model of acute pancreatitis and the potential involvement of MAP kinases. Cerulein pancreatitis was induced in wild-type, CB(1)-/-, and MK2-/- mice pretreated with selective cannabinoid receptor agonists or antagonists. Severity of pancreatitis was determined by serum amylase and IL-6 levels, intracellular activation of pancreatic trypsinogen, lung myeloperoxidase activity, pancreatic edema, and histological examinations. Pancreatic lysates were investigated by Western blotting using phospho-specific antibodies against p38 and JNK. Quantitative PCR data, Western blotting experiments, and immunohistochemistry clearly show that CB(1) and CB(2) are expressed in mouse pancreatic acini. During acute pancreatitis, an upregulation especially of CB(2) on apoptotic cells occurred. The unselective CB(1)/CB(2) agonist HU210 ameliorated pancreatitis in wild-type and CB(1)-/- mice, indicating that this effect is mediated by CB(2). Furthermore, blockade of CB(2), not CB(1), with selective antagonists engraved pathology. Stimulation with a selective CB(2) agonist attenuated acute pancreatitis and an increased activation of p38 was observed in the acini. With use of MK2-/- mice, it could be demonstrated that this attenuation is dependent on MK2. Hence, using the MK2-/- mouse model we reveal a novel CB(2)-activated and MAP kinase-dependent pathway that modulates cytokine expression and reduces pancreatic injury and affiliated complications. PMID:23139224

  2. Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation Review

    OpenAIRE

    Rom, Slava; Persidsky, Yuri

    2013-01-01

    An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB1, CB2) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthr...

  3. Cannabinoids in the management of spasticity associated with multiple sclerosis

    OpenAIRE

    Anna Maria Malfitano; Maria Chiara Proto; Maurizio Bifulco

    2008-01-01

    Anna Maria Malfitano, Maria Chiara Proto, Maurizio BifulcoDipartimento di Scienze Farmaceutiche, Università degli Studi di SalernoAbstract: The endocannabinoid system and cannabinoid-based treatments have been involved in a wide number of diseases. In particular, several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis (MS). In this study we highlight the main findings reported in literature about the r...

  4. Medical cannabis vs. synthetic cannabinoids: What does the future hold?

    Science.gov (United States)

    Bolognini, D; Ross, R A

    2015-06-01

    The medical use of cannabis has an intricate therapeutic history that finds its roots in ancient China (∼2700 BC). The main psychoactive component of cannabis, Δ(9) -tetrahydrocannabinol (Δ(9) -THC), was discovered in 1964. This was a significant breakthrough, as it allowed the generation of synthetic analogs of Δ(9) -THC, the discovery of cannabinoid receptors, and the generation of synthetic small molecules. Despite this, today there is still a paucity of drugs that target the cannabinoid system. PMID:25761845

  5. Cannabinoids and cancer: pros and cons of an antitumour strategy

    OpenAIRE

    Bifulco, Maurizio; Laezza, Chiara; Pisanti, Simona; Gazzerro, Patrizia

    2006-01-01

    In the last two decades, research has dramatically increased the knowledge of cannabinoids biology and pharmacology. In mammals, compounds with properties similar to active components of Cannabis sativa, the so called ‘endocannabinoids', have been shown to modulate key cell-signalling pathways involved in cancer cell growth, invasion and metastasis. To date, cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increased evidences showed direct antiprol...

  6. A Win-Win-Win Proposition -- Academia and Industry Working Together for Students

    Science.gov (United States)

    Cogswell, J.

    2011-12-01

    geoscience, to include having applied real problem solving via a robust field camp experience. In addition, we look for the maturity and ability to conduct independent research, to integrate broad suites of data, and to work as a team. We look for the ability to communicate results. We do not look for a focus on petroleum. We have many decades of experience in how to best develop that particular discipline quickly, to meet current and future business conditions. There are recurring themes that facilitate successful transition from Academia to a practicing industry geoscientist. These themes include giving students a good grounding in STEM, not just geology; one-on-one mentoring; sharing our passion for the science by sharing our research; and sharing the entire breadth of career opportunities. Similar best practices have been identified to encourage under-represented minority students and women to study STEM. Perhaps this is a suite of habits we should be practicing more broadly. This suite of habits takes extra time, extra effort, and extra money. But if geoscience mentors in Academia, Industry, and professional societies work together, we will be able to create a win for Academia, a win for Industry, and a win for students. (1) Gonzales and Keane, 2011, "Status of the Geoscience Workforce -- 2011," AGI, p. 123.

  7. [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor

    OpenAIRE

    Burns, H. Donald; Van Laere, Koen; Sanabria-Bohórquez, Sandra; Hamill, Terence G.; Bormans, Guy; Eng, Wai-si; Gibson, Ray; Ryan, Christine; Connolly, Brett; Patel, Shil; Krause, Stephen; Vanko, Amy; Van Hecken, Anne; DUPONT, Patrick; De Lepeleire, Inge

    2007-01-01

    [(18)F]MK-9470 is a selective, high-affinity, inverse agonist (human IC(50), 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed for use in human brain imaging. Autoradiographic studies in rhesus monkey brain showed that [(18)F]MK-9470 binding is aligned with the reported distribution of CB1 receptors with high specific binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Positron emission tomography (PET) imaging...

  8. Global Fold of Human Cannabinoid Type 2 Receptor Probed by Solid-State 13C-, 15N-MAS NMR and Molecular Dynamics Simulations

    OpenAIRE

    Kimura, Tomohiro; Vukoti, Krishna; Lynch, Diane L.; Hurst, Dow P.; Grossfield, Alan; Pitman, Michael C.; Reggio, Patricia H.; Yeliseev, Alexei A.; Gawrisch, Klaus

    2013-01-01

    The global fold of human cannabinoid type 2 (CB2) receptor in the agonist-bound active state in lipid bilayers was investigated by solid-state 13C- and 15N magic-angle spinning (MAS) NMR, in combination with chemical-shift prediction from a structural model of the receptor obtained by microsecond-long molecular dynamics (MD) simulations. Uniformly 13C-, and 15N-labeled CB2 receptor was expressed in milligram quantities by bacterial fermentation, purified, and functionally reconstituted into l...

  9. Effects of cannabinoid CB(1) receptor agonism and antagonism on SKF81297-induced dyskinesia and haloperidol-induced dystonia in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Madsen, Morten V; Peacock, Linda P; Werge, Thomas;

    2011-01-01

    Antipsychotic drugs may cause extrapyramidal symptoms (EPS), such as dyskinesia and dystonia. These effects are believed to involve dysfunctional striatal dopamine transmission. Patients with schizophrenia show increased prevalence of cannabis abuse and this has been linked to severity of EPS....... Endocannabinoids modulate striatal dopamine activity via type 1 cannabinoid (CB(1)) receptors, and studies in rats and humans suggest beneficial effects of CB(1) ligands on EPS. The present study explored the effects of CB(1) receptor ligands on oral dyskinesia induced by the dopamine D(1) receptor agonist SKF...

  10. Cannabinoids decrease the th17 inflammatory autoimmune phenotype.

    Science.gov (United States)

    Kozela, Ewa; Juknat, Ana; Kaushansky, Nathali; Rimmerman, Neta; Ben-Nun, Avraham; Vogel, Zvi

    2013-12-01

    Cannabinoids, the Cannabis constituents, are known to possess anti-inflammatory properties but the mechanisms involved are not understood. Here we show that the main psychoactive cannabinoid, Δ-9-tetrahydrocannabinol (THC), and the main nonpsychoactive cannabinoid, cannabidiol (CBD), markedly reduce the Th17 phenotype which is known to be increased in inflammatory autoimmune pathologies such as Multiple Sclerosis. We found that reactivation by MOG35-55 of MOG35-55-specific encephalitogenic T cells (cells that induce Experimental Autoimmune Encephalitis when injected to mice) in the presence of spleen derived antigen presenting cells led to a large increase in IL-17 production and secretion. In addition, we found that the cannabinoids CBD and THC dose-dependently (at 0.1-5 μM) suppressed the production and secretion of this cytokine. Moreover, the mRNA and protein of IL-6, a key factor in Th17 induction, were also decreased. Pretreatment with CBD also resulted in increased levels of the anti-inflammatory cytokine IL-10. Interestingly, CBD and THC did not affect the levels of TNFα and IFNγ. The downregulation of IL-17 secretion by these cannabinoids does not seem to involve the CB1, CB2, PPARγ, 5-HT1A or TRPV1 receptors. In conclusion, the results show a unique cannabinoid modulation of the autoimmune cytokine milieu combining suppression of the pathogenic IL-17 and IL-6 cytokines along with boosting the expression of the anti-inflammatory cytokine IL-10. PMID:23892791

  11. Cellular mechanisms underlying the interaction between cannabinoid and opioid system.

    Science.gov (United States)

    Parolaro, D; Rubino, T; Viganò, D; Massi, P; Guidali, C; Realini, N

    2010-04-01

    Recently, the presence of functional interaction between the opioid and cannabinoid system has been shown in various pharmacological responses. Although there is an increasing interest for the feasible therapeutic application of a co-administration of cannabinoids and opioids in some disorders (i.e. to manage pain, to modulate immune system and emotions) and the combined use of the two drugs by drug abusers is becoming largely diffuse, only few papers focused on cellular and molecular mechanisms underlying this interaction. This review updates the biochemical and molecular underpinnings of opioid and cannabinoid interaction, both within the central nervous system and periphery. The most convincing theory for the explanation of this reciprocal interaction involves (i) the release of opioid peptides by cannabinoids or endocannabinoids by opioids, (ii) the existence of a direct receptor-receptor interaction when the receptors are co-expressed in the same cells, and (iii) the interaction of their intracellular pathways. Finally, the cannabinoid/opioid interaction might be different in the brain rewarding networks and in those accounting for other pharmacological effects (antinociception, modulation of emotionality and cognitive behavior), as well as between the central nervous system and periphery. Further insights about the cannabinoid/opioid interaction could pave the way for new and promising therapeutic approaches. PMID:20017730

  12. The effects of win-win conditions on revenue-sharing contracts

    NARCIS (Netherlands)

    Timmer, J.B.

    2004-01-01

    This paper studies revenue-sharing contracts in distribution chains in the presence of win-win conditions. Revenue-sharing contracts are a mechanism to coordinate the firms in a distribution chain. Under these contracts the retailer shares its revenue with the supplier in exchange for a lower wholes

  13. 26 CFR 1.50B-1 - Definitions of WIN expenses and WIN employees.

    Science.gov (United States)

    2010-04-01

    ..., beneficiary of an estate or trust, or a shareholder of an electing small business corporation, by such partnership, estate, trust, or electing small business corporation) under a work incentive (WIN) program... employee. (c) Trade or business expenses. The term “WIN expenses” includes only salaries and wages...

  14. Challenging the win-win discourse on conservation and development: analyzing support for marine protected areas

    Directory of Open Access Journals (Sweden)

    Tomas Chaigneau

    2016-03-01

    Full Text Available Conservation designations such as protected areas are increasing in numbers around the world, yet it is widely reported that many are failing to reach their objectives. They are frequently promoted as opportunities for win-win outcomes that can both protect biodiversity and lead to economic benefits for affected communities. This win-win view characterizes the dominant discourse surrounding many protected areas. Although this discourse and the arguments derived from it may lead to initial acceptance of conservation interventions, this study shows how it does not necessarily result in compliance and positive attitudes toward specific protected areas. Consequently, the discourse has important implications not just for making the case for protected area implementation, but also for the likelihood of protected areas reaching their objectives. We explain how the win-win discourse influences support for marine protected areas (MPAs and, ultimately, their success. Using data from focus groups, questionnaires, and in-depth interviews at three MPA sites in the Philippines, we identified three reasons why the win-win discourse can negatively influence prolonged support for MPAs: dashed expectations, inequity, and temptation. Through an understanding of these issues, it becomes possible to suggest improvements that can be made pre-MPA implementation that can lead to prolonged support of MPAs. A focus on less tangible and economic MPA benefits, aligning MPA goals with cultural and social values, and higher levels of transparency when describing MPA outcomes are all ways in which prolonged support of MPAs can be bolstered.

  15. CB1 cannabinoid receptor antagonism promotes remodeling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infarction

    OpenAIRE

    Wagner, Jens A.; Hu, Kai; Karcher, Jan; Bauersachs, Johann; Schäfer, Andreas; Laser, Martin; Han, Hong; Ertl, Georg

    2003-01-01

    To study the long-term effects of altered cannabinoid receptor activity on myocardial and vascular function, Wistar rats were treated with the selective CB1 antagonist AM-251 (0.5 mg kg−1 d−1), the potent synthetic cannabinoid HU-210 (50 μg kg−1 d−1) or vehicle for 12 weeks after coronary artery ligation or sham operation.AM-251 further reduced the pressure-generating capacity, shifted the pressure volume curve to the right (P

  16. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB{sub 1} receptors and apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Tomiyama, Ken-ichi; Funada, Masahiko, E-mail: mfunada@ncnp.go.jp

    2014-01-01

    The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB{sub 1} receptor antagonist AM251, but not with the selective CB{sub 2} receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB{sub 1} receptors.

  17. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death

    International Nuclear Information System (INIS)

    The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB1 receptor antagonist AM251, but not with the selective CB2 receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB1 receptor, but not by the CB2 receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB1 receptor, but not by the CB2 receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB1 receptors

  18. Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training

    NARCIS (Netherlands)

    Morena, M.; Roozendaal, B.; Trezza, V.; Ratano, P.; Peloso, A.; Hauer, D.; Atsak, P.; Trabace, L.; Cuomo, V.; McGaugh, J.L.; Schelling, G.; Campolongo, P.

    2014-01-01

    Previous studies have provided extensive evidence that administration of cannabinoid drugs after training modulates the consolidation of memory for an aversive experience. The present experiments investigated whether the memory consolidation is regulated by endogenously released cannabinoids. The ex

  19. Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects.

    Directory of Open Access Journals (Sweden)

    Emmanuel S Onaivi

    Full Text Available BACKGROUND: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R but not (H316Y polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.

  20. R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.

    Directory of Open Access Journals (Sweden)

    Philipp Bishay

    Full Text Available BACKGROUND: R-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: We show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB, which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPARgamma and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists. CONCLUSION: Our results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain.

  1. Dopaminergic agonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy....

  2. Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression

    OpenAIRE

    Rieder, Sadiye Amcaoglu; Chauhan, Ashok; Singh, Ugra; Nagarkatti, Mitzi; Nagarkatti, Prakash

    2009-01-01

    Cannabinoids are a group of compounds present in Cannabis plant (Cannabis sativa L.). They mediate their physiological and behavioral effects by activating specific cannabinoid receptors. With the recent discovery of the cannabinoid receptors (CB1 and CB2) and the endocannabinoid system, research in this field has expanded exponentially. Cannabinoids have been shown to act as potent immunosuppressive and anti-inflammatory agents and have been shown to mediate beneficial effects in a wide rang...

  3. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...... presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide and...... liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  4. Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery.

    Science.gov (United States)

    Hu, Jianping; Feng, Zhiwei; Ma, Shifan; Zhang, Yu; Tong, Qin; Alqarni, Mohammed Hamed; Gou, Xiaojun; Xie, Xiang-Qun

    2016-06-27

    Cannabinoid receptor 2 (CB2), a G protein-coupled receptor (GPCR), is a promising target for the treatment of neuropathic pain, osteoporosis, immune system, cancer, and drug abuse. The lack of an experimental three-dimensional CB2 structure has hindered not only the development of studies of conformational differences between the inactive and active CB2 but also the rational discovery of novel functional compounds targeting CB2. In this work, we constructed models of both inactive and active CB2 by homology modeling. Then we conducted two comparative 100 ns molecular dynamics (MD) simulations on the two systems-the active CB2 bound with both the agonist and G protein and the inactive CB2 bound with inverse agonist-to analyze the conformational difference of CB2 proteins and the key residues involved in molecular recognition. Our results showed that the inactive CB2 and the inverse agonist remained stable during the MD simulation. However, during the MD simulations, we observed dynamical details about the breakdown of the "ionic lock" between R131(3.50) and D240(6.30) as well as the outward/inward movements of transmembrane domains of the active CB2 that bind with G proteins and agonist (TM5, TM6, and TM7). All of these results are congruent with the experimental data and recent reports. Moreover, our results indicate that W258(6.48) in TM6 and residues in TM4 (V164(4.56)-L169(4.61)) contribute greatly to the binding of the agonist on the basis of the binding energy decomposition, while residues S180-F183 in extracellular loop 2 (ECL2) may be of importance in recognition of the inverse agonist. Furthermore, pharmacophore modeling and virtual screening were carried out for the inactive and active CB2 models in parallel. Among all 10 hits, two compounds exhibited novel scaffolds and can be used as novel chemical probes for future studies of CB2. Importantly, our studies show that the hits obtained from the inactive CB2 model mainly act as inverse agonist(s) or neutral

  5. Winning a competition predicts dishonest behavior

    Science.gov (United States)

    Schurr, Amos; Ritov, Ilana

    2016-01-01

    Winning a competition engenders subsequent unrelated unethical behavior. Five studies reveal that after a competition has taken place winners behave more dishonestly than competition losers. Studies 1 and 2 demonstrate that winning a competition increases the likelihood of winners to steal money from their counterparts in a subsequent unrelated task. Studies 3a and 3b demonstrate that the effect holds only when winning means performing better than others (i.e., determined in reference to others) but not when success is determined by chance or in reference to a personal goal. Finally, study 4 demonstrates that a possible mechanism underlying the effect is an enhanced sense of entitlement among competition winners. PMID:26831083

  6. Control of Inhibition by the Direct Action of Cannabinoids on GABAA Receptors

    NARCIS (Netherlands)

    Golovko, Tatiana; Min, R.; Lozovaya, Natalia; Falconer, Caroline; Yatsenko, Natalia; Tsintsadze, Timur; Tsintsadze, Vera; Ledent, Catherine; Harvey, Robert J; Belelli, Delia; Lambert, Jeremy J; Rozov, Andrei; Burnashev, Nail

    2015-01-01

    Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB1 receptors (CB1Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABAA receptors (GABAARs), potentiating currents a

  7. Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2.

    Science.gov (United States)

    Tang, Jun; Chen, Qianwei; Guo, Jing; Yang, Liming; Tao, Yihao; Li, Lin; Miao, Hongping; Feng, Hua; Chen, Zhi; Zhu, Gang

    2016-04-01

    Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns leading to detrimental neurological sequelae. Minocycline has been reported to play a key role in neurological inflammatory diseases by controlling some mechanisms that involve cannabinoid receptor 2 (CB2R). The current study investigated whether minocycline reduces neuroinflammation and protects the brain from injury in a rat model of collagenase-induced GMH by regulating CB2R activity. To test this hypothesis, the effects of minocycline and a CB2R antagonist (AM630) were evaluated in male rat pups that were post-natal day 7 (P7) after GMH. We found that minocycline can lead to increased CB2R mRNA expression and protein expression in microglia. Minocycline significantly reduced GMH-induced brain edema, microglial activation, and lateral ventricular volume. Additionally, minocycline enhanced cortical thickness after injury. All of these neuroprotective effects of minocycline were prevented by AM630. A cannabinoid CB2 agonist (JWH133) was used to strengthen the hypothesis, which showed the identical neuroprotective effects of minocycline. Our study demonstrates, for the first time, that minocycline attenuates neuroinflammation and brain injury in a rat model of GMH, and activation of CBR2 was partially involved in these processes. PMID:25833102

  8. How to win friends and influence people

    CERN Document Server

    Carnegie, Dale

    2010-01-01

    For more than sixty years the rock-solid, time-tested advice in this book has carried thousands of now famous people up the ladder of success in their business and personal lives. With more than fifteen million copies sold, How to Win Friends and Influence People is one of the best known motivational books in history, with proven advice for achieving success in life. You’ll learn: three fundamental techniques in handling people; six ways to make people like you; twelve ways to win people to you way of thinking; nine ways to change people without arousing resentment; and much, much more!

  9. FTW (For the Win / Fuck the World)

    OpenAIRE

    Summers, Francis; Minkin, Louisa

    2012-01-01

    Participation in the group exhibition curated by Bernice Donszelmann, Tim Renshaw and Mary McLean. Exhibited the work FTW (For the Win / Fuck the World) made in collaboration with Louisa Minkin. Here we use the format of the triumphal procession to pose questions around the twinned states of glory and nihilism. FTW! (For The Win / Fuck The World) is a banner that combines a letter to a generic addressee alongside a selection of internet memes, rage comic figures and images of disaster and cel...

  10. Stellar students win fantastic prizes

    Science.gov (United States)

    2008-05-01

    School students and teachers across Europe and around the world are discovering today who has won fantastic prizes in "Catch a Star", the international astronomical competition run by ESO and the European Association for Astronomy Education (EAAE). CAS2008 artwork ESO PR Photo 14/08 One of the winning artworks "We were extremely impressed by the high quality of the entries, and the number of participants was even higher than last year. We wish to congratulate everybody who took part," said Douglas Pierce-Price, Education Officer at ESO. "'Catch a Star' clearly shows astronomy's power to inspire and excite students of all ages," added Fernand Wagner, President of the EAAE. The top prize, of a week-long trip to Chile to visit the ESO Very Large Telescope (VLT) on Paranal, was won by students Roeland Heerema, Liesbeth Schenkels, and Gerben Van Ranst from the Instituut Spijker in Hoogstraten, Belgium, together with their teacher Ann Verstralen. With their "story of aged binary stars... Live and Let Die", they take us on a vivid tour of the amazing zoo of binary stars, and the life and death of stars like our Sun. The students show how state-of-the-art telescopes, particularly those at ESO's sites of La Silla and Paranal, help us understand these stars. They take as an illustrative example the binary star system V390 Velorum. In the last phases of its life, V390 Velorum will shed its outer shell of gas and dust, turning from a celestial chrysalis into a beautiful cosmic butterfly. The students also involved other pupils from their school, showing them how to test their eyesight by observing the binary star system of Alcor and Mizar. But perhaps the most important discovery they made is that, as they write in their report, "Astronomy lives! Discoveries are being made each day and there is still very much to be found and learned by astronomers!" The team will travel to Chile and visit the ESO VLT - the world's most advanced optical/infrared telescope. At Paranal, they

  11. The therapeutic potential of cannabinoids for movement disorders.

    Science.gov (United States)

    Kluger, Benzi; Triolo, Piera; Jones, Wallace; Jankovic, Joseph

    2015-03-01

    There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid-based chemicals within the medical community and, particularly, for neurological conditions. This interest is driven both by changes in the legal status of cannabis in many areas and increasing research into the roles of endocannabinoids within the central nervous system and their potential as symptomatic and/or neuroprotective therapies. We review basic science as well as preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders. The pharmacology of cannabis is complex, with over 60 neuroactive chemicals identified to date. The endocannabinoid system modulates neurotransmission involved in motor function, particularly within the basal ganglia. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits, but more consistently suggest potential neuroprotective effects in several animal models of Parkinson's (PD) and Huntington's disease (HD). Clinical observations and clinical trials of cannabinoid-based therapies suggests a possible benefit of cannabinoids for tics and probably no benefit for tremor in multiple sclerosis or dyskinesias or motor symptoms in PD. Data are insufficient to draw conclusions regarding HD, dystonia, or ataxia and nonexistent for myoclonus or RLS. Despite the widespread publicity about the medical benefits of cannabinoids, further preclinical and clinical research is needed to better characterize the pharmacological, physiological, and therapeutic effects of this class of drugs in movement disorders. PMID:25649017

  12. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide and...... liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  13. Winning the sustainable development debate

    International Nuclear Information System (INIS)

    on a vast scale Access to energy - and in particular, electricity - will be critical if the world is to achieve these human goals. Access to clean electricity - and on a vast scale - will be necessary if the world is to meet the twin challenges of human need and environmental security. Anti-nuclear forces, which have held sway in the Kyoto process thus far, argue that nuclear energy is a dying technology and assert passionately that it has no place in tomorrow's sustainable development agenda. These ideologically driven arguments ignore underlying realities both as to what is feasible and what is actually occurring. Today, nuclear power plants are operational in countries comprising 64% of the world's population, and new power reactors are in the planning or construction stage in countries representing no less than 50% of the world's population. Among the latter are the world's two largest developing countries, China and India, which alone represent 40% of humankind and about half the developing world. With active nuclear reactor construction under way as we speak, these leading nations have already made nuclear power a part of their sustainable development strategies for the 21st century. Winning the sustainable development debate - This presentation will share information materials about sustainable development. It will describe the work of the World Nuclear Association Sustainable Development Strategy Group, its preparations for the World Summit on Sustainable Development, and how participants to PIME can get involved. (author)

  14. Using cannabinoids in pain and palliative care.

    Science.gov (United States)

    Peat, Sue

    2010-10-01

    Interest in the use of cannabinoids in a clinical setting is gradually increasing, particularly in patients where more conventional treatments have failed. They have been reported as offering perceived benefits in a wide range of conditions, but the major interest at present is centred on their place in pain management and in the palliation of symptoms secondary to terminal cancer and neurological disease. The potential benefits include symptomatic relief for patients suffering from intractable neuropathic pain, anorexia, anxiety and muscle spasm. There is clear consensus that cannibinoids should not be used as a first-line monotherapy, but should be considered as valuable adjuvants to more commonly indicated therapeutic options in the management of palliative care patients. Scientific evidence documenting the benefits of the canibinoids nabilone and sativex is accumulating, but needs to be evaluated carefully in the light of the paucity of available data. Both drugs are usually used under the guidance of specialist units. Nabilone and Sativex are now controlled drugs, and are frequently used outside of their licensed indication (control of chemotherapy-induced nausea and vomiting) and hence particular care needs to be taken in evaluating the rational for their use. Sativex has been recently licenced for use in the management of patients with multiple sclerosis. PMID:20972379

  15. Therapeutic Potential of Cannabinoids in Psychosis.

    Science.gov (United States)

    Leweke, F Markus; Mueller, Juliane K; Lange, Bettina; Rohleder, Cathrin

    2016-04-01

    Over recent years, the interest in the endocannabinoid system (ECS) as a new target for the treatment of schizophrenia has evolved. The ECS represents one of the most relevant neurotransmitter systems in the brain and mainly fulfills a homeostatic role in terms of neurotransmission but also with respect to inflammatory processes. Two main approaches to the modulation of endocannabinoid functioning have been chosen so far. First, the selective blockade or inverse agonism of the type 1 cannabinoid receptor has been tested for the improvement of acute psychotic symptoms, as well as for the improvement of cognitive functions in schizophrenia. This was not effective in either case. Second, the modulation of endocannabinoid levels by use of the phytocannabinoid cannabidiol and selective fatty acid amide hydrolase inhibitors has been proposed, and the antipsychotic properties of cannabidiol are currently being investigated in humans. Unfortunately, for most of these trials that have focused on psychopathological and cognitive effects of cannabidiol, no published data are available. However, there is first evidence that cannabidiol may ameliorate psychotic symptoms with a superior side-effect profile compared with established antipsychotics. In conclusion, several clinical trials targeting the ECS in acute schizophrenia have either been completed or are underway. Although publicly available results are currently limited, preliminary data indicate that selected compounds modulating the ECS may be effective in acute schizophrenia. Nevertheless, so far, sample sizes of patients investigated are not sufficient to come to a final judgment, and no maintenance studies are available to ensure long-term efficacy and safety. PMID:26852073

  16. Evaluation of principal cannabinoids in airborne particulates

    Energy Technology Data Exchange (ETDEWEB)

    Balducci, C., E-mail: balducci@iia.cnr.it [Italian National Research Council, Institute for Atmospheric Pollution (CNR-IIA), Monterotondo Stazione (Italy); Nervegna, G.; Cecinato, A. [Italian National Research Council, Institute for Atmospheric Pollution (CNR-IIA), Monterotondo Stazione (Italy)

    2009-05-08

    The determination of delta(9)-tetrahydrocannabinol ({Delta}{sup 9}-THC), cannabidiol (CND) and cannabinol (CNB), primary active components in cannabis preparation, was carried out on airborne particulates by applying a specific procedure consisting of soot extraction by ultrasonic bath, purification by solvent partitioning, derivatization with N-(t-butyldimethylsilyl)-N-methyl-trifluoroacetamide, and separation/detection through gas chromatography coupled with tandem mass spectrometry. The optimized procedure was found suitable for measuring the three psychotropic substances at concentrations ranging from ca. 0.001 to ca. 5.0 ng cm{sup -3} of air, with recoveries always higher than 82%, accuracy >7.3% and precision >90%. Application of the procedure performed on field in Rome and Bari, Italy, demonstrated that all three compounds contaminate the air in Italian cities whereas in Algiers, Algeria, only cannabinol, the most stable in the atmosphere, exceeded the limit of quantification of the method. The relative percentages of the three cannabinoids in general reproduced those typical of the Cannabis sativa plant and were very different from those found in human blood, urine and sweat.

  17. Evaluation of principal cannabinoids in airborne particulates

    International Nuclear Information System (INIS)

    The determination of delta(9)-tetrahydrocannabinol (Δ9-THC), cannabidiol (CND) and cannabinol (CNB), primary active components in cannabis preparation, was carried out on airborne particulates by applying a specific procedure consisting of soot extraction by ultrasonic bath, purification by solvent partitioning, derivatization with N-(t-butyldimethylsilyl)-N-methyl-trifluoroacetamide, and separation/detection through gas chromatography coupled with tandem mass spectrometry. The optimized procedure was found suitable for measuring the three psychotropic substances at concentrations ranging from ca. 0.001 to ca. 5.0 ng cm-3 of air, with recoveries always higher than 82%, accuracy >7.3% and precision >90%. Application of the procedure performed on field in Rome and Bari, Italy, demonstrated that all three compounds contaminate the air in Italian cities whereas in Algiers, Algeria, only cannabinol, the most stable in the atmosphere, exceeded the limit of quantification of the method. The relative percentages of the three cannabinoids in general reproduced those typical of the Cannabis sativa plant and were very different from those found in human blood, urine and sweat.

  18. A runner's high depends on cannabinoid receptors in mice.

    Science.gov (United States)

    Fuss, Johannes; Steinle, Jörg; Bindila, Laura; Auer, Matthias K; Kirchherr, Hartmut; Lutz, Beat; Gass, Peter

    2015-10-20

    Exercise is rewarding, and long-distance runners have described a runner's high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both β-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner's high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models. PMID:26438875

  19. Symptomatic treatment of multiple sclerosis using cannabinoids: recent advances.

    Science.gov (United States)

    Smith, Paul F

    2007-09-01

    Recent years have seen a dramatic increase in the number of clinical trials investigating the potential efficacy of medicinal cannabinoids for the symptomatic treatment of chronic pain and spasticity in multiple sclerosis (MS). A number of different cannabinoids have been used, including: delta9-tetrahydrocannabinol (THC) itself; the synthetic delta9-THC, dronabinol; a 1:1 ratio of delta9-THC:cannabidiol (Sativex); and the synthetic delta9-THC metabolites CT-3 and nabilone. Other Cannabis extracts have also been tested. While 2-3 years ago there was little consensus in the literature, now the majority of studies are beginning to suggest that cannabinoids are useful in the treatment of MS in at least a subset of individuals. Their adverse side-effect profile has generally been mild compared with other drugs used for pain and spasticity; nonetheless, there is still concern about potential long-term side effects, particularly psychiatric side effects and effects on fetal development. PMID:17868014

  20. Studies of the brain cannabinoid system using positron emission tomography

    International Nuclear Information System (INIS)

    Studies using radiolabeled psychoactive drugs in conjunction with positron emission tomography (PET) have permitted the imaging of binding sites in the human brain. Similar studies of marijuana have been hampered by the unsuitability of radiolabeled THC for PET studies, and the current unavailability of other in vivo imaging agents for cannabinoid receptors. Recent developments in medicinal chemistry suggest that a PET radiotracer for cannabinoid receptors will soon become available. This chapter briefly reviews these developments, together with the results of PET studies of the effects of marijuana and other abused drugs on brain metabolism. It also reviews PET studies of cocaine binding sites, to demonstrate the kind of investigations that will be possible when a cannabinoid receptor PET radioligand becomes available

  1. Studies of the brain cannabinoid system using positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Gatley, S.J.; Volkow, N.D.

    1995-10-01

    Studies using radiolabeled psychoactive drugs in conjunction with positron emission tomography (PET) have permitted the imaging of binding sites in the human brain. Similar studies of marijuana have been hampered by the unsuitability of radiolabeled THC for PET studies, and the current unavailability of other in vivo imaging agents for cannabinoid receptors. Recent developments in medicinal chemistry suggest that a PET radiotracer for cannabinoid receptors will soon become available. This chapter briefly reviews these developments, together with the results of PET studies of the effects of marijuana and other abused drugs on brain metabolism. It also reviews PET studies of cocaine binding sites, to demonstrate the kind of investigations that will be possible when a cannabinoid receptor PET radioligand becomes available.

  2. Labor Supply Effects of Winning a Lottery

    NARCIS (Netherlands)

    Picchio, Matteo; Suetens, Sigrid; van Ours, Jan

    2015-01-01

    This paper investigates how winning a substantial lottery prize affects labor supply. Analyzing data from Dutch State Lottery winners, we find that earnings are affected but not employment. Lottery prize winners reduce their hours of work but they are not very likely to withdraw from the labor force

  3. Deisgn of Win32-based EPICS IOC

    International Nuclear Information System (INIS)

    Design and implementation of Win32-based EPICS IOC are discussed in this paper. Some approaches for integrating EPICS IOC and Microsoft technologies are proposed. Some high performance oscilloscopes are developed as EPICS IOCs and work well with the whole EPICS control system. (authors)

  4. The "One Belt and One Road" is an Important Mutually Beneficial and Win-win Strategy

    Institute of Scientific and Technical Information of China (English)

    Long; Kaifeng

    2015-01-01

    The"One Belt and One Road"strategic conception carries the dream of development and prosperity of countries concerned,and gives the ancient Silk Road a brand new content of the time.In September and October 2013,President Xi Jinping proposed building the"New Silk Road Economic Belt"(One Belt)and the"Twenty-first Century Maritime Silk Road"(One Road)strategic conception respectively,emphasizing a mutual-beneficial and win-win

  5. Winning or not winning : the influence on coach-athlete relationships and goal achievement

    OpenAIRE

    Mata, Rui Trocado; Gomes, António Rui

    2013-01-01

    This study analyses the relation between sports success and athletes’ perception of coaches’ leadership, athletes’ satisfaction with coaches’ leadership, coach-athlete compatibility, and goal achievement. Sixty-six athletes who qualified for the final Division I play-offs of a professional volleyball championship were grouped into winning (n = 21) and non-winning teams (n = 45). Leadership styles, satisfaction with leadership, coach-athlete compatibility, and goal achievement were evaluated. ...

  6. Win-win strategies in directing low-carbon resilient development path

    International Nuclear Information System (INIS)

    This section explores big win-win strategies in directing low carbon resilient development path. There are lots of “leapfrog” development possibilities in developing countries, which go directly from a status of under-development through to efficient and environmentally benign lifestyle. To achieve low carbon resilient paths, not only technology development but also institutional and behavioral changes are required. Science-policy nexus is also discussed.

  7. Beyond THC: the new generation of cannabinoid designer drugs

    Directory of Open Access Journals (Sweden)

    Liana eFattore

    2011-09-01

    Full Text Available Synthetic cannabinoids are functionally similar to delta9-tetrahydrocannabinol (THC, the psychoactive principle of cannabis, and bind to the same cannabinoid receptors in the brain and peripheral organs. From 2008, synthetic cannabinoids were detected in herbal smoking mixtures sold on websites and in head shops under the brand name of Spice Gold, Yucatan Fire, Aroma, and others. Although these products (also known as Spice drugs or legal highs do not contain tobacco or cannabis, when smoked they produce effects similar to THC. Intoxication, withdrawal, psychosis and death have been recently reported after consumption, posing difficult social, political and health challenges. More than 140 different Spice products have been identified to date. The ability to induce strong cannabis-like psychoactive effects, along with the fact that they are readily available on the Internet, still legal in many countries, marketed as natural safe substances, and undetectable by conventional drug screening tests, has rendered these drugs very popular and particularly appealing to young and drug-naïve individuals seeking new experiences. An escalating number of compounds with cannabinoid receptor activity are currently being found as ingredients of Spice, of which almost nothing is known in terms of pharmacology, toxicology and safety. Since legislation started to control the synthetic cannabinoids identified in these herbal mixtures, many new analogs have appeared on the market. New cannabimimetic compounds are likely to be synthesized in the near future to replace banned synthetic cannabinoids, leading to a dog chasing its tail situation. Spice smokers are exposed to drugs that are extremely variable in composition and potency, and are at risk of serious, if not lethal, outcomes. Social and health professionals should maintain a high degree of alertness for Spice use and its possible psychiatric effects in vulnerable people.

  8. Efecto neuroprotector de los cannabinoides en las enfermedades neurodegenerativas

    OpenAIRE

    Carlos Suero-García; Lucia Martín-Banderas; Mª Ángeles Holgado

    2015-01-01

    Objetivos: Se analiza la situación actual de las investigaciones relacionadas con las sustancias cannabinoides, así como su interacción con el organismo, clasificación, efectos terapéuticos y su uso en las enfermedades neurodegenerativas. Métodos: Se realiza una exhaustiva revisión bibliográfica relacionada con las sustancias cannabinoides y sus derivados sintéticos, haciendo especial hincapié en la forma de interactuar con el organismo y los efectos que provocan dichas interacciones. Concret...

  9. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation

    OpenAIRE

    De Petrocellis, Luciano; Melck, Dominique; Palmisano, Antonella; Bisogno, Tiziana; Laezza, Chiara; Bifulco, Maurizio; Di Marzo, Vincenzo

    1998-01-01

    Anandamide was the first brain metabolite shown to act as a ligand of “central” CB1 cannabinoid receptors. Here we report that the endogenous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently inhibited the proliferation of MCF-7 and EFM-19 cells with IC50 values between 0.5 and 1.5 μM and 83–92% maximal inhibition at 5–10 μM. The proliferation of several other nonmammary tumoral cell lines was not affected by 10 ...

  10. Chemical probes for the study of the endogenous cannabinoid system

    OpenAIRE

    Rueda Zubiaurre, Ainoa

    2015-01-01

    La química biológica nació hace dos décadas con objeto de estudiar la interfase entre la química y la biología, utilizando para ello herramientas capaces de interrogar los distintos sistemas biológicos, facilitando así la comprensión de los mismos.1-3 Sin embargo, existen sistemas biológicos de gran relevancia cuyo estudio no ha sido abordado hasta ahora. Uno de ellos es el sistema cannabinoide endógeno (endogenous cannabinoid system, ECS), que durante los últimos años ha sido relacionado con...

  11. Cannabinoids and Reproduction: A Lasting and Intriguing History

    Directory of Open Access Journals (Sweden)

    Gilda Cobellis

    2010-10-01

    Full Text Available Starting from an historical overview of lasting Cannabis use over the centuries, we will focus on a description of the cannabinergic system, with a comprehensive analysis of chemical and pharmacological properties of endogenous and synthetic cannabimimetic analogues. The metabolic pathways and the signal transduction mechanisms, activated by cannabinoid receptors stimulation, will also be discussed. In particular, we will point out the action of cannabinoids and endocannabinoids on the different neuronal networks involved in reproductive axis, and locally, on male and female reproductive tracts, by emphasizing the pivotal role played by this system in the control of fertility.

  12. AGONISTIC BEHAVIOR OF LABORATORY MICE

    OpenAIRE

    D. Cinghiţă; D. Stănescu

    2005-01-01

    In this work we study agonistic behavior of laboratory white mice when they are kept in captivity. For all this experimental work we used direct observation of mice, in small lists, because we need a reduced space to emphasize characteristics of agonistic behavior. Relations between members of the same species that live in organized groups are based in most cases on hierarchical structure. Relations between leader and subservient, decided by fighting, involve a thorough observation between i...

  13. Synthetic Cannabinoids-Further Evidence Supporting the Relationship Between Cannabinoids and Psychosis.

    Science.gov (United States)

    Fattore, Liana

    2016-04-01

    Consumption of synthetic mind-altering compounds, also known as "new psychoactive substances," is increasing globally at an alarming rate. Synthetic cannabinoids (SCs) are among the most commonly used new psychoactive substances. They are usually purchased as marijuana-like drugs, marketed as herbal blends and perceived as risk-free by inexperienced users. Yet, contrary to Δ(9)-tetrahydrocannabinol, SCs may lead to severe health consequences, including anxiety, tachycardia, hallucinations, violent behavior, and psychosis. This review focuses on the latest (2010-2015) evidence of psychotic symptoms induced by ingestion of products containing SCs. Reports suggesting that SCs may either exacerbate previously stable psychotic symptoms (in vulnerable individuals) or trigger new-onset psychosis (in individuals with no previous history of psychosis) are reviewed. Pharmacology and toxicology of these compounds are discussed, with particular reference to their psychoactive effects. PMID:26970364

  14. Cannabinoids: new promising agents in the treatment of neurological diseases.

    Science.gov (United States)

    Giacoppo, Sabrina; Mandolino, Giuseppe; Galuppo, Maria; Bramanti, Placido; Mazzon, Emanuela

    2014-01-01

    Nowadays, Cannabis sativa is considered the most extensively used narcotic. Nevertheless, this fame obscures its traditional employ in native medicine of South Africa, South America, Turkey, Egypt and in many regions of Asia as a therapeutic drug. In fact, the use of compounds containing Cannabis and their introduction in clinical practice is still controversial and strongly limited by unavoidable psychotropic effects. So, overcoming these adverse effects represents the main open question on the utilization of cannabinoids as new drugs for treatment of several pathologies. To date, therapeutic use of cannabinoid extracts is prescribed in patients with glaucoma, in the control of chemotherapy-related vomiting and nausea, for appetite stimulation in patients with anorexia-cachexia syndrome by HIV, and for the treatment of multiple sclerosis symptoms. Recently, researcher efforts are aimed to employ the therapeutic potentials of Cannabis sativa in the modulation of cannabinoid receptor activity within the central nervous system, particularly for the treatment of neurodegenerative diseases, as well as psychiatric and non-psychiatric disorders. This review evaluates the most recent available data on cannabinoids utilization in experimental and clinical studies, and highlights their beneficial effects in the prevention of the main neurological diseases and for the clinical treatment of symptoms with them correlated. PMID:25407719

  15. Cannabinoids: New Promising Agents in the Treatment of Neurological Diseases

    Directory of Open Access Journals (Sweden)

    Sabrina Giacoppo

    2014-11-01

    Full Text Available Nowadays, Cannabis sativa is considered the most extensively used narcotic. Nevertheless, this fame obscures its traditional employ in native medicine of South Africa, South America, Turkey, Egypt and in many regions of Asia as a therapeutic drug. In fact, the use of compounds containing Cannabis and their introduction in clinical practice is still controversial and strongly limited by unavoidable psychotropic effects. So, overcoming these adverse effects represents the main open question on the utilization of cannabinoids as new drugs for treatment of several pathologies. To date, therapeutic use of cannabinoid extracts is prescribed in patients with glaucoma, in the control of chemotherapy-related vomiting and nausea, for appetite stimulation in patients with anorexia-cachexia syndrome by HIV, and for the treatment of multiple sclerosis symptoms. Recently, researcher efforts are aimed to employ the therapeutic potentials of Cannabis sativa in the modulation of cannabinoid receptor activity within the central nervous system, particularly for the treatment of neurodegenerative diseases, as well as psychiatric and non-psychiatric disorders. This review evaluates the most recent available data on cannabinoids utilization in experimental and clinical studies, and highlights their beneficial effects in the prevention of the main neurological diseases and for the clinical treatment of symptoms with them correlated.

  16. Clinical pharmacology of cannabinoids in early phase drug development

    NARCIS (Netherlands)

    Zuurman, Hillie Henka

    2008-01-01

    Although cannabis is especially known for its recreational use as a ‘soft drug’, its potential therapeutic properties have been recognized for hundreds of years. Since the isolation of THC from Cannabis sativa L, the discovery of cannabinoid receptors and their natural ligands (endocannabinoids) the

  17. WIN Global. 1977/98 Activities at a First Glance

    International Nuclear Information System (INIS)

    WIN is a worldwide association of women working professionally in the fields of nuclear energy and applications of radiation. The goal of WIN is to contribute to objectively inform the public on nuclear and radiation. WIN's principal objective is to emphasis and support the role that women can and do have in addressing the general public's concerns about nuclear energy and the application of radiation and nuclear technology. WIN is doing this through educational programmes, information exchange and arranging study visits. Members of WIN all have one thing in common: they want the general public to have a better understanding of nuclear and radiation matters. Membership status as ao April 21, 1998 was 605 members from 39 countries. During the year 7 new countries have joined to WIN ant two national WIN groups have been formed. Purpose of this paper is to present, to the Spanish Nuclear Society members, the WIN Global activities all over the world for the period 1997/98. The information included herein comes from different sources and WIN members and is, of course, a quick look over those activities. Win Spain activities for the period will be presented in a different paper of this Annual Meeting. (Author) 2 refs

  18. WinXP和FreeBSD的IPSec通信

    Institute of Scientific and Technical Information of China (English)

    董晖

    2007-01-01

    如今,网络通信的数据安全成为一个重要的课题.各种针对TCP/IP通信的安全协议不断涌现.其中,IPSec协议是保证基于IP通信的重要数据安全的有力手段.具体地描述了实现WinXP和FreeBSD间IPSec通信的具体方法.

  19. What makes for prize-winning television?

    OpenAIRE

    Connolly, Sara; HANRETTY, Chris; Hargreaves-Heap, Shaun; Street, John

    2015-01-01

    We investigate the determinants of success in four international television awards festivals between 1994 and 2012. We find that countries with larger markets and greater expenditure on public broadcasting tend to win more awards, but that the degree of concentration in the market for television and rates of penetration of pay-per-view television are unrelated to success. These findings are consistent with general industrial organisation literature on quality and market size, and with media p...

  20. On Auctions with Withdrawable Winning Bids

    OpenAIRE

    Michael H. Rothkopf

    1991-01-01

    This paper considers sealed bidding in which bidders may submit two or more bids and after the bids are opened may, perhaps at a cost, withdraw bids that are more aggressive than would be necessary to win. Such withdrawal strategies are sometimes followed, but currently are surreptitious. However, legitimization of them would create potentially useful market mechanisms of potential interest to government agencies. These market mechanisms are also of theoretical interest since they are interme...

  1. Cannabinoid effects on CB1 receptor density in the adolescent brain: an autoradiographic study using the synthetic cannabinoid HU210.

    Science.gov (United States)

    Dalton, Victoria S; Zavitsanou, Katerina

    2010-11-01

    The short- and long-term behavioral effects of cannabinoids differ in adolescent and adult rodents. Few studies though have examined the underlying neurochemical changes that occur in the brain following adolescent cannabinoid exposure. In this study, we examined the effect of treatment with the synthetic cannabinoid, HU210, on CB1 receptor density in the brain and on body weight in adolescent male rats. Rats were treated daily with 25, 50, or 100 μg/kg HU210 for 4 or 14 days, or received a single dose of 100 μg/kg HU210 and sacrificed 24 h later. Receptor density was investigated using in vitro autoradiography with the CB1 receptor ligand [(3)H] CP55,940. In contrast to adult animals treated under the same paradigm in a previous study, adolescents continued on average, to gain weight over the course of the study. Weight gain was slowest in the 100 μg/kg group and improved dose dependently with controls gaining the most weight. Following the acute dose of HU210, a trend for a reduction in [(3)H] CP55,940 binding and a significant effect of treatment was observed. Statistically significant, dose-dependent, region-specific decreases in binding were observed in all brain regions examined following 4 and 14 days treatment. The pattern of CB1 receptor downregulation was similar to that observed in adults treated with cannabinoids in previous studies; however, its magnitude was smaller in adolescents. This reduced compensatory response may contribute to some acute behavioral effects, the pharmacological cross-tolerance and the long-lasting, adverse psychological consequences of cannabinoid exposure during adolescence. PMID:20842718

  2. The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

    Science.gov (United States)

    Bow, Eric W.; Rimoldi, John M.

    2016-01-01

    The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (−)-Δ9-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles. PMID:27398024

  3. The Structure-Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation.

    Science.gov (United States)

    Bow, Eric W; Rimoldi, John M

    2016-01-01

    The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (-)-Δ(9)-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure-CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure-activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure-activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles. PMID:27398024

  4. Win-win opportunities & environmental regulation: Testing of porter hypothesis for Indian manufacturing industries

    OpenAIRE

    M.N. Murthy; Surender Kumar

    2001-01-01

    This paper studies the effect of environmental regulation relating to water pollution by the Indian industry on the productive efficiency of firms. The panel data of 92 water- polluting firms for the three years 1996-97, 1997-98, and 1998-99 are used to test the Porter hypothesis of having win-win opportunities for the firms subjected to the regulation. The main empirical result is that the technical efficiency of firms increases with the intensity of environmental regulation and the water co...

  5. Synthesis and biological evaluation of novel compounds as potential modulators of cannabinoid signalling pathways

    OpenAIRE

    De Bank, Paul A

    2001-01-01

    Most of the biological effects of cannabis are due to the activation of specific cannabinoid receptors. To date, two such receptors have been discovered and are found predominantly in the central nervous system (the CB1 receptor) or the immune system (the CB2 receptor). Endogenous cannabinoid receptor ligands, the endocannabinoids, have also been isolated and the mechanisms of their synthesis and degradation postulated. By modulating the activation of cannabinoid receptors and endocannabinoid...

  6. Dissimilar cannabinoid substitution patterns in mice trained to discriminate Δ9-tetrahydrocannabinol or methanandamide from vehicle

    OpenAIRE

    Wiley, Jenny L.; Walentiny, D. Matthew; Vann, Robert E.; Baskfield, Cassandra Y.

    2011-01-01

    Δ9-Tetrahydrocannabinol (THC) discrimination in rodents is a behavioral assay that has been used to probe differences among classes of cannabinoids in rats. The purpose of this study was to determine whether traditional and anandamide-like cannabinoids were distinguishable in cannabinoid discrimination procedures in mice. Male mice were trained to discriminate 30 mg/kg THC or 70 mg/kg methanandamide from vehicle in a two-lever milk-reinforced drug discrimination procedure. After acquisition, ...

  7. Repeated Cannabinoid Injections into the Rat Periaqueductal Gray Enhances Subsequent Morphine Antinociception

    OpenAIRE

    Wilson, Adrianne R.; Maher, Lauren; Morgan, Michael M

    2008-01-01

    Cannabinoids and opiates inhibit pain, in part, by activating the periaqueductal gray (PAG). Evidence suggests this activation occurs through distinct mechanisms. If the antinociceptive mechanisms are distinct, then cross-tolerance between opioids and cannabinoids should not develop. This hypothesis was tested by measuring the antinociceptive effect of microinjecting morphine into the ventrolateral PAG of rats pretreated with the cannabinoid HU-210 for two days. Male Spraque-Dawley rats were ...

  8. Cannabinoid receptor activation reverses kainate-induced synchronized population burst firing in rat hippocampus

    OpenAIRE

    Rob Mason; Cheer, Joseph F

    2009-01-01

    Cannabinoids have been shown to possess anticonvulsant properties in whole animal models of epilepsy. The present investigation sought to examine the effects of cannabinoid receptor activation on kainic acid (KA)-induced epileptiform neuronal excitability. Under urethane anesthesia, acute KA treatment (10 mg/kg, i.p.) entrained the spiking mode of simultaneously recorded neurons from random firing to synchronous bursting (% change in burst rate). Injection of the high-affinity cannabinoid a...

  9. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors

    OpenAIRE

    O'Sullivan, S E

    2007-01-01

    Cannabinoids act at two classical cannabinoid receptors (CB1 and CB2), a 7TM orphan receptor and the transmitter-gated channel transient receptor potential vanilloid type-1 receptor. Recent evidence also points to cannabinoids acting at members of the nuclear receptor family, peroxisome proliferator-activated receptors (PPARs, with three subtypes α, β (δ) and γ), which regulate cell differentiation and lipid metabolism. Much evidence now suggests that endocannabinoids are natural activators o...

  10. Hämodynamische Auswirkungen synthetischer, pflanzlicher und endogener Cannabinoide im Modell der isolierten Kaninchenlunge

    OpenAIRE

    Wolf, Jürgen

    2005-01-01

    Cannabinoide zeigen komplexe kardiovaskuläre Effekte. Das endogene Cannabinoid Anandamid (Arachidonylethanolamid) induziert in verschiedenen Organsystemen eine hauptsächlich über periphere CB1-Rezeptoren vermittelte Vasodilatation. Der Einfluss von Cannabinoiden auf die pulmonale Strombahn ist jedoch unklar. Am Modell einer isolierten, perfundierten und ventilierten Kaninchenlunge konnte gezeigt werden, dass die endogenen Cannabinoide Anandamid und 2-Arachidonylglycerol (2-AG) dosisabhängig d...

  11. Cannabinoids as modulators of cancer cell viability, neuronal differentiation, and embryonal development

    OpenAIRE

    Gustafsson, Sofia

    2012-01-01

    Cannabinoids (CBs) are compounds that activate the CB1 and CB2 receptors. CB receptors mediate many different physiological functions, and cannabinoids have been reported to decrease tumor cell viability, proliferation, migration, as well as to modulate metastasis. In this thesis, the effects of cannabinoids on human colorectal carcinoma Caco-2 cells (Paper I) and mouse P19 embryonal carcinoma (EC) cells (Paper III) were studied.  In both cell lines, the compounds examined produced a concentr...

  12. Prevention of Alzheimer's disease pathology by cannabinoids: Neuroprotection mediated by blockade of microglial activation

    OpenAIRE

    Ramírez, B.G.; Blázquez, Cristina; Gómez del Pulgar, Teresa; Guzmán, M.; De Ceballos, ML

    2005-01-01

    Alzheimer's disease (AD) is characterized by enhanced β-amyloid peptide (βA) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after βA treatment, both in vivo and in vitro. He...

  13. Cannabinoid Receptor Activation Reverses Kainate-Induced Synchronized Population Burst Firing in Rat Hippocampus

    OpenAIRE

    Mason, Rob; Cheer, Joseph F

    2009-01-01

    Cannabinoids have been shown to possess anticonvulsant properties in whole animal models of epilepsy. The present investigation sought to examine the effects of cannabinoid receptor activation on kainic acid (KA)-induced epileptiform neuronal excitability. Under urethane anesthesia, acute KA treatment (10 mg kg−1, i.p.) entrained the spiking mode of simultaneously recorded neurons from random firing to synchronous bursting (% change in burst rate). Injection of the high-affinity cannabinoid a...

  14. Synthetic cannabinoids: the multi-organ failure and metabolic derangements associated with getting high

    OpenAIRE

    Dolkar Sherpa; Paudel, Bishow M.; Subedi, Bishnu H.; Robert Dobbin Chow

    2015-01-01

    Synthetic cannabinoids (SC), though not detected with routine urine toxicology screening, can cause severe metabolic derangements and widespread deleterious effects in multiple organ systems. The diversity of effects is related to the wide distribution of cannabinoid receptors in multiple organ systems. Both cannabinoid-receptor-mediated and non-receptor-mediated effects can result in severe cardiovascular, renal, and neurologic manifestations. We report the case of a 45-year-old African Amer...

  15. A study of cannabinoid-1 receptors during the early phase of excitotoxic damage to rat spinal locomotor networks in vitro.

    Science.gov (United States)

    Veeraraghavan, Priyadharishini; Dekanic, Ana; Nistri, Andrea

    2016-10-01

    Endocannabinoids acting on cannabinoid-1 receptors (CB1Rs) are proposed to protect brain and spinal neurons from excitotoxic damage. The ability to recover from spinal cord injury (SCI), in which excitotoxicity is a major player, is usually investigated at late times after modulation of CB1Rs whose role in the early phases of SCI remains unclear. Using the rat spinal cord in vitro as a model for studying SCI initial pathophysiology, we investigated if agonists or antagonists of CB1Rs might affect SCI induced by the excitotoxic agent kainate (KA) within 24h from a transient (1h) application of this glutamate agonist. The CB1 agonist anandamide (AEA or pharmacological block of its degradation) did not limit excitotoxic depolarization of spinal networks: cyclic adenosine monophosphate (cAMP) assay demonstrated that CB1Rs remained functional 24h later and similarly expressed among dead or survived cells. Locomotor-like network activity recorded from ventral roots could not recover with such treatments and was associated with persistent depression of synaptic transmission. Motoneurons, that are particularly vulnerable to KA, were not protected by AEA. Application of 2-arachidonoylglycerol also did not attenuate the electrophysiological and histological damage. The intensification of damage by the CB1 antagonist AM251 suggested that endocannabinoids were operative after excitotoxic stimulation, yet insufficient to contrast it efficiently. The present data indicate that the early phases of excitotoxic SCI could not be arrested by pharmacologically exploiting the endocannabinoid system, consistent with the notion that AEA and its derivatives are more useful to treat late SCI phases. PMID:27450568

  16. The Relationship between Teachers' and Principals' Decision-Making Power: Is It a Win-Win Situation or a Zero-Sum Game?

    Science.gov (United States)

    Shen, Jianping; Xia, Jiangang

    2012-01-01

    Is the power relationship between public school teachers and principals a win-win situation or a zero-sum game? By applying hierarchical linear modeling to the 1999-2000 nationally representative Schools and Staffing Survey data, we found that both the win-win and zero-sum-game theories had empirical evidence. The decision-making areas…

  17. Role of Cannabinoids in the Regulation of Bone Remodelling

    Directory of Open Access Journals (Sweden)

    Aymen I Idris

    2012-11-01

    Full Text Available The endocannabinoid system plays a key role in regulating a variety of physiological processes such as appetite control and energy balance, pain perception, and immune responses. Recent studies have implicated the endocannabinoid system in the regulation of bone cell activity and bone remodelling. These studies showed that endogenous cannabinoid ligands, cannabinoid receptors and the enzymes responsible for ligand synthesis and breakdown all play important roles in bone mass and in the regulation of bone disease. These findings suggest that the endocannabinoid pathway could be of value as a therapeutic target for the prevention and treatment of bone diseases. Here, we review the role of the skeletal endocannabinoid system in the regulation of bone remodelling in health and disease.

  18. Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease.

    Science.gov (United States)

    Kokona, Despina; Georgiou, Panagiota-Christina; Kounenidakis, Mihalis; Kiagiadaki, Foteini; Thermos, Kyriaki

    2016-01-01

    The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease. PMID:26881135

  19. Mice Expressing a "Hyper-Sensitive" Form of the Cannabinoid Receptor 1 (CB1) Are Neither Obese Nor Diabetic.

    Science.gov (United States)

    Marcus, David J; Zee, Michael L; Davis, Brian J; Haskins, Chris P; Andrews, Mary-Jeanette; Amin, Randa; Henderson-Redmond, Angela N; Mackie, Ken; Czyzyk, Traci A; Morgan, Daniel J

    2016-01-01

    Multiple lines of evidence implicate the endocannabinoid signaling system in the modulation of metabolic disease. Genetic or pharmacological inactivation of CB1 in rodents leads to reduced body weight, resistance to diet-induced obesity, decreased intake of highly palatable food, and increased energy expenditure. Cannabinoid agonists stimulate feeding in rodents and increased levels of endocannabinoids can disrupt lipid metabolism. Therefore, the hypothesis that sustained endocannabinoid signaling can lead to obesity and diabetes was examined in this study using S426A/S430A mutant mice expressing a desensitization-resistant CB1 receptor. These mice display exaggerated and prolonged responses to acute administration of phytocannabinoids, synthetic cannabinoids, and endocannabinoids. As a consequence these mice represent a novel model for determining the effect of enhanced endocannabinoid signaling on metabolic disease. S426A/S430A mutants consumed equivalent amounts of both high fat (45%) and low fat (10%) chow control diet compared to wild-type littermate controls. S426A/S430A mutants and wild-type mice fed either high or low fat control diet displayed similar fasting blood glucose levels and normal glucose clearance following a 2 g/kg glucose challenge. Furthermore, S426A/S430A mutants and wild-type mice consumed similar amounts of chow following an overnight fast. While both THC and JZL195 significantly increased food intake two hours after injection, this increase was similar between the S426A/S430A mutant and wildtype control mice Our results indicate that S426A/S430A mutant mice expressing the desensitization-resistant form of CB1 do not exhibit differences in body weight, food intake, glucose homeostasis, or re-feeding following a fast. PMID:27501235

  20. Cannabinoid control of neuroinflammation related to multiple sclerosis

    OpenAIRE

    Baker, D.; Jackson, S. J.; Pryce, G.

    2007-01-01

    The cannabis plant (Cannabis sativa) has been known by many names but the question remains ‘Can we call it medicine?' There has been renewed interest in the value of cannabis for the control of neuroinflammatory conditions such as multiple sclerosis, where it has been shown to have some effect on spasticity and pain both experimentally and in clinical trials in humans. However, in addition to symptom control potential, the question remains whether cannabinoids can modify the neuroinflammatory...

  1. Cannabinoid-Rezeptor1 und Essstörungen

    OpenAIRE

    Reichard, Heidi

    2010-01-01

    Hintergrund und Ziele Das Endocannabinoidsystem ist ein zentrales Element in der Regulation von Appetit, Nahrungsaufnahme und Energiehomöostase. Bei Patientinnen mit Anorexia nervosa (AN) wurden erhöhte Raten des Endocannabinoids Anandamid gemessen. Auch eine Assoziation zwischen dem restriktiven Typus der Anorexie und einem funktionellen Polymorphismus des Cannabinoid-Rezeptors1 (CB1) konnte aufgedeckt werden. Ein Ziel unserer Studie war, mögliche Unterschiede der CB1-mRNA-Ausprägung bei Fra...

  2. Potencial terapéutico de los cannabinoides

    Directory of Open Access Journals (Sweden)

    L. M. Torres

    2013-06-01

    Full Text Available Los cannabinoides demuestran eficacia en modelos experimentales de dolor agudo y crónico. Parecen seguros en los ensayos desarrollados para algunas indicaciones de dolor y otras. Las nuevas tecnologías han abierto nuevas posibilidades de tratamiento al proporcionar nuevas vías de administración. Se precisan ensayos en pacientes para determinar el verdadero rol de estas sustancias en el tratamiento del dolor.

  3. Potencial terapéutico de los cannabinoides

    OpenAIRE

    L. M. Torres; J. M. Trinidad; E. Calderón

    2013-01-01

    Los cannabinoides demuestran eficacia en modelos experimentales de dolor agudo y crónico. Parecen seguros en los ensayos desarrollados para algunas indicaciones de dolor y otras. Las nuevas tecnologías han abierto nuevas posibilidades de tratamiento al proporcionar nuevas vías de administración. Se precisan ensayos en pacientes para determinar el verdadero rol de estas sustancias en el tratamiento del dolor.

  4. The endogenous cannabinoid system protects against colonic inflammation

    OpenAIRE

    Massa, Federico; MARSICANO, Giovanni; Hermann, Heike; Cannich, Astrid; Monory, Krisztina; Cravatt, Benjamin F.; Ferri, Gian-Luca; Sibaev, Andrei; Storr, Martin; Lutz, Beat

    2004-01-01

    Excessive inflammatory responses can emerge as a potential danger for organisms’ health. Physiological balance between pro- and anti-inflammatory processes constitutes an important feature of responses against harmful events. Here, we show that cannabinoid receptors type 1 (CB1) mediate intrinsic protective signals that counteract proinflammatory responses. Both intrarectal infusion of 2,4-dinitrobenzene sulfonic acid (DNBS) and oral administration of dextrane sulfate sodium induced stronger ...

  5. Finding cannabinoids in hair does not prove cannabis consumption

    OpenAIRE

    Bjoern Moosmann; Nadine Roth; Volker Auwärter

    2015-01-01

    Hair analysis for cannabinoids is extensively applied in workplace drug testing and in child protection cases, although valid data on incorporation of the main analytical targets, ∆9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-THC (THC-COOH), into human hair is widely missing. Furthermore, ∆9-tetrahydrocannabinolic acid A (THCA-A), the biogenetic precursor of THC, is found in the hair of persons who solely handled cannabis material. In the light of the serious consequences of positive tes...

  6. High Alert For Cannabinoid Hyperemesis Syndrome: A Case Report

    OpenAIRE

    Madhur Rathi

    2015-01-01

    Background: A 32-year-old Caucasian man presented with intractable nausea, psychogenic vomiting, abdominal pain and compulsive hot-water bathing behaviors following the habitual use of cannabis for years, consistent with the uncommon and frequently overlooked diagnosis of Cannabinoid Hyperemesis Syndrome. This was his third admission to the emergency department with the same complaints and symptoms which had persisted for over two years without a recognizable etiology. All imaging studies don...

  7. Medical education on cannabis and cannabinoids: Perspectives, challenges, and opportunities.

    Science.gov (United States)

    Ware, M A; Ziemianski, D

    2015-06-01

    The global regulatory landscape regarding the medical use of cannabis and cannabinoids is changing rapidly. This has considerable impact on health care professionals who currently receive little or no education on issues regarding medical cannabis. We propose a 'cannabis curriculum' that covers the spectrum of historical, botanical, physiological, clinical and legal issues to allow health care professionals to engage in meaningful discussions with their patients and colleagues around this stigmatized and controversial subject. PMID:25728558

  8. Cannabinoids act as necrosis-inducing factors in Cannabis sativa

    OpenAIRE

    Shoyama, Yoshinari; Sugawa, Chitomi; Tanaka, Hiroyuki; Morimoto, Satoshi

    2008-01-01

    Cannabis sativa is well known to produce unique secondary metabolites called cannabinoids. We recently discovered that Cannabis leaves induce cell death by secreting tetrahydrocannabinolic acid (THCA) into leaf tissues. Examinations using isolated Cannabis mitochondria demonstrated that THCA causes mitochondrial permeability transition (MPT) though opening of MPT pores, resulting in mitochondrial dysfunction (the important feature of necrosis). Although Ca2+ is known to cause opening of anima...

  9. Finding cannabinoids in hair does not prove cannabis consumption.

    Science.gov (United States)

    Moosmann, Bjoern; Roth, Nadine; Auwärter, Volker

    2015-01-01

    Hair analysis for cannabinoids is extensively applied in workplace drug testing and in child protection cases, although valid data on incorporation of the main analytical targets, ∆9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-THC (THC-COOH), into human hair is widely missing. Furthermore, ∆9-tetrahydrocannabinolic acid A (THCA-A), the biogenetic precursor of THC, is found in the hair of persons who solely handled cannabis material. In the light of the serious consequences of positive test results the mechanisms of drug incorporation into hair urgently need scientific evaluation. Here we show that neither THC nor THCA-A are incorporated into human hair in relevant amounts after systemic uptake. THC-COOH, which is considered an incontestable proof of THC uptake according to the current scientific doctrine, was found in hair, but was also present in older hair segments, which already grew before the oral THC intake and in sebum/sweat samples. Our studies show that all three cannabinoids can be present in hair of non-consuming individuals because of transfer through cannabis consumers, via their hands, their sebum/sweat, or cannabis smoke. This is of concern for e.g. child-custody cases as cannabinoid findings in a child's hair may be caused by close contact to cannabis consumers rather than by inhalation of side-stream smoke. PMID:26443501

  10. Cannabinoid Control of Learning and Memory through HCN Channels.

    Science.gov (United States)

    Maroso, Mattia; Szabo, Gergely G; Kim, Hannah K; Alexander, Allyson; Bui, Anh D; Lee, Sang-Hun; Lutz, Beat; Soltesz, Ivan

    2016-03-01

    The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP), and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation. PMID:26898775

  11. Inhibition of platelet aggregation by vanilloid-like agents is not mediated by transient receptor potential vanilloid-1 channels or cannabinoid receptors.

    Science.gov (United States)

    Almaghrabi, Safa; Geraghty, Dominic; Ahuja, Kiran; Adams, Murray

    2016-06-01

    Vanilloid-like agents, including capsaicin, N-arachidonoyl-dopamine and N-oleoyldopamine inhibit platelet aggregation, however little is known about the precise mechanism(s) of action. The authors have previously shown that blocking of the capsaicin receptor, transient receptor potential vanilloid-1 (TRPV1), does not interfere with capsaicin action during adenosine diphosphate (ADP)-induced aggregation. This research is extended to investigate the effect of these vanilloid-like-agents on platelet count, and to test whether the effect of these agents is mediated through TRPV1 and/or cannabinoid (CB1 and CB2) receptors in the presence of other agonists, including collagen and arachidonic acid. Incubation of platelets with each of the individual vanilloids, or with receptor antagonists of TRPV1 (SB452533), CB1 (AM251) and CB2 (AM630), for up to 2 h did not significantly affect the platelet count. Similarly, the effect of individual vanilloids on the inhibition of platelet aggregation was not significantly different in the presence of receptor agonists compared to control, irrespective of the agonist used, suggesting that the inhibitory effect of vanilloids on platelet aggregation is independent of TRPV1, CB1 and CB2 receptors. Further research on the antiplatelet activity of vanilloids should focus on mechanisms other than those associated with vanilloid receptors. PMID:26991025

  12. Cannabinoid 2 (CB2) receptor agonism reduces lithium chloride-induced vomiting in Suncus murinus and nausea-induced conditioned gaping in rats.

    Science.gov (United States)

    Rock, Erin M; Boulet, Nathalie; Limebeer, Cheryl L; Mechoulam, Raphael; Parker, Linda A

    2016-09-01

    We aimed to investigate the potential anti-emetic and anti-nausea properties of targeting the cannabinoid 2 (CB2) receptor. We investigated the effect of the selective CB2 agonist, HU-308, on lithium chloride- (LiCl) induced vomiting in Suncus murinus (S. murinus) and conditioned gaping (nausea-induced behaviour) in rats. Additionally, we determined whether these effects could be prevented by pretreatment with AM630 (a selective CB2 receptor antagonist/inverse agonist). In S. murinus, HU-308 (2.5, 5mg/kg, i.p.) reduced, but did not completely block, LiCl-induced vomiting; an effect that was prevented with AM630. In rats, HU-308 (5mg/kg, i.p.) suppressed, but did not completely block, LiCl-induced conditioned gaping to a flavour; an effect that was prevented by AM630. These findings are the first to demonstrate the ability of a selective CB2 receptor agonist to reduce nausea in animal models, indicating that targeting the CB2 receptor may be an effective strategy, devoid of psychoactive effects, for managing toxin-induced nausea and vomiting. PMID:27263826

  13. Synthetic cannabinoid JWH-018 and its halogenated derivatives JWH-018-Cl and JWH-018-Br impair Novel Object Recognition in mice: Behavioral, electrophysiological and neurochemical evidence.

    Science.gov (United States)

    Barbieri, M; Ossato, A; Canazza, I; Trapella, C; Borelli, A C; Beggiato, S; Rimondo, C; Serpelloni, G; Ferraro, L; Marti, M

    2016-10-01

    It is well known that an impairment of learning and memory function is one of the major physiological effects caused by natural or synthetic cannabinoid consumption in rodents, nonhuman primates and in humans. JWH-018 and its halogenated derivatives (JWH-018-Cl and JWH-018-Br) are synthetic CB1/CB2 cannabinoid agonists, illegally marketed as "Spice" and "herbal blend" for their Cannabis-like psychoactive effects. In the present study the effects of acute exposure to JWH-018, JWH-018-Cl, JWH-018-Br (JWH-018-R compounds) and Δ(9)-THC (for comparison) on Novel Object Recognition test (NOR) has been investigated in mice. Moreover, to better characterize the effects of JWH-018-R compounds on memory function, in vitro electrophysiological and neurochemical studies in hippocampal preparations have been performed. JWH-018, JWH-018-Cl and JWH-018-Br dose-dependently impaired both short- and long-memory retention in mice (respectively 2 and 24 h after training session). Their effects resulted more potent respect to that evoked by Δ(9)-THC. Moreover, in vitro studies showed as JWH-018-R compounds negatively affected electrically evoked synaptic transmission, LTP and aminoacid (glutamate and GABA) release in hippocampal slices. Behavioral, electrophysiological and neurochemical effects were fully prevented by CB1 receptor antagonist AM251 pretreatment, suggesting a CB1 receptor involvement. These data support the hypothesis that synthetic JWH-018-R compounds, as Δ(9)-THC, impair cognitive function in mice by interfering with hippocampal synaptic transmission and memory mechanisms. This data outline the danger that the use and/or abuse of these synthetic cannabinoids may represent for the cognitive process in human consumer. PMID:27346209

  14. Setting Win Limits: An Alternative Approach to "Responsible Gambling"?

    Science.gov (United States)

    Walker, Douglas M; Litvin, Stephen W; Sobel, Russell S; St-Pierre, Renée A

    2015-09-01

    Social scientists, governments, and the casino industry have all emphasized the need for casino patrons to "gamble responsibly." Strategies for responsible gambling include self-imposed time limits and loss limits on gambling. Such strategies help prevent people from losing more than they can afford and may help prevent excessive gambling behavior. Yet, loss limits also make it more likely that casino patrons leave when they are losing. Oddly, the literature makes no mention of "win limits" as a potential approach to responsible gambling. A win limit would be similar to a loss limit, except the gambler would leave the casino upon reaching a pre-set level of winnings. We anticipate that a self-imposed win limit will reduce the gambler's average loss and, by default, also reduce the casino's profit. We test the effect of a self-imposed win limit by running slot machine simulations in which the treatment group of players has self-imposed and self-enforced win and loss limits, while the control group has a self-imposed loss limit or no limit. We find that the results conform to our expectations: the win limit results in improved player performance and reduced casino profits. Additional research is needed, however, to determine whether win limits could be a useful component of a responsible gambling strategy. PMID:24567070

  15. CERN exhibition wins yet another design prize

    CERN Multimedia

    Joannah Caborn Wengler

    2012-01-01

    The “Universe of Particles” exhibition in CERN’s Globe wins the silver design prize from the German direct business communications association FAMAB.   Not only do tens of thousands of people visit the “Universe of Particles” exhibition each year, but juries for design prizes are crossing its threshold more and more frequently too. In 2011 alone it claimed 8 awards, including winning outright the 2011 Annual Multimedia award, the iF Communication Design for Corporate Architecture award and the Modern Decoration Media award (the Bulletin already reported on some of these in July 2011). The FAMAB award is the latest to join the prestigious list. The jury of FAMAB’s “ADAM 2011” award was particularly impressed by the hands-on nature of the exhibition, which encourages visitors to get interested in science. They also appreciated the way that the space in the Globe is not just a container for the exhibits, but itself ...

  16. Metabolomics and bioanalysis of terpenoid derived secondary metabolites : Analysis of Cannabis sativa L. metabolite production and prenylases for cannabinoid production

    NARCIS (Netherlands)

    Muntendam, Remco

    2015-01-01

    Cannabinoid research has gained a renenewed interest by both the public and scientist. Focus is mainly directed to the medicinal activities, as reported for various cannabinoid structures. This thesis focusses on prenyl-derived secondary metabolites with main focus on cannabinoids. Firstly the produ

  17. GnRH agonist triggering

    DEFF Research Database (Denmark)

    Kol, Shahar; Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2013-01-01

    The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages...... triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients. Routinely, human chorionic gonadotrophin (HCG) is used to induce ovulation in fertility treatments. This approach deviates...... significantly from physiology and often results in insufficient hormonal support in early pregnancy and in ovarian hyperstimulation syndrome (OHSS). An alternative approach is to use a gonadotrophin-releasing hormone (GnRH) agonist which allows a more physiological trigger of ovulation and, most importantly...

  18. Efecto neuroprotector de los cannabinoides en las enfermedades neurodegenerativas

    Directory of Open Access Journals (Sweden)

    Carlos Suero-García

    2015-01-01

    Full Text Available Objetivos: Se analiza la situación actual de las investigaciones relacionadas con las sustancias cannabinoides, así como su interacción con el organismo, clasificación, efectos terapéuticos y su uso en las enfermedades neurodegenerativas. Métodos: Se realiza una exhaustiva revisión bibliográfica relacionada con las sustancias cannabinoides y sus derivados sintéticos, haciendo especial hincapié en la forma de interactuar con el organismo y los efectos que provocan dichas interacciones. Concretamente, se estudiarán sus efectos neuroantiinflamatorio y analgésico lo que conlleva al efecto neuroprotector en enfermedades neurodegenerativas tales como Alzheimer, Parkinson, Huntington, esclerosis múltiple y esclerosis lateral amiotrófica. Resultados: Desde hace miles de años la planta Cannabis Sativa ha sido utilizada por muchas culturas con distintos fines, de ocio, textiles, analgésicos, pero no es hasta finales del siglo XX cuando se empieza a incentivar los estudios científicos relacionados con ésta. La planta posee una mezcla de unos 400 componentes, de los cuales 60 pertenecen al grupo de los cannabinoides siendo los principales el cannabinol, cannabidiol y tetrahidrocannabinol. Con el descubrimiento de las sustancias cannabinoides, sus derivados, y los receptores que interactúan, se amplían las posibilidades terapéuticas teniendo un especial interés el efecto neuroprotector que estas sustancias contienen. Conclusiones. Se ha demostrado el gran potencial de los cannabinoides como sustancias terapéuticas más allá de su uso analgésico o antiemético, esto es, en enfermedades neurodegenerativas en las que pueden no solo disminuir los síntomas, sino frenar el proceso de la enfermedad. Otra posible aplicación puede ser en el campo oncológico, siendo particularmente intensa la actividad investigadora realizada en los últimos 15 años.

  19. A Gut Gone to Pot: A Case of Cannabinoid Hyperemesis Syndrome due to K2, a Synthetic Cannabinoid

    Directory of Open Access Journals (Sweden)

    Anene Ukaigwe

    2014-01-01

    Full Text Available Cannabinoid Hyperemesis Syndrome (CHS was first described in 2004. Due to its novelty, CHS is often unrecognized by clinicians leading to expensive workup of these patients with cyclical symptoms. It may take up to 9 years to diagnose CHS. CHS is characterized by cyclical nausea and vomiting, abdominal pain, and an unusual compulsion to take hot showers in the presence of chronic use of cannabinoids. Cannabicyclohexanol is a synthetic cannabinoid, popularly known as K2 spice. It is a popular marijuana alternative among teenagers and young adults since it is readily available as herbal incense. Unlike marijuana, many users know that K2 is not detected in conventional urine drug screens, allowing those users to conceal their intake from typical detection methods. Serum or urine gas chromatography mass spectrophotometry is diagnostic, though not widely available. Thus, it is imperative for clinicians to recognize CHS, even with negative UDS, to provide cost-effective care. We present a 38-year-old man with a 10-year history of cannabis, and 1-year history of K2 abuse admitted with 1-week history of episodes of nausea, vomiting of clear fluids, and epigastric discomfort. Symptoms are relieved only by hot showers. Extensive laboratory, radiologic, and endoscopic evaluation was unrevealing. CHS was diagnosed, based on proposed criteria by Simonetti et al.

  20. Synthetic cannabinoids: In silico prediction of the cannabinoid receptor 1 affinity by a quantitative structure-activity relationship model.

    Science.gov (United States)

    Paulke, Alexander; Proschak, Ewgenij; Sommer, Kai; Achenbach, Janosch; Wunder, Cora; Toennes, Stefan W

    2016-03-14

    The number of new synthetic psychoactive compounds increase steadily. Among the group of these psychoactive compounds, the synthetic cannabinoids (SCBs) are most popular and serve as a substitute of herbal cannabis. More than 600 of these substances already exist. For some SCBs the in vitro cannabinoid receptor 1 (CB1) affinity is known, but for the majority it is unknown. A quantitative structure-activity relationship (QSAR) model was developed, which allows the determination of the SCBs affinity to CB1 (expressed as binding constant (Ki)) without reference substances. The chemically advance template search descriptor was used for vector representation of the compound structures. The similarity between two molecules was calculated using the Feature-Pair Distribution Similarity. The Ki values were calculated using the Inverse Distance Weighting method. The prediction model was validated using a cross validation procedure. The predicted Ki values of some new SCBs were in a range between 20 (considerably higher affinity to CB1 than THC) to 468 (considerably lower affinity to CB1 than THC). The present QSAR model can serve as a simple, fast and cheap tool to get a first hint of the biological activity of new synthetic cannabinoids or of other new psychoactive compounds. PMID:26795018

  1. Mapping CB1 cannabinoid receptors with [3H]OMAR in the Flinders rodent model of depression

    DEFF Research Database (Denmark)

    Nahimi, A.; Gjedde, A.; Wong, D. F.;

    2012-01-01

    H]OMAR, a highly selective CB1 receptor antagonist (Horti et al, 2006) in the Flinders rodent model of depression. Methods: The Flinders sensitive line (FSL) (N = 5-6) was used as a model of depression and the Flinders resistant line (FRL) (N= 6-8) served as controls (Wegener et al. 2010). In these......Background: The endocannabinoid system regulates cognitive and emotional processes and pathology of this system is implicated in psychiatric disorders, including depression and schizophrenia. The precise role of the endocannabinoid system in psychiatric disorders remains unclear, but changes in...... expression of CB1 receptors and subsequent altered modulation of monoamines is suggested in depression (Esteban & Garcia-Sevilla, 2011). CB1 receptor agonists, such as WIN55,212-2 and CP55,940 regulate synthesis and release of monoamines and are suggested as a novel therapy in the treatment of depression...

  2. Evaluation of a radioimmunoassay (/sup 125/I) kit for cannabinoid metabolites in urine and whole blood

    Energy Technology Data Exchange (ETDEWEB)

    Childs, P.S.; McCurdy, H.H.

    The Abuscreen kit (Roche Diagnostics) for the analysis of 11-nor-..delta../sup 9/-tetrahydrocannabinol-9-carboxylic acid and other cannabinoids in urine was evaluated in terms of its accuracy, reproducibility, and sensitivity. A procedure is also presented for the analysis of total cannabinoids in whole blood using the RIA kit.

  3. Expresión de receptores cannabinoides en el desarrollo embrionario del pez cebra

    OpenAIRE

    Florido García, Virginia

    2009-01-01

    [ES]Este trabajo trata sobre la expresión de receptores cannabinoides en el desarrollo embrionario del pez cebra [EN]This paper deals with the expression of cannabinoid receptors in the embryonic development of zebrafish Trabajo de Fin de Máster del Máster en Neurociencias, curso 2008-2009.

  4. Structure of a cannabinoid receptor and functional expression of the cloned cDNA.

    Science.gov (United States)

    Matsuda, L A; Lolait, S J; Brownstein, M J; Young, A C; Bonner, T I

    1990-08-01

    Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana. PMID:2165569

  5. Type 1 cannabinoid receptor modulates water deprivation-induced homeostatic responses.

    Science.gov (United States)

    Ruginsk, Silvia G; Vechiato, Fernanda M V; Uchoa, Ernane T; Elias, Lucila L K; Antunes-Rodrigues, Jose

    2015-12-01

    The present study investigated the type 1 cannabinoid receptor (CB1R) as a potential candidate to mediate the homeostatic responses triggered by 24 h of water deprivation, which constitutes primarily a hydroelectrolytic challenge and also significantly impacts energy homeostasis. The present results demonstrated for the first time that CB1R mRNA expression is increased in the hypothalamus of water-deprived (WD) rats. Furthermore, the administration of ACEA, a CB1R selective agonist, potentiated WD-induced dipsogenic effect, whereas AM251, a CB1R antagonist, attenuated not only water but also salt intake in response to WD. In parallel with the modulation of thirst and salt appetite, we confirmed that CB1Rs are essential for the development of appropriated neuroendocrine responses. Although the administration of ACEA or AM251 did not produce any effects on WD-induced arginine vasopressin (AVP) secretion, oxytocin (OXT) plasma concentrations were significantly decreased in WD rats treated with ACEA. At the genomic level, ACEA significantly decreased AVP and OXT mRNA expression in the hypothalamus of WD rats, whereas AM251 potentiated both basal and WD-induced stimulatory effects on the transcription of AVP and OXT genes. In addition, we showed that water deprivation alone upregulated proopiomelanocortin, Agouti-related peptide, melanin-concentrating hormone, and orexin A mRNA levels in the hypothalamus, and that CB1Rs regulate main central peptidergic pathways controlling food intake, being that most of these effects were also significantly influenced by the hydration status. In conclusion, the present study demonstrated that CB1Rs participate in the homeostatic responses regulating fluid balance and energy homeostasis during water deprivation. PMID:26468265

  6. Synthetic Ligands of Cannabinoid Receptors Affect Dauer Formation in the Nematode Caenorhabditis elegans.

    Science.gov (United States)

    Reis Rodrigues, Pedro; Kaul, Tiffany K; Ho, Jo-Hao; Lucanic, Mark; Burkewitz, Kristopher; Mair, William B; Held, Jason M; Bohn, Laura M; Gill, Matthew S

    2016-01-01

    Under adverse environmental conditions the nematode Caenorhabditis elegans can enter an alternate developmental stage called the dauer larva. To identify lipophilic signaling molecules that influence this process, we screened a library of bioactive lipids and found that AM251, an antagonist of the human cannabinoid (CB) receptor, suppresses dauer entry in daf-2 insulin receptor mutants. AM251 acted synergistically with glucose supplementation indicating that the metabolic status of the animal influenced the activity of this compound. Similarly, loss of function mutations in the energy-sensing AMP-activated kinase subunit, aak-2, enhanced the dauer-suppressing effects of AM251, while constitutive activation of aak-2 in neurons was sufficient to inhibit AM251 activity. Chemical epistasis experiments indicated that AM251 acts via G-protein signaling and requires the TGF-β ligand DAF-7, the insulin peptides DAF-28 and INS-6, and a functional ASI neuron to promote reproductive growth. AM251 also required the presence of the SER-5 serotonin receptor, but in vitro experiments suggest that this may not be via a direct interaction. Interestingly, we found that other antagonists of mammalian CB receptors also suppress dauer entry, while the nonselective CB receptor agonist, O-2545, not only inhibited the activity of AM251, but also was able to promote dauer entry when administered alone. Since worms do not have obvious orthologs of CB receptors, the effects of synthetic CBs on neuroendocrine signaling in C. elegans are likely to be mediated via another, as yet unknown, receptor mechanism. However, we cannot exclude the existence of a noncanonical CB receptor in C. elegans. PMID:27172180

  7. Functional residues essential for the activation of the CB1 cannabinoid receptor.

    Science.gov (United States)

    Shim, Joong-Youn; Padgett, Lea

    2013-01-01

    Recently developed X-ray crystal structures of active state G-protein-coupled receptors have opened the way for detailed examination of the movement of the transmembrane (TM) helices and the specific residues involved in the receptor activation upon ligand binding. Previous modeling studies have indicated that the brain cannabinoid (CB1) receptor binds with a ligand at least in part through a hydrophobic tail on the ligand. This interaction is believed to be similar to the rotameric toggle switch proposed for the β2 adrenergic receptor (β2AR). In the present study, an active state model for the CB1 receptor, guided by the X-ray structure of the active state for β2AR, was constructed with HU210 bound as a ligand. Molecular dynamics (MD) simulations were employed to provide a smooth progression between inactive and active states of the receptor. This model was compared with our previously published CB1 receptor model to identify the functional residues that play key roles in triggering receptor conformational changes upon agonist binding. Movements in TM helices and functional residues are discussed. W279(5.43), contributing to an inward movement of the fifth TM helix (TM5) to the helical core, could serve as another rotameric switch for receptor activation. V282(5.46), interacting with the ligand's hydrophobic C3 alkyl chain, appears to play a key role in TM5 inward movement centered at L286(5.50) and subsequent coupling to V204(3.40). V204(3.40), closely interacting with the TM5 and TM6 hydrophobic patch residues in the middle of the receptor, particularly I290(5.54) and L352(6.44), appears to facilitate helical rearrangements, leading to the breakage of the ionic lock and the rotameric change of Y397(7.53), which are key features of the active state. PMID:23332708

  8. Therapeutic potential of cannabinoids in counteracting chemotherapy-induced adverse effects: an exploratory review.

    Science.gov (United States)

    Ostadhadi, Sattar; Rahmatollahi, Mahdieh; Dehpour, Ahmad-Reza; Rahimian, Reza

    2015-03-01

    Cannabinoids (the active constituents of Cannabis sativa) and their derivatives have got intense attention during recent years because of their extensive pharmacological properties. Cannabinoids first developed as successful agents for alleviating chemotherapy associated nausea and vomiting. Recent investigations revealed that cannabinoids have a wide range of therapeutic effects such as appetite stimulation, inhibition of nausea and emesis, suppression of chemotherapy or radiotherapy-associated bone loss, chemotherapy-induced nephrotoxicity and cardiotoxicity, pain relief, mood amelioration, and last but not the least relief from insomnia. In this exploratory review, we scrutinize the potential of cannabinoids to counteract chemotherapy-induced side effects. Moreover, some novel and yet important pharmacological aspects of cannabinoids such as antitumoral effects will be discussed. PMID:25504799

  9. Win-CC Control Extension Development: Pressure-Enthalpy Win-CC Panel

    CERN Document Server

    Gaona, Daniel

    2013-01-01

    This report reviews in detail the development and implementation of a Win-CC Control Extension for both Windows and Linux Platforms. The Control Extension consists in a Win-CC panel linked by dynamic libraries (*.dll or *.so) to the NIST Thermodynamics properties library. This linking permits to handle in real time different thermodynamic properties of a wide range of refrigerants. The Win-CC panel uses this information to produce a Pressure-Enthalpy Diagram of any required refrigeration cycle. In general, the p-H diagram enhance the understanding of the refrigeration cycle and facilitate the control and supervision of the system. Ideally, this control extension will be part of several Cooling Projects at CERN such as ATLAS IBL and CMS TIF. The development of this tool required several weeks of programming in C++ in both Linux and Windows platforms. At the end, the tool was constructed successfully and tested in both operating systems. The following sections go deeper into the develop, operation, and impleme...

  10. Antagonism of Dopamine Receptor 2 Long Affects Cannabinoid Receptor 1 Signaling in a Cell Culture Model of Striatal Medium Spiny Projection Neurons.

    Science.gov (United States)

    Bagher, Amina M; Laprairie, Robert B; Kelly, Melanie E M; Denovan-Wright, Eileen M

    2016-06-01

    Activation of dopamine receptor 2 long (D2L) switches the signaling of type 1 cannabinoid receptor (CB1) from Gαi to Gαs, a process thought to be mediated through CB1-D2L heteromerization. Given the clinical importance of D2 antagonists, the goal of this study was to determine if D2 antagonists could modulate CB1 signaling. Interactions between CB1 and D2L, Gαi, Gαs, and β-arrestin1 were studied using bioluminescence resonance energy transfer 2 (BRET(2)) in STHdh(Q7/Q7) cells. CB1-dependent extracellular regulated kinase (ERK)1/2, CREB phosphorylation, and CB1 internalization following cotreatment of CB1 agonist and D2 antagonist were quantified. Preassembled CB1-Gαi complexes were detected by BRET(2) Arachidonyl-2'-chloroethylamide (ACEA), a selective CB1 agonist, caused a rapid and transient increase in BRET efficiency (BRETEff) between Gαi-Rluc and CB1-green fluorescent protein 2 (GFP(2)), and a Gαi-dependent increase in ERK phosphorylation. Physical interactions between CB1 and D2L were observed using BRET(2) Cotreatment of STHdh(Q7/Q7) cells with ACEA and haloperidol, a D2 antagonist, inhibited BRETEff signals between Gαi-Rluc and CB1-GFP(2) and reduced the EMax and pEC50 of ACEA-mediated Gαi-dependent ERK phosphorylation. ACEA and haloperidol cotreatments produced a delayed and sustained increase in BRETEff between Gαs-Rluc and CB1-GFP(2) and increased the EMax and pEC50 of ACEA-induced Gαs-dependent cAMP response element-binding protein phosphorylation. In cells expressing CB1 and D2L treated with ACEA, binding of haloperidol to D2 receptors switched CB1 coupling from Gαi to Gαs In addition, haloperidol treatment reduced ACEA-induced β-arrestin1 recruitment to CB1 and CB1 internalization. D2 antagonists allosterically modulate cannabinoid-induced CB1 coupling, signaling, and β-arrestin1 recruitment through binding to CB1-D2L heteromers. These findings indicate that D2 antagonism, like D2 agonists, change agonist-mediated CB1 coupling and

  11. Winning Strategies in Multimove Chess (i,j)

    OpenAIRE

    Berger, Emily Rita; Dubbs, Alexander

    2014-01-01

    We propose a class of chess variants, Multimove Chess (i,j), in which White gets i moves per turn and Black gets j moves per turn. One side is said to win when it takes the opponent's king. All other rules of chess apply. We prove that if (i,j) is not (1,1) or (2,2), and if $i \\geq \\min(j,4)$, then White always has a winning strategy, and otherwise Black always has a winning strategy.

  12. Customer Satisfaction Perceptions of Dislocated Workers Served by WIN Job Centers in the Mississippi Corridor Consortium

    Science.gov (United States)

    Washburn, Dava Michelle

    2009-01-01

    The purpose of this study was to determine the perceptions of satisfaction of dislocated workers served by WIN Job Centers in the Mississippi Corridor Consortium. Four WIN Job Centers participated in this study: Northeast Mississippi Community College WIN Job Center in Corinth, Northwest Mississippi Community College WIN Job Center in Oxford,…

  13. PPARγ Agonist Beyond Glucose Lowering Effect

    OpenAIRE

    Sugawara, Akira; Uruno, Akira; Kudo, Masataka; Matsuda, Ken; Yang, Chul Woo; Ito, Sadayoshi

    2011-01-01

    The nuclear hormone receptor PPARγ is activated by several agonists, including members of the thiazolidinedione group of insulin sensitizers. Pleiotropic beneficial effects of these agonists, independent of their blood glucose-lowering effects, have recently been demonstrated in the vasculature. PPARγ agonists have been shown to lower blood pressure in animals and humans, perhaps by suppressing the renin-angiotensin (Ang)-aldosterone system (RAAS), including the inhibition of Ang II type 1 re...

  14. [Cannabinoid drugs for neurological diseases: what is behind?].

    Science.gov (United States)

    Fernández-Ruiz, Javier

    2012-05-16

    In recent years progress has been made in the development of pharmaceuticals based on the plant Cannabis sativa or on synthetic molecules with a similar action. Some of these pharmaceuticals, such as the mouth spray Sativex, have recently been approved for the treatment of spasticity in multiple sclerosis, but they are not the first and others, such as Marinol or Cesamet for the treatment of vomiting and nausea, and anorexia-cachexia syndrome, had already been approved. This incipient clinical use of cannabinoid drugs confirms something that was already known from fairly ancient times up to practically the last century, which is the potential use of this plant for medicinal applications - something which was brought to a standstill by the abusive use of preparations of the plant for recreational purposes. In any case, this incipient clinical use of cannabinoid drugs is not backed just by the anecdote of the medicinal use of cannabis since ancient times, but instead the boost it has been given by scientific research, which has made it possible to identify the target molecules that are activated or inhibited by these substances. These targets are part of a new system of intercellular communication that is especially active in the central nervous system, which is called the 'endogenous cannabinoid system' and, like many other systems, can be manipulated pharmacologically. The aim of this review is to probe further into the scientific knowledge about this system generated in the last few years, as a necessary step to justify the development of pharmaceuticals based on its activation or inhibition and which can be useful in different neurological diseases. PMID:22573509

  15. Activation of type 2 cannabinoid receptors (CB2R) promotes fatty acid oxidation through the SIRT1/PGC-1α pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Xuqin [Department of Endocrinology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province 210029 (China); Sun, Tao [Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province 210002 (China); Wang, Xiaodong, E-mail: xdwang666@hotmail.com [Department of Endocrinology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province 210029 (China)

    2013-07-05

    Highlights: •TC, a CB2R specific agonist, stimulates SIRT1 activity by PKA/CREB pathway. •TC promotes PGC-1α transcriptional activity by increasing its deacetylation. •TC increases the expression of genes linked to FAO and promotes the rate of FAO. •The effects of TC in FAO are dependent on CB2R. •Suggesting CB2R as a target to treat diseases with lipid dysregulation. -- Abstract: Abnormal fatty acid oxidation has been associated with obesity and type 2 diabetes. At the transcriptional level, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) has been reported to strongly increase the ability of hormone nuclear receptors PPARα and ERRα to drive transcription of fatty acid oxidation enzymes. In this study, we report that a specific agonist of the type 2 cannabinoid receptor (CB2R) can lead to fatty acid oxidation through the PGC-1α pathway. We have found that CB2R is expressed in differentiated C2C12 myotubes, and that use of the specific agonist trans-caryophyllene (TC) stimulates sirtuin 1 (SIRT1) deacetylase activity by increasing the phosphorylation of cAMP response element-binding protein (CREB), thus leading to increased levels of PGC-1α deacetylation. This use of TC treatment increases the expression of genes linked to the fatty acid oxidation pathway in a SIRT1/PGC-1α-dependent mechanism and also drastically accelerates the rate of complete fatty acid oxidation in C2C12 myotubes, neither of which occur when CB2R mRNA is knocked down using siRNA. These results reveal that activation of CB2R by a selective agonist promotes lipid oxidation through a signaling/transcriptional pathway. Our findings imply that pharmacological manipulation of CB2R may provide therapeutic possibilities to treat metabolic diseases associated with lipid dysregulation.

  16. Uso terapéutico de los cannabinoides

    OpenAIRE

    Capellà Hereu, Dolors; Duran Delmas, M.

    2004-01-01

    Actualmente hay dos cannabinoides comercializados en algunos países para uso terapéutico. El dronabinol o D9tetrahidrocannabinol (THC) y su análogo babilona para el tratamiento de las náuseas y vómitos secundarios a la quimioterapia antineoplásica que no responde a los tratamientos habituales; pero su lugar en terapéutica como antieméticos ha sido cuestionado porque no se dispone de ensayos clínicos comparativos con los tratamientos de referencia (inhibidores de la serotonina). El dronabinol ...

  17. Cannabinoid hyperemesis syndrome and the onset of a manic episode.

    Science.gov (United States)

    Gregoire, Phillip; Tau, Michael; Robertson, David

    2016-01-01

    Cannabinoid hyperemesis syndrome is a rare, recently described, clinically diagnosed condition that is characterised by a chronic history of cannabis use, cyclic nausea and vomiting, symptomatic relief with hot water bathing, and resolution with cessation of use. We present a case of this syndrome concurrent in a patient with bipolar mania. We suggest that a 3-week period of vomiting in the context of this syndrome contributed to the precipitation of a manic episode by lowering mood stabiliser serum levels, and that this syndrome will have significant consequences for the patient's mental health. PMID:27122104

  18. Modulation of breast cancer cell viability by a cannabinoid receptor 2 agonist, JWH-015, is calcium dependent

    OpenAIRE

    Hanlon KE; Lozano-Ondoua AN; Umaretiya PJ; Symons-Liguori AM; Chandramouli A; Moy JK; Kwass WK; Mantyh PW; Nelson MA; Vanderah TW

    2016-01-01

    Katherine E Hanlon,1,2 Alysia N Lozano-Ondoua,1 Puja J Umaretiya,1 Ashley M Symons-Liguori,1 Anupama Chandramouli,1 Jamie K Moy,1 William K Kwass,1 Patrick W Mantyh,1 Mark A Nelson,3 Todd W Vanderah,11Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA; 2Department of Biomedical Sciences, University of New England College of Osteopathic Medicine, Biddeford, ME, USA; 3Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA Introdu...

  19. Pharmacological activation of cannabinoid 2 receptor attenuates inflammation, fibrogenesis, and promotes re-epithelialization during skin wound healing.

    Science.gov (United States)

    Wang, Lin-Lin; Zhao, Rui; Li, Jiao-Yong; Li, Shan-Shan; Liu, Min; Wang, Meng; Zhang, Meng-Zhou; Dong, Wen-Wen; Jiang, Shu-Kun; Zhang, Miao; Tian, Zhi-Ling; Liu, Chang-Sheng; Guan, Da-Wei

    2016-09-01

    Previous studies showed that cannabinoid 2 (CB2) receptor is expressed in multiple effector cells during skin wound healing. Meanwhile, its functional involvement in inflammation, fibrosis, and cell proliferation in other organs and skin diseases implied CB2 receptor might also regulate skin wound healing. To verify this hypothesis, mice excisional wounds were created and treated with highly selective CB2 receptor agonist GP1a (1-(2,4-dichlorophenyl)-6-methyl- N-piperidin-1-yl-4H-indeno[1,2-c]pyrazole-3-carboxamide) and antagonist AM630 ([6-iodo-2- methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone) respectively. The inflammatory infiltration, cytokine expression, fibrogenesis, and wound re-epithelialization were analyzed. After CB2 receptor activation, neutrophil and macrophage infiltrations were reduced, and expressions of monocyte chemotactic protein (MCP)-1, stromal cell-derived factor (SDF)-1, Interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF)-A were decreased. Keratinocyte proliferation and migration were enhanced. Wound re-epithelialization was accelerated. Fibroblast accumulation and fibroblast-to-myofibroblast transformation were attenuated, and expression of pro-collagen I was decreased. Furthermore, HaCaT cells in vitro were treated with GP1a or AM630, which revealed that CB2 receptor activation promoted keratinocyte migration by inducing the epithelial to mesenchymal transition. These results, taken together, indicate that activating CB2 receptor could ameliorate wound healing by reducing inflammation, accelerating re-epithelialization, and attenuating scar formation. Thus, CB2 receptor agonist might be a novel perspective for skin wound therapy. PMID:27268717

  20. Pharmacokinetics and metabolism of the plant cannabinoids, delta9-tetrahydrocannabinol, cannabidiol and cannabinol.

    Science.gov (United States)

    Huestis, M A

    2005-01-01

    Increasing interest in the biology, chemistry, pharmacology, and toxicology of cannabinoids and in the development of cannabinoid medications necessitates an understanding of cannabinoid pharmacokinetics and disposition into biological fluids and tissues. A drug's pharmacokinetics determines the onset, magnitude, and duration of its pharmacodynamic effects. This review of cannabinoid pharmacokinetics encompasses absorption following diverse routes of administration and from different drug formulations, distribution of analytes throughout the body, metabolism by different tissues and organs, elimination from the body in the feces, urine, sweat, oral fluid, and hair, and how these processes change over time. Cannabinoid pharmacokinetic research has been especially challenging due to low analyte concentrations, rapid and extensive metabolism, and physicochemical characteristics that hinder the separation of drugs of interest from biological matrices--and from each other--and lower drug recovery due to adsorption of compounds of interest to multiple surfaces. delta9-Tetrahydrocannabinol, the primary psychoactive component of Cannabis sativa, and its metabolites 11-hydroxy-delta9-tetrahydrocannabinol and 11-nor-9-carboxy-tetrahydrocannabinol are the focus of this chapter, although cannabidiol and cannabinol, two other cannabinoids with an interesting array of activities, will also be reviewed. Additional material will be presented on the interpretation of cannabinoid concentrations in human biological tissues and fluids following controlled drug administration. PMID:16596792

  1. Safety profile of WinRho anti-D.

    Science.gov (United States)

    Hong, F; Ruiz, R; Price, H; Griffiths, A; Malinoski, F; Woloski, M

    1998-01-01

    WinRho anti-D is manufactured with multiple processes to minimize the risk of transmitting blood-borne diseases such as viruses. These safety features include donor selection, plasma testing, solvent-detergent viral inactivation, and nanofiltration. To date, there has not been any case of viral transmission in association with use of WinRho anti-D. Adverse drug reactions are infrequent and generally mild; the most common are headache, fever, and chills. Some degree of hemolysis is inevitable due to the mechanism of action of WinRho anti-D, but this is predictable and transient. A few cases of intravascular hemolysis have been reported; hypersensitivity reactions are very rare. WinRho anti-D has been shown in both clinical trials and postmarketing surveillance to be safe and effective in the treatment of idiopathic thrombocytopenic purpura (ITP) and in the prevention of Rh isoimmunization. PMID:9523744

  2. Leaders in high temperature superconductivity commercialization win superconductor industry award

    CERN Multimedia

    2007-01-01

    CERN's Large Hadron Collider curretn leads project head Amalia Ballarino named superconductor industry person of the year 2006. Former high temperature superconductivity program manager at the US Department of energy James Daley wins lifetime achievement award. (1,5 page)

  3. College of Engineering robotics students win awards around the world

    OpenAIRE

    Crumbley, Liz

    2007-01-01

    Students from the Virginia Tech College of Engineering's Robotics and Mechanics Laboratory have traveled the United States and abroad this summer, winning a number of honors for robotics research and development.

  4. BMC Ecology Image Competition 2016: the winning images.

    Science.gov (United States)

    Simundza, Julia; Palmer, Matthew; Settele, Josef; Jacobus, Luke M; Hughes, David P; Mazzi, Dominique; Blanchet, Simon

    2016-01-01

    The 2016 BMC Ecology Image Competition marked another celebration of the astounding biodiversity, natural beauty, and biological interactions documented by talented ecologists worldwide. For our fourth annual competition, we welcomed guest judge Dr. Matthew Palmer of Columbia University, who chose the winning image from over 140 entries. In this editorial, we highlight the award winning images along with a selection of highly commended honorable mentions. PMID:27503341

  5. The Sport League's Dilemma: Competitive Balance versus Incentives to Win

    OpenAIRE

    Palomino, F.A.; Rigotti, L.

    2000-01-01

    We analyze a dynamic model of strategic interaction between a professional sport league that organizes a tournament, the teams competing to win it, and the broadcasters paying for the rights to televise it. Teams and broadcasters maximize expected profits, while the league's objective may be either to maximize the demand for the sport or to maximize the teams' joint profits. Demand depends positively on symmetry among teams (competitive balance) and how aggressively teams try to win (incenti...

  6. Cannabinoid HU210 protects isolated rat stomach against impairment caused by serum of rats with experimental acute pancreatitis.

    Science.gov (United States)

    Cao, Ming-hua; Li, Yong-yu; Xu, Jing; Feng, Ya-jing; Lin, Xu-hong; Li, Kun; Han, Tong; Chen, Chang-jie

    2012-01-01

    Acute pancreatitis (AP), especially severe acute pancreatitis often causes extra-pancreatic complications, such as acute gastrointestinal mucosal lesion (AGML) which is accompanied by a considerably high mortality, yet the pathogenesis of AP-induced AGML is still not fully understood. In this report, we investigated the alterations of serum components and gastric endocrine and exocrine functions in rats with experimental acute pancreatitis, and studied the possible contributions of these alterations in the pathogenesis of AGML. In addition, we explored the intervention effects of cannabinoid receptor agonist HU210 and antagonist AM251 on isolated and serum-perfused rat stomach. Our results showed that the AGML occurred after 5 h of AP replication, and the body homeostasis was disturbed in AP rat, with increased levels of pancreatic enzymes, lipopolysaccharide (LPS), proinflammtory cytokines and chemokines in the blood, and an imbalance of the gastric secretion function. Perfusing the isolated rat stomach with the AP rat serum caused morphological changes in the stomach, accompanied with a significant increment of pepsin and [H+] release, and increased gastrin and decreased somatostatin secretion. HU210 reversed the AP-serum-induced rat pathological alterations, including the reversal of transformation of the gastric morphology to certain degree. The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis. PMID:23285225

  7. Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.

    Science.gov (United States)

    Gomis-González, Maria; Matute, Carlos; Maldonado, Rafael; Mato, Susana; Ozaita, Andrés

    2016-01-01

    Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability. The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1) receptor. In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects. In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg) manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD). In addition, low doses of rimonabant (from 0.01 mg/kg) equally normalized the cognitive deficit in the mouse model of FXS. These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice. These data further support targeting CB1 receptors as a relevant therapy for FXS. PMID:27589806

  8. On Winning Conditions of High Borel Complexity in Pushdown Games

    CERN Document Server

    Finkel, Olivier

    2008-01-01

    Some decidable winning conditions of arbitrarily high finite Borel complexity for games on finite graphs or on pushdown graphs have been recently presented by O. Serre in [ Games with Winning Conditions of High Borel Complexity, in the Proceedings of the International Conference ICALP 2004, LNCS, Volume 3142, p. 1150-1162 ]. We answer in this paper several questions which were raised by Serre in the above cited paper. We first show that, for every positive integer n, the class C_n(A), which arises in the definition of decidable winning conditions, is included in the class of non-ambiguous context free omega languages, and that it is neither closed under union nor under intersection. We prove also that there exists pushdown games, equipped with such decidable winning conditions, where the winning sets are not deterministic context free languages, giving examples of winning sets which are non-deterministic non-ambiguous context free languages, inherently ambiguous context free languages, or even non context fre...

  9. Cannabinoids and centrak neuropathic pain. A review (Cannabinoidi e dolore neuropatico centrale. Una rassegna

    Directory of Open Access Journals (Sweden)

    Francesco Crestani

    2014-03-01

    Full Text Available Only recently, the medical community highlighted the pharmacological scientific bases of the effects of Cannabis. The most important active principle, Delta-9-tetrahydrocannabinol was identified in the second half of the last century, and receptors were subsequently identified and endogenous ligands, called endocannabinoids, were characterized. The effectiveness of the cannabinoids in the treatment of nausea and vomit due to anti-neoplastic chemotherapy and in the wasting-syndrome during AIDS is recognized. Moreover, the cannabinoids have shown analgesic properties, particularly interesting with regard to the central neuropathic pain. This article will review the current knowledge and will give practical guidance on how to proceed in prescribing cannabinoids.

  10. Cannabinoids induce incomplete maturation of cultured human leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Murison, G.; Chubb, C.B.H.; Maeda, S.; Gemmell, M.A.; Huberman, E.

    1987-08-01

    Monocyte maturation markers were induced in cultured human myeloblastic ML-2 leukemia cells after treatment for 1-6 days with 0.03-30 ..mu..M ..delta../sup 9/-tetrahydrocannabinol (THC), the major psychoactive component of marijuana. After a 2-day or longer treatment, 2- to 5-fold increases were found in the percentages of cells exhibiting reactivity with either the murine OKM1 monoclonal antibody of the Leu-M5 monoclonal antibody, staining positively for nonspecific esterase activity, and displaying a promonocyte morphology. The increases in these differentiation markers after treatment with 0.03-1 ..mu..M THC were dose dependent. At this dose range, THC did not cause an inhibition of cell growth. The THC-induced cell maturation was also characterized by specific changes in the patterns of newly synthesized proteins. The THC-induced differentiation did not, however, result in cells with a highly developed mature monocyte phenotype. However, treatment of these incompletely matured cells with either phorbol 12-myristate 13-acetate of 1..cap alpha..,25-dihydroxycholecalciferol, which are inducers of differentiation in myeloid leukemia cells (including ML-2 cells), produced cells with a mature monocyte morphology. The ML-2 cell system described here may be a useful tool for deciphering critical biochemical events that lead to the cannabinoid-induced incomplete cell differentiation of ML-2 cells and other related cell types. Findings obtained from this system may have important implications for studies of cannabinoid effects on normal human bone-marrow progenitor cells.

  11. A model for establishing a win-win relationship between a wood pellets manufacturer and its customers

    International Nuclear Information System (INIS)

    This paper investigates the possibility of establishing a win-win relationship between a wood pellets manufacturer and its customers when the manufacturer possesses a power plant fueled by biomass and buys wood material from forest companies. Two prerequisites must be fulfilled for this relationship. First, the price of wood pellets should be lower than the fuel currently used by potential wood pellets customers and, second, the price of wood material as a raw material for producing the wood pellets should not jeopardize the profitability of the operations of the wood pellets manufacturer, who also produces electricity from biomass and sells it to the state at the feed-in tariff price. A mathematical model has been developed for each prerequisite and applied to several examples. The results demonstrate that a win-win relation can be established in Croatia and most of the Member States of the EU. (author)

  12. Beta-agonists and animal welfare

    Science.gov (United States)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  13. The "Win-Win" Strategy for Sustainable Development : A Case Study of Recycling System in European Countries <論説>

    OpenAIRE

    Ueda, Yoshifumi

    1999-01-01

    According to static mindset, any regulation for ecological preservation means an unavoidable cost imposed on private economic activities, and promotes only a "end-of-pipe" type of technology. However, regulations devised from the view point of evolutionary mindset can reconcile economic development with ecological sustainability by encouraging an ecologically benign technology on micro level. However, the "win-win" strategy may result in "wrong-wrong" strategies, unless the private initiative...

  14. CERN repeats last year's running win

    CERN Multimedia

    2000-01-01

    The CERN first team successfully defended the title won last year in the 20th annual Cross Inter-Entreprises held at Collex-Bossy on Saturday 7 October. 101 teams of four runners representing firms from all over the Geneva area finished the 6.2 km race, through forest and over fields. In spite of two members of last year’s winning team being absent through injury this time, the first team was still 38 seconds faster than in 1999. The second and third CERN teams also excelled with places in the first 15 teams. In this race the teams start at one-minute intervals and the time of each team is that of its third runner to finish, so they try to run in a group of three or four all the way. The full results of all teams can be found at: http://www.Club-association.ch/CHP Placings of the CERN teams 1st 21:53 Cornelis, Ecarnot, Ehmele, Nisbet 6th 22:50 Cornet, Eklund, Rick, Ruiz Llamas 13th 24:24 Dunkel, Guillot, Montejo Raez, Zamiatin 35th 28:22 Cameron, Galbraith, Revol, Scalisi

  15. Win a lift to the future!

    CERN Multimedia

    CERN Bulletin

    2010-01-01

    The Communication Group is organising a competition offering people at CERN the chance to submit their ideas and win a ticket to the Lift10 Conference, which will be held in Geneva from 5 to7 May.   Lift is a community of technology "pioneers", created in 2006. It now involves more than 4,000 people from over 60 countries, who meet regularly in Europe and in Asia to explore the social implications of new technologies and the major shifts ahead. CERN is one of the academic partners of the next Lift conference, whose theme is "Connected people”. For this occasion, 10 free tickets to the conference will be awarded to the "CERNois" who come up with the best answers to the question: “How would you contribute to Lift10?” Those taking part in the competition can choose from among the following categories: - run workshop(s); - cover the conference on a blog; - coordinate a discussion during the breaks; - organize a lift@home ...

  16. [Adrenergic beta-agonist intoxication].

    Science.gov (United States)

    Carrola, Paulo; Devesa, Nuno; Silva, José Manuel; Ramos, Fernando; Alexandrino, Mário B; Moura, José J

    2003-01-01

    The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestión of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a ß-adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency. PMID:22226216

  17. β2-agonist therapy in lung disease.

    Science.gov (United States)

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  18. International cooperation for nuclear science and energy development- A win win perspective

    International Nuclear Information System (INIS)

    Full-text: International and regional cooperation is fundamental for the safe and effective introduction and expansion of nuclear power programme (NPP). A win-win situation can be harnessed as experienced countries in NPP are able to offer a myriad of benefits to new comer countries as well as countries planning for NPP whilst new comer countries are able to offer education and training opportunities and business opportunities to advanced countries in NPP. Countries with long experience in nuclear power programme (NPP) are able to offer experience, knowledge, advisory as well as sharing of resources and facilities with new comer countries. As skilled and competent personnel in the entire nuclear value-chain are critical to support NPP, this paper will provide an overview of some of the experience and resources of advanced countries in NPP that could be shared with new comer countries, with a focus in the area of education and training, as well as in industrial development. The paper will conclude by offering some recommendations as a way forward for establishing international cooperation in Nuclear Education and Training, as well as for industrial development. (author)

  19. Achieving ecological restoration by working with local people: a Chinese scholar seeks win-win paths

    Directory of Open Access Journals (Sweden)

    Heran Zheng

    2014-09-01

    Full Text Available Environmental degradation and poverty are linked, and this means that conservation and poverty reduction must be tackled together. However, finding a successful integrated strategy has been an elusive goal. We describe the career of a Chinese scholar, Shixiong Cao, whose persistent efforts to find and follow win-win paths have led to ecological restoration accompanied by long-term benefits for local residents. Cao’s story illustrates how development that combines environmental and economic perspectives can both help people to escape the poverty trap and restore degraded environments. His experience demonstrates that when environmental managers find solutions that can mitigate or eliminate poverty through the development of green enterprises, they can combine them with environmental restoration efforts to produce long-term sustainable solutions. In this paper, we share Cao’s 28 years of experience because we believe that his scientific and practical spirit, and his belief that it is necessary to work directly with the people affected by environmental projects, will inspire other scholars and practitioners to achieve similar successes.

  20. Ombud's Corner: fellows and students – a win-win equation

    CERN Multimedia

    Sudeshna Datta-Cockerill

    2014-01-01

    The hundreds of Fellows and students working at CERN bring precious new blood into the Laboratory. At the same time, CERN offers them invaluable work experience that will have a significant impact on their future careers. It is important that we all work together to make this a win-win situation with lasting positive effects for all concerned over the years to come.   Fellows and students are just setting out on a great professional adventure.  Some of them are very young, others are a bit more experienced … and what happens during this early period can have vast consequences on their approach to work and indeed on their overall careers. They all come here with their hard earned skills and a high degree of motivation, ready to make the most out of an internship at CERN. Sometimes, they are called to integrate into well-established units; at other times, they are asked to join complex collaborations. Almost always they have to deal with new information, new cultures, new t...

  1. Death Associated With the Use of the Synthetic Cannabinoid ADB-FUBINACA.

    Science.gov (United States)

    Shanks, Kevin G; Clark, William; Behonick, George

    2016-04-01

    Synthetic cannabinoids have been found in herbal incense products for the last several years. We report the rapid death of an individual that was certified as synthetic cannabinoid-associated. The autopsy blood specimen was extracted by a liquid-liquid extraction at pH 10.2 into a hexane-ethyl acetate mixture and analyzed by a generalized synthetic cannabinoid LC-MS-MS method. For this case report, we briefly describe the instrumental analysis and extraction methods for the detection of ADB-FUBINACA in postmortem blood, toxicological results for the postmortem blood specimen (ADB-FUBINACA, 7.3 ng/mL; THC, 1.1 ng/mL; THC-COOH, 4.7 ng/mL), case information and circumstances and pertinent findings at autopsy. The cause of death was certified as coronary arterial thrombosis in combination with synthetic cannabinoid use. Manner of death was accident. PMID:26755539

  2. Cannabinoids and Tremor Induced by Motor-related Disorders: Friend or Foe?

    Science.gov (United States)

    Arjmand, Shokouh; Vaziri, Zohreh; Behzadi, Mina; Abbassian, Hassan; Stephens, Gary J; Shabani, Mohammad

    2015-10-01

    Tremor arises from an involuntary, rhythmic muscle contraction/relaxation cycle and is a common disabling symptom of many motor-related diseases such as Parkinson disease, multiple sclerosis, Huntington disease, and forms of ataxia. In the wake of anecdotal, largely uncontrolled, observations claiming the amelioration of some symptoms among cannabis smokers, and the high density of cannabinoid receptors in the areas responsible for motor function, including basal ganglia and cerebellum, many researchers have pursued the question of whether cannabinoid-based compounds could be used therapeutically to alleviate tremor associated with central nervous system diseases. In this review, we focus on possible effects of cannabinoid-based medicines, in particular on Parkinsonian and multiple sclerosis-related tremors and the common probable molecular mechanisms. While, at present, inconclusive results have been obtained, future investigations should extend preclinical studies with different cannabinoids to controlled clinical trials to determine potential benefits in tremor. PMID:26152606

  3. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    International Nuclear Information System (INIS)

    Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells

  4. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    Energy Technology Data Exchange (ETDEWEB)

    Massi, Paola [Department of Pharmacology, Chemotherapy and Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan (Italy); Valenti, Marta; Solinas, Marta; Parolaro, Daniela, E-mail: daniela.parolaro@uninsubria.it [Department of Structural and Functional Biology, Section of Pharmacology, Center of Neuroscience, University of Insubria, Via A. da Giussano 10, 20152 Busto Arsizio, Varese (Italy)

    2010-05-26

    Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells.

  5. Screening of Danish traffic cases for synthetic cannabinoids in whole blood by LC-MS/MS

    DEFF Research Database (Denmark)

    Holm, Niels Bjerre; Pineda, Rebeca; Andersen, David Wederkinck; Rasmussen, Brian Schou; Dalsgaard, Petur Weihe; Hoegberg, Lotte; Johansen, Sys Stybe; Linnet, Kristian

    2013-01-01

    A target screening method for the detection of 13 synthetic cannabinoids in whole blood was developed and validated. Samples underwent automated solid-phase extraction, and sample extracts were analyzed by liquid chromatography-positive electrospray ionization-tandem mass spectrometry using two...... drugs. No synthetic cannabinoids were identified in these samples. Additionally, the method was applied to a clinical intoxication case, and the synthetic cannabinoid AM-2201 was identified in serum. We conclude that the prevalence of driving under the influence of synthetic cannabinoids in Denmark is...... transitions in multiple reaction monitoring mode. The limit of detection was between 0.1-2.5 ng/mL for the compounds except HU-210, and extraction recovery ranged from 59 to 78%. The method was used to screen 393 Danish traffic cases from 2012, where the driver was suspected of driving under the influence of...

  6. Gastric acid inhibitory and gastric protective effects of Cannabis and cannabinoids.

    Science.gov (United States)

    Abdel-Salam, Omar

    2016-05-01

    Cannabis sativa has long been known for its psychotropic effect. Only recently with the discovery of the cannabinoid receptors, their endogenous legends and the enzymes responsible for their synthesis and degradation, the role of this 'endocannabinoid system' in different pathophysiologic processes is beginning to be delineated. There is evidence that CB1 receptor stimulation with synthetic cannabinoids or Cannabis sativa extracts rich in Δ(9)-tetrahydrocannabinol inhibit gastric acid secretion in humans and experimental animals. This is specially seen when gastric acid secretion is stimulated by pentagastrin, carbachol or 2-deoxy-d-glucose. Cannabis and/or cannabinoids protect the gastric mucosa against noxious challenge with non-steroidal anti-inflammatory drugs, ethanol as well as against stress-induced mucosal damage. Cannabis/cannabinoids might protect the gastric mucosa by virtue of its antisecretory, antioxidant, anti-inflammatory, and vasodilator properties. PMID:27261847

  7. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Paola Massi

    2010-05-01

    Full Text Available Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells.

  8. 2012 Division of Medicinal Chemistry Award Address: Trekking the Cannabinoid Road: A Personal Perspective

    OpenAIRE

    Makriyannis, Alexandros

    2014-01-01

    My involvement with the field of cannabinoids spans close to three decades, and covers a major part of my scientific career. It also reflects the robust progress in this initially largely unexplored area of biology. During this period of time, I have witnessed the growth of modern cannabinoid biology, starting from the discovery of its two receptors and followed by the characterization of its endogenous ligands and the identification of the enzyme systems involved in their biosynthesis and bi...

  9. Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans

    OpenAIRE

    Rabinak, Christine A.; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R; Liberzon, Israel; Phan, K. Luan

    2013-01-01

    Pre-extinction administration of ∆9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely involves via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a fu...

  10. Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside

    OpenAIRE

    Rahn, Elizabeth J; Hohmann, Andrea G.

    2009-01-01

    Neuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults. Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics. Cannabinoids, drugs that share the same target as Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. Here, we review studies evaluating cannabinoids for neuropathic pain management in the c...

  11. Opposing actions of chronic Δ9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation

    OpenAIRE

    Hoffman, Alexander F; Oz, Murat; Yang, Ruiqin; Lichtman, Aron H.; Carl R Lupica

    2007-01-01

    Memory deficits produced by marijuana arise partly via interaction of the psychoactive component, Δ9-tetrahydrocannabinol (Δ9-THC), with cannabinoid receptors in the hippocampus. Although cannabinoids acutely reduce glutamate release and block hippocampal long-term potentiation (LTP), a potential substrate for learning and memory, the consequences of prolonged exposure to Δ9-THC for hippocampal function are poorly understood. Rats were injected with Δ9-THC (10 mg/kg, i.p., q.d.) for 1, 3, or ...

  12. Opposite function of dopamine D1 and NMDA receptors in striatal cannabinoid-mediated signaling

    OpenAIRE

    Daigle, Tanya L.; Wetsel, William C.; Caron, Marc G.

    2011-01-01

    It is well established that the cannabinoid and dopamine systems interact at various levels to regulate basal ganglia function. While it is well known that acute administration of cannabinoids to mice can modify dopamine-dependent behaviors, an understanding of the intraneuronal signaling pathways employed by these agents in the striatum is not well understood. Here we use knockout (KO) mouse models to examine the regulation of striatal ERK1/2 signaling by behaviorally relevant doses of canna...

  13. Cannabinoid Type 1 Receptors Transiently Silence Glutamatergic Nerve Terminals of Cultured Cerebellar Granule Cells

    OpenAIRE

    Ramírez-Franco, Jorge; Bartolomé-Martín, David; Alonso, Beatris; Torres, Magdalena; Sánchez-Prieto, José

    2014-01-01

    Cannabinoid receptors are the most abundant G protein-coupled receptors in the brain and they mediate retrograde short-term inhibition of neurotransmitter release, as well as long-term depression of synaptic transmission at many excitatory synapses. The induction of presynaptically silent synapses is a means of modulating synaptic strength, which is important for synaptic plasticity. Persistent activation of cannabinoid type 1 receptors (CB1Rs) mutes GABAergic terminals, although it is unclea...

  14. Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection

    OpenAIRE

    More, Sandeep Vasant; Choi, Dong-Kug

    2015-01-01

    Parkinson’s disease (PD) is a slow insidious neurological disorder characterized by a loss of dopaminergic neurons in the midbrain. Although several recent preclinical advances have proposed to treat PD, there is hardly any clinically proved new therapeutic for its cure. Increasing evidence suggests a prominent modulatory function of the cannabinoid signaling system in the basal ganglia. Hence, use of cannabinoids as a new therapeutic target has been recommended as a promising therapy for PD....

  15. Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism

    OpenAIRE

    Lim, Chung Thong; Kola, Blerina; Feltrin, Daniel; Perez-Tilve, Diego; Tschöp, Matthias H.; Grossman, Ashley B; Korbonits, Márta

    2013-01-01

    Introduction Ghrelin is a potent orexigenic brain-gut peptide with lipogenic and diabetogenic effects, possibly mediated by growth hormone secretagogue receptor (GHS-R1a). Cannabinoids also have orexigenic and lipogenic effects. AMPK is a regulator of energy homeostasis and we have previously shown that ghrelin and cannabinoids stimulate hypothalamic AMPK activity while inhibiting it in the liver and adipose tissue, suggesting that AMPK mediates both the central appetite-inducing and peripher...

  16. Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects

    OpenAIRE

    Jiang, Wen; Zhang, Yun; Xiao, Lan; Van Cleemput, Jamie; Ji, Shao-Ping; Bai, Guang; Zhang, Xia

    2005-01-01

    The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible cor...

  17. Cannabinoid receptor activation in the rostral ventrolateral medulla oblongata evokes cardiorespiratory effects in anaesthetised rats

    OpenAIRE

    Padley, James R; Li, Qun; Pilowsky, Paul M.; Goodchild, Ann K

    2003-01-01

    The nature of the cardiorespiratory effects mediated by cannabinoids in the hindbrain is poorly understood. In the present study we investigated whether cannabinoid receptor activation in the rostral ventrolateral medulla oblongata (RVLM) affects cardiovascular and/or respiratory function.Initially, we looked for evidence of CB1 receptor gene expression in rostral and caudal sections of the rat ventrolateral medulla (VLM) using reverse transcription–polymerase chain reaction. Second, the pote...

  18. The Role of Cannabinoid Receptors in the Descending Modulation of Pain

    Directory of Open Access Journals (Sweden)

    Francesco Rossi

    2010-08-01

    Full Text Available The endogenous antinociceptive descending pathway represents a circuitry of the supraspinal central nervous system whose task is to counteract pain. It includes the periaqueductal grey (PAG-rostral ventromedial medulla (RVM-dorsal horn (DH axis, which is the best characterized pain modulation system through which pain is endogenously inhibited. Thus, an alternative rational strategy for silencing pain is the activation of this anatomical substrate. Evidence of the involvement of cannabinoid receptors (CB in the supraspinal modulation of pain can be found in several studies in which intra-cerebral microinjections of cannabinoid ligands or positive modulators have proved to be analgesic in different pain models, whereas cannabinoid receptor antagonists or antisense nucleotides towards CB1 receptors have facilitated pain. Like opioids, cannabinoids produce centrally-mediated analgesia by activating a descending pathway which includes PAG and its projection to downstream RVM neurons, which in turn send inhibitory projections to the dorsal horn of the spinal cord. Indeed, several studies underline a supraspinal regulation of cannabinoids on g-aminobutyric acid (GABA and glutamate release which inhibit and enhance the antinociceptive descending pathway, respectively. Cannabinoid receptor activation expressed on presynaptic GABAergic terminals reduces the probability of neurotransmitter release thus dis-inhibiting the PAG-RVM-dorsal horn antinociceptive pathway. Cannabinoids seem to increase glutamate release (maybe as consequence of GABA decrease and to require glutamate receptor activation to induce antinociception. The consequent outcome is behavioral analgesia, which is reproduced in several pain conditions, from acute to chronic pain models such as inflammatory and neuropathic pain. Taken together these findings would suggest that supraspinal cannabinoid receptors have broad applications, from pain control to closely related central nervous system

  19. Frequency-Dependent Cannabinoid Receptor-Independent Modulation of Glycine Receptors by Endocannabinoid 2-AG

    OpenAIRE

    Natalia eLozovaya; Marat eMukhtarov; Timur eTsintsadze; Catherine eLedent; Nail eBurnashev; Piotr eBregestovski

    2011-01-01

    Endocannabinoids are known as retrograde messengers, being released from the postsynaptic neuron and acting on specific presynaptic G-protein-coupled cannabinoid (CB) receptors to decrease neurotransmitter release. Also, at physiologically relevant concentrations cannabinoids can directly modulate the function of voltage-gated and receptor-operated ion channels. Using patch-clamp recording we analyzed the consequences of the direct action of an endocannabinoid, 2-arachidonoylglycerol (2-AG), ...

  20. Design, synthesis and evaluation of fluorescent CB2 cannabinoid receptor ligands

    OpenAIRE

    Holt, Christopher James

    2009-01-01

    Cannabis has been used as a medicinal and natural product for thousands of years. Whether it has been used to make rope or paper, or been used to treat pain or depression, cannabis has always had a place in human civilisation. With the isolation of the psychoactive compounds responsible for cannabis’ effects, the discovery of two human cannabinoid receptors and an expanding knowledge of the therapeutic uses of cannabis, interest in the development of novel cannabinoids grew. The CB2 cann...

  1. Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions

    OpenAIRE

    Mendizábal, V E; Adler-Graschinsky, E

    2007-01-01

    In addition to their classical known effects, such as analgesia, impairment of cognition and learning and appetite enhancement, cannabinoids have also been related to the regulation of cardiovascular responses and implicated in cardiovascular pathology. Elevated levels of endocannabinoids have been related to the extreme hypotension associated with various forms of shock as well as to the cardiovascular abnormalities that accompany cirrhosis. In contrast, cannabinoids have also been associate...

  2. Hippocampal Cannabinoid Transmission Modulates Dopamine Neuron Activity: Impact on Rewarding Memory Formation and Social Interaction

    OpenAIRE

    Loureiro, Michael; Renard, Justine; Zunder, Jordan; Laviolette, Steven R

    2015-01-01

    Disturbances in cannabinoid type 1 receptor (CB1R) signaling have been linked to emotional and cognitive deficits characterizing neuropsychiatric disorders, including schizophrenia. Thus, there is growing interest in characterizing the relationship between cannabinoid transmission, emotional processing, and dopamine (DA)-dependent behavioral deficits. The CB1R is highly expressed in the mammalian nervous system, particularly in the hippocampus. Activation of the ventral hippocampal subregion ...

  3. WINS. Market Simulation Tool for Facilitating Wind Energy Integration

    Energy Technology Data Exchange (ETDEWEB)

    Shahidehpour, Mohammad [Illinois Inst. of Technology, Chicago, IL (United States)

    2012-10-30

    Integrating 20% or more wind energy into the system and transmitting large sums of wind energy over long distances will require a decision making capability that can handle very large scale power systems with tens of thousands of buses and lines. There is a need to explore innovative analytical and implementation solutions for continuing reliable operations with the most economical integration of additional wind energy in power systems. A number of wind integration solution paths involve the adoption of new operating policies, dynamic scheduling of wind power across interties, pooling integration services, and adopting new transmission scheduling practices. Such practices can be examined by the decision tool developed by this project. This project developed a very efficient decision tool called Wind INtegration Simulator (WINS) and applied WINS to facilitate wind energy integration studies. WINS focused on augmenting the existing power utility capabilities to support collaborative planning, analysis, and wind integration project implementations. WINS also had the capability of simulating energy storage facilities so that feasibility studies of integrated wind energy system applications can be performed for systems with high wind energy penetrations. The development of WINS represents a major expansion of a very efficient decision tool called POwer Market Simulator (POMS), which was developed by IIT and has been used extensively for power system studies for decades. Specifically, WINS provides the following superiorities; (1) An integrated framework is included in WINS for the comprehensive modeling of DC transmission configurations, including mono-pole, bi-pole, tri-pole, back-to-back, and multi-terminal connection, as well as AC/DC converter models including current source converters (CSC) and voltage source converters (VSC); (2) An existing shortcoming of traditional decision tools for wind integration is the limited availability of user interface, i.e., decision

  4. Effect of synthetic cannabinoid HU210 on memory deficits and neuropathology in Alzheimer's disease mouse model.

    Science.gov (United States)

    Chen, B; Bromley-Brits, K; He, G; Cai, F; Zhang, X; Song, W

    2010-05-01

    Cannabinoids have been shown to increase neurogenesis in adult brain, as well as protect neurons from excitotoxicity, calcium influx, inflammation, and ischemia. Recent studies have shown that synthetic cannabinoids can alleviate water maze impairments in rats treated with intracranial amyloid beta protein (Abeta); however it is unknown whether this effect is due to the cannabinoids' anti-inflammatory properties or whether it affects Abeta processing. Here we investigate whether cannabinoids have any effect on Alzheimer's disease in vivo. We found that HU210, a potent synthetic cannabinoid, did not improve water maze performance or a contextual fear conditioning task in an APP23/PS45 double transgenic mouse model of AD. HU210 had no effect on APP processing and Abeta generation, as well as neuritic plaque formation in the brains of AD transgenic mice. Our study showed that synthetic cannabinoid HU210 had no beneficial effects on AD neuropathology and behavioral deficits of AD model mice, which advises caution of such drug's application in AD therapies. PMID:20043809

  5. Lack of positive allosteric modulation of mutated alpha(1)S267I glycine receptors by cannabinoids.

    Science.gov (United States)

    Foadi, Nilufar; Leuwer, Martin; Demir, Reyhan; Dengler, Reinhard; Buchholz, Vanessa; de la Roche, Jeanne; Karst, Matthias; Haeseler, Gertrud; Ahrens, Jörg

    2010-05-01

    Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. Ajulemic acid and HU210 are non-psychotropic, synthetic cannabinoids. Cannabidiol is a non-psychotropic plant constituent of cannabis sativa. There are hints that non-cannabinoid receptor mechanisms of these cannabinoids might be mediated via glycine receptors. In this study, we investigated the impact of the amino acid residue serine at position 267 on the glycine-modulatory effects of ajulemic acid, cannabidiol and HU210. Mutated alpha(1)S267I glycine receptors transiently expressed in HEK293 cells were studied by utilising the whole-cell clamp technique. The mutation of the alpha(1) subunit TM2 serine residue to isoleucine abolished the co-activation and the direct activation of the glycine receptor by the investigated cannabinoids. The nature of the TM2 (267) residue of the glycine alpha(1) subunit is crucial for the glycine-modulatory effect of ajulemic acid, cannabidiol and HU210. An investigation of the impact of such mutations on the in vivo interaction of cannabinoids with glycine receptors should permit a better understanding of the molecular determinants of action of cannabinoids. PMID:20339834

  6. Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation.

    Science.gov (United States)

    McCoy, Kathleen L

    2016-01-01

    Since the discovery of the endocannabinoid system consisting of cannabinoid receptors, endogenous ligands, and biosynthetic and metabolizing enzymes, interest has been renewed in investigating the promise of cannabinoids as therapeutic agents. Abundant evidence indicates that cannabinoids modulate immune responses. An inflammatory response is triggered when innate immune cells receive a danger signal provided by pathogen- or damage-associated molecular patterns engaging pattern-recognition receptors. Toll-like receptor family members are prominent pattern-recognition receptors expressed on innate immune cells. Cannabinoids suppress Toll-like receptor-mediated inflammatory responses. However, the relationship between the endocannabinoid system and innate immune system may not be one-sided. Innate immune cells express cannabinoid receptors and produce endogenous cannabinoids. Hence, innate immune cells may play a role in regulating endocannabinoid homeostasis, and, in turn, the endocannabinoid system modulates local inflammatory responses. Studies designed to probe the interaction between the innate immune system and the endocannabinoid system may identify new potential molecular targets in developing therapeutic strategies for chronic inflammatory diseases. This review discusses the endocannabinoid system and Toll-like receptor family and evaluates the interaction between them. PMID:27597805

  7. Metabolomics and bioanalysis of terpenoid derived secondary metabolites: Analysis of Cannabis sativa L. metabolite production and prenylases for cannabinoid production

    OpenAIRE

    Muntendam, Remco

    2015-01-01

    Cannabinoid research has gained a renenewed interest by both the public and scientist. Focus is mainly directed to the medicinal activities, as reported for various cannabinoid structures. This thesis focusses on prenyl-derived secondary metabolites with main focus on cannabinoids. Firstly the production patterns and production location were investigated for standardiozed cultivated medicinal C.sativa variants. Metabolic profiling discriminated variants during the complete cultivation. Moreov...

  8. Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents.

    Science.gov (United States)

    Shook, J E; Burks, T F

    1989-05-01

    Marijuana has been reported to be an effective antinauseant and antiemetic in patients receiving cancer chemotherapy. Whether this is due to psychological changes, central antiemetic properties and/or direct effects on gastrointestinal (GI) function is not known. The purpose of these investigations was to determine whether the major constituents of marijuana and the synthetic cannabinoid nabilone have any effects on GI function which can be detected in rodent models of GI transit and motility. Intravenous delta 9-tetrahydrocannabinol (delta 9-THC) slowed the rate of gastric emptying and small intestinal transit in mice and in rats. Delta 9,11-THC, cannabinol and nabilone given i.v. also inhibited small intestinal transit in mice, but were less effective in reducing gastric emptying. Cannabidiol given i.v. had no effect on gastric emptying or intestinal transit. Those cannabinoids which inhibited GI transit did so at doses equal to, or lower, than those reported to produce central nervous system activity. In rats, delta 9-THC produced greater inhibition of gastric emptying and small intestinal transit than large bowel transit, indicating a selectivity for the more proximal sections of the gut. In addition, i.v. delta 9-THC decreased the frequency of both gastric and intestinal contractions without altering intraluminal pressure. Such changes probably reflect a decrease in propulsive activity, without change in basal tone. These data indicate that delta 9-THC, delta 9,11-THC, cannabinol and nabilone (but not cannabidiol) exert an inhibitory effect on GI transit and motility in rats. PMID:2542532

  9. Prevention by the cannabinoid antagonist, SR141716A, of cannabinoid-mediated blockade of long-term potentiation in the rat hippocampal slice.

    OpenAIRE

    D. R. Collins; Pertwee, R. G.; Davies, S. N.

    1995-01-01

    Incubation of rat hippocampal slices in the presence of the synthetic cannabinoid (-)-11-OH-delta 8-dimethylheptyl tetrahydrocannabinol (HU-210) (100 nM) prevented the induction of long-term potentiation (LTP). Slices co-incubated with both HU-210 (100 nM) and the cannabinoid antagonist, SR141716A (100 nM), exhibited tetanically induced LTP, comparable to control slices. Intriguingly, coincubation with HU-210 and SR141716A prevented the induction of the early, short-term phase of LTP.

  10. Cannabinoid receptor 2 expression modulates Gβ(1)γ(2) protein interaction with the activator of G protein signalling 2/dynein light chain protein Tctex-1.

    Science.gov (United States)

    Nagler, Marina; Palkowitsch, Lysann; Rading, Sebastian; Moepps, Barbara; Karsak, Meliha

    2016-01-01

    The activator of G protein signalling AGS2 (Tctex-1) forms protein complexes with Gβγ, and controls cell proliferation by regulating cell cycle progression. A direct interaction of Tctex-1 with various G protein-coupled receptors has been reported. Since the carboxyl terminal portion of CB2 carries a putative Tctex-1 binding motif, we investigated the potential interplay of CB2 and Tctex-1 in the absence and presence of Gβγ. The supposed interaction of cannabinoid receptor CB2 with Tctex-1 and the influence of CB2 on the formation of Tctex-1-Gβγ-complexes were studied by co- and/or immunoprecipitation experiments in transiently transfected HEK293 cells. The analysis on Tctex-1 protein was performed in the absence and presence of the ligands JWH 133, 2-AG, and AM 630, the protein biosynthesis inhibitor cycloheximide or the protein degradation blockers MG132, NH4Cl/leupeptin or bafilomycin. Our results show that CB2 neither directly nor indirectly via Gβγ interacts with Tctex-1, but competes with Tctex-1 in binding to Gβγ. The Tctex-1-Gβγ protein interaction was disrupted by CB2 receptor expression resulting in a release of Tctex-1 from the complex, and its degradation by the proteasome and partly by lysosomes. The decrease in Tctex-1 protein levels is induced by CB2 expression "dose-dependently" and is independent of stimulation by agonist or blocking by an inverse agonist treatment. The results suggest that CB2 receptor expression independent of its activation by agonists is sufficient to competitively disrupt Gβγ-Tctex-1 complexes, and to initiate Tctex-1 degradation. These findings implicate that CB2 receptor expression modifies the stability of intracellular protein complexes by a non-canonical pathway. PMID:26410677

  11. Winning at litigation through decision analysis creating and executing winning strategies in any litigation or dispute

    CERN Document Server

    Celona, John

    2016-01-01

    This book is the first in-depth guide to applying the philosophy, theory, and methods of decision analysis to creating and executing winning legal strategies. With explanations that progress from introductory to advanced and practice problems at the end of each chapter, this is a book the reader will want to use and refer to for years to come. Practicing decision analysts, operations research and management science students, attorneys and law students will find this book an invaluable addition to their knowledge and skills. John Celona has over three decades of experience in teaching and applying decision analysis. John lectures in the School of Engineering at Stanford University and is on faculty at The Stanford Center for Professional Development, the American Course on Drug Development and Regulatory Sciences, and the Academy of the American Society for Healthcare Risk Management.

  12. LenaWin 1.0, user's guide

    International Nuclear Information System (INIS)

    LenaWin is a program for dispersion and dose calculations, mainly connected to accidents in nuclear facilities. Besides that, it may, however, also be used for other kinds of releases. It is designed to be used both for training purpose, and in real situations. Great care has therefore been taken to ensure a simple and quick handling of the program, also in difficult situations. The program is a true Windows application, and works with version 3.0 and higher of Microsoft Windows. It was developed at the Swedish Radiation Protection Institute (SSI) during 1991-1992, and is used by the institute in its regular work. LenaWin is part in a larger system to handle accidental situations. An important part of this system is a database and a database handler to manage all kinds of measured data after a release. LenaWin has functions to display data taken from this database on maps

  13. Winning at Pocker and Games of Chance Winning at Pocker and Games of Chance

    Directory of Open Access Journals (Sweden)

    Anita Flanders Rebelo

    2008-04-01

    Full Text Available It's the modern consumer mind - compete to eat, save to the grave, throw to the wind to win! Never the game that's im portant - it's the beer , the fag. . . and if you're broke it's just the "odds" to turn you on. "Socrates didn't play dice games. He drank a lot. And when he was drunk he would go watch the game and give advice. It was because of bad advice that he was eventually sentenced to death. . . Back then it was more fun. Nobody knew anything about odds. It was just put down your money, you toss the dice, you laugh, you take another drink." - to Cassidy,it's knowing the odds that's put everybody on pot. Rack Cassidy's Winning at Poker and Games of Chance lampoons the illogic logic of modern "instructed" man. It is a disturbingly funny caricature of a nonsensical consumer's mind trying to ratio nalize the game of life, and what comes out is "hash" - not meat and potatoes. The book is high philosophical slapstick comedy ila Charlie Chaplin on paper in today's scene. To Cassidy, consumer thinking has made intellectual nitwits of us. We're always ex plaining in detail about what we don't have the slightest real understanding of, but we go on and on like automats spitting out words and words which in the long run make no sense to our__ selves and much less to the other poor broken down human calculat ing machines - especially when we try to give logic to our il/logical vices and fears.

  14. Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy

    OpenAIRE

    Jakubík, J; Janíčková, H; El-Fakahany, EE; Doležal, V

    2011-01-01

    BACKGROUND AND PURPOSE Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5′-γ−thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M2 muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. EXPERIMENTAL APPROACH Filtration and scintillation proximity ass...

  15. COMPARATIVE EFFECTS OF CHLOPYRIFOS IN WILD TYPE AND CANNABINIOID CB1 RECEPTOR KNOCKOUT MICE

    OpenAIRE

    Baireddy, Praveena; Liu, Jing; Hinsdale, Myron; Pope, Carey

    2011-01-01

    Endocannabinoids (eCBs) modulate neurotransmission by inhibiting the release of a variety of neurotransmitters. The cannabinoid receptor agonist WIN 55,212-2 (WIN) can modulate organophosphorus (OP) anticholinesterase toxicity in rats, presumably by inhibiting acetylcholine (ACh) release. Some OP anticholinesterases also inhibit eCB-degrading enzymes. We studied the effects of the OP insecticide chlorpyrifos (CPF) on cholinergic signs of toxicity, cholinesterase activity and ACh release in ti...

  16. Thrombopoietin Receptor Agonists in Primary ITP

    OpenAIRE

    Siegal, Deborah; Crowther, Mark; Cuker, Adam

    2013-01-01

    Thrombopoietin (TPO) regulates thrombopoiesis through activation of TPO receptors on the megakaryocyte cell surface, resulting in increased platelet production. The TPO receptor agonists are novel treatments for patients with chronic ITP aimed at increasing platelet production through interactions with the TPO receptor on megakaryocytes. Two TPO receptor agonists, romiplostim and eltrombopag, have received regulatory approval. In patients with chronic ITP who remain at risk of bleeding follow...

  17. Winning the jackpot and depression: Money cannot buy happiness.

    Science.gov (United States)

    Nisslé, Sonja; Bschor, Tom

    2002-01-01

    Life event research examines the effect of life events on the course of psychiatric diseases, but the published literature considers almost only negative events. We describe the cases of two female patients who had to be hospitalized for depression after lottery winnings of over 1M DM. The 4-year follow-up shows a good outcome in both patients. Case analyses suggest that in both patients, winning was a life event relevant to the development of the depressive episode. Desirable life events might influence the course of a psychiatric illness just as negative events do. (Int J Psych Clin Pract 2002; 6: 183-186). PMID:24945208

  18. PPAR Agonists and Cardiovascular Disease in Diabetes

    Directory of Open Access Journals (Sweden)

    Anna C. Calkin

    2008-01-01

    Full Text Available Peroxisome proliferators activated receptors (PPARs are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

  19. Dihydrocodeine / Agonists for Alcohol Dependents

    Directory of Open Access Journals (Sweden)

    Albrecht eUlmer

    2012-03-01

    Full Text Available Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients.Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC to 102 heavily alcohol addict-ed patients, later, also Buprenorphine, Clomethiazole (>6 weeks, Baclofen and in one case Amphetamine, each on individual indication. This paper focuses on the data with DH, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC-treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-step scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details.Conclusions: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around ¼ of the patients already. Many further

  20. Critical appraisal of the potential use of cannabinoids in cancer management

    International Nuclear Information System (INIS)

    Cannabinoids have been attracting a great deal of interest as potential anticancer agents. Originally derived from the plant Cannabis sativa, there are now a number of endo-, phyto- and synthetic cannabinoids available. This review summarizes the key literature to date around the actions, antitumor activity, and mechanisms of action for this broad range of compounds. Cannabinoids are largely defined by an ability to activate the cannabinoid receptors – CB1 or CB2. The action of the cannabinoids is very dependent on the exact ligand tested, the dose, and the duration of exposure. Some cannabinoids, synthetic or plant-derived, show potential as therapeutic agents, and evidence across a range of cancers and evidence in vitro and in vivo is starting to be accumulated. Studies have now been conducted in a wide range of cell lines, including glioma, breast, prostate, endothelial, liver, and lung. This work is complemented by an increasing body of evidence from in vivo models. However, many of these results remain contradictory, an issue that is not currently able to be resolved through current knowledge of mechanisms of action. While there is a developing understanding of potential mechanisms of action, with the extracellular signal-regulated kinase pathway emerging as a critical signaling juncture in combination with an important role for ceramide and lipid signaling, the relative importance of each pathway is yet to be determined. The interplay between the intracellular pathways of autophagy versus apoptosis is a recent development that is discussed. Overall, there is still a great deal of conflicting evidence around the future utility of the cannabinoids, natural or synthetic, as therapeutic agents

  1. Acute Poisonings from Synthetic Cannabinoids - 50 U.S. Toxicology Investigators Consortium Registry Sites, 2010-2015.

    Science.gov (United States)

    Riederer, Anne M; Campleman, Sharan L; Carlson, Robert G; Boyer, Edward W; Manini, Alex F; Wax, Paul M; Brent, Jeffrey A

    2016-01-01

    Recent reports suggest that acute intoxications by synthetic cannabinoids are increasing in the United States (1,2). Synthetic cannabinoids, which were research compounds in the 1980s, are now produced overseas; the first shipment recognized to contain synthetic cannabinoids was seized at a U.S. border in 2008 (3). Fifteen synthetic cannabinoids are Schedule I controlled substances (3), but enforcement is hampered by the continual introduction of new chemical compounds (1,3). Studies of synthetic cannabinoids indicate higher cannabinoid receptor binding affinities, effects two to 100 times more potent than Δ(9)-tetrahydrocannabinol (the principal psychoactive constituent of cannabis), noncannabinoid receptor binding, and genotoxicity (4,5). Acute synthetic cannabinoid exposure reportedly causes a range of mild to severe neuropsychiatric, cardiovascular, renal, and other effects (4,6,7); chronic use might lead to psychosis (6,8). During 2010-2015, physicians in the Toxicology Investigators Consortium (ToxIC) treated 456 patients for synthetic cannabinoid intoxications; 277 of the 456 patients reported synthetic cannabinoids as the sole toxicologic agent. Among these 277 patients, the most common clinical signs of intoxication were neurologic (agitation, central nervous system depression/coma, and delirium/toxic psychosis). Relative to all cases logged by 50 different sites in the ToxIC Case Registry, there was a statistically significant association between reporting year and the annual proportion of synthetic cannabinoid cases. In 2015, reported cases of synthetic cannabinoid intoxication increased at several ToxIC sites, corroborating reported upward trends in the numbers of such cases (1,2) and underscoring the need for prevention. PMID:27413997

  2. Windows Calorimeter Control (WinCal) program computer software design description

    International Nuclear Information System (INIS)

    The Windows Calorimeter Control (WinCal) Program System Design Description contains a discussion of the design details for the WinCal product. Information in this document will assist a developer in maintaining the WinCal system. The content of this document follows the guidance in WHC-CM-3-10, Software Engineering Standards, Standard for Software User Documentation

  3. Abstinence and Relapse Rates Following a College Campus-Based Quit & Win Contest

    Science.gov (United States)

    Thomas, Janet L.; An, Larry; Luo, Xianghua; Scherber, Robyn M.; Berg, Carla J.; Golden, Dave; Ehlinger, Edward P.; Murphy, Sharon E.; Hecht, Stephen S.; Ahluwalia, Jasjit S.

    2010-01-01

    Objective: To conduct and evaluate Quit & Win contests at 2 2-year college and 2 4-year university campuses. Participants: During Spring semester, 2006, undergraduates (N = 588) interested in quitting smoking signed up for a Quit & Win 30-day cessation contest for a chance to win a lottery prize. Methods: Participants (N = 588) completed a…

  4. Design, Synthesis, Binding and Docking-Based 3D-QSAR Studies of 2-Pyridylbenzimidazoles—A New Family of High Affinity CB1 Cannabinoid Ligands

    Directory of Open Access Journals (Sweden)

    Patricio Iturriaga-Vásquez

    2013-04-01

    Full Text Available A series of novel 2-pyridylbenzimidazole derivatives was rationally designed and synthesized based on our previous studies on benzimidazole 14, a CB1 agonist used as a template for optimization. In the present series, 21 compounds displayed high affinities with Ki values in the nanomolar range. JM-39 (compound 39 was the most active of the series (KiCB1 = 0.53 nM, while compounds 31 and 44 exhibited similar affinities to WIN 55212-2. CoMFA analysis was performed based on the biological data obtained and resulted in a statistically significant CoMFA model with high predictive value (q2 = 0.710, r2 = 0.998, r2pred = 0.823.

  5. Researcher for Virginia Tech program wins Nobel Prize

    OpenAIRE

    Virginia Tech News

    2009-01-01

    The first woman to win a Nobel Prize in economics is a researcher for a Virginia Tech-managed international program. Elinor Ostrom has won a share of the 2009 prize based on her work on how community institutions can prevent conflict.

  6. Nobel Prize-winning economist to speak on Oct. 3

    OpenAIRE

    Doss, Catherine

    2009-01-01

    Nobel Prize winning economist Eric Maskin, professor of social science at the Institute for Advanced Study, Princeton, will present "Mechanism Design: How to Implement Social Goals," on Saturday, Oct. 3 at 2 p.m. in Pamplin Hall Room 1045 on the Virginia Tech campus.

  7. Tight Focus on Instruction Wins Texas District Prize

    Science.gov (United States)

    Maxwell, Lesli A.

    2009-01-01

    It took a while for four-time finalist Aldine, Texas, to win the Broad Prize for Urban Education. But it took even longer to craft the system that ultimately put the district over the top. Educators in Aldine district have been working for more than a decade to refine their "managed instruction" system. Reviewers examined how the school district,…

  8. Winning Facebook - and the Rest of the World?

    DEFF Research Database (Denmark)

    Hoff, Jens Villiam; Hansen, Kasper Møller; Schwartz, Sander Andreas;

    2014-01-01

    This article presents a study of nine leading candidates’ communication on Facebook during the parliament election campaign in Denmark in fall 2011. It relates their communication to the historical use of social media in Denmark by politicians, to Danish candidate campaign communication in general...... conclude that certain types of content may win Facebook, but the election itself is still largely won through TV....

  9. A SAS Interface for Bayesian Analysis with WinBUGS

    Science.gov (United States)

    Zhang, Zhiyong; McArdle, John J.; Wang, Lijuan; Hamagami, Fumiaki

    2008-01-01

    Bayesian methods are becoming very popular despite some practical difficulties in implementation. To assist in the practical application of Bayesian methods, we show how to implement Bayesian analysis with WinBUGS as part of a standard set of SAS routines. This implementation procedure is first illustrated by fitting a multiple regression model…

  10. Method for the unmanned winning of thin, flat coal strata

    Energy Technology Data Exchange (ETDEWEB)

    Levkovich, P.Ye.; Bratishcheva, L.L.; Kiselev, Ye.I.; Savich, N.S.; Tverezyy, Yu.F.

    1981-09-05

    The purpose of the invention is to reduce the coal losses in interchamber pillars through their partial liquidation. The formulated purpose is achieved through the fact that the back fill of the rock into the chamber is accomplished by using one branch of drives and the winning of the coal from the interchamber pillars is done simultaneously using the second branch of the drives.

  11. Economic Education Experiences of Award Winning Alaska Teachers.

    Science.gov (United States)

    Thomas, Monica, Ed.

    Award-winning economic education projects devised by Alaska teachers included three elementary (K-6) projects and three second level (7-12) ones. Faith Greenough's students (Chinook Elementary School, Anchorage) compared Tlingit traditional and market economies in Alaska, so economics became an integrated part of elementary instruction. Marie…

  12. The Probability of Winning a Lotto Jackpot Twice.

    Science.gov (United States)

    Noone, Emeric T., Jr.

    2000-01-01

    Proposes lotto games as a source of problems and exercises for classroom activities as well as applications of basic probability concepts in a practical setting which leads to a greater understanding of the remote chance anyone has of winning a lottery game. (KHR)

  13. Blackboard Wins Payment from Competitor in Patent Case

    Science.gov (United States)

    Mangan, Katherine

    2008-01-01

    A federal jury in Texas awarded Blackboard Inc. $3.1-million last month, saying that a smaller Canadian competitor, Desire2Learn Inc., had infringed Blackboard's patent for a system of delivering course materials online. The case has been closely watched by campus-technology officials, many of whom feared that a Blackboard win could stifle…

  14. Interior design students win two IDEC Student Design Competition awards

    OpenAIRE

    Watson-Bloch, Cathy

    2005-01-01

    Interior Design students in the School of Architecture + Design at Virginia Tech won two of the four awards presented in the 2004-2005 Interior Design Educators Council (IDEC) Student Design Competition. Winners were selected at the International IDEC Conference in Savannah, Ga. with Virginia Tech Interior Design students winning second place and honorable mention.

  15. The Sport League's Dilemma : Competitive Balance versus Incentives to Win

    NARCIS (Netherlands)

    Palomino, F.A.; Rigotti, L.

    2000-01-01

    We analyze a dynamic model of strategic interaction between a professional sport league that organizes a tournament, the teams competing to win it, and the broadcasters paying for the rights to televise it.Teams and broadcasters maximize expected profits, while the league's objective may be either t

  16. Use of synthetic cannabinoids in patients with psychotic disorders: case series.

    Science.gov (United States)

    Celofiga, Andreja; Koprivsek, Jure; Klavz, Janez

    2014-01-01

    An increasing number of synthetic cannabinoids have become available on the black market in recent years, and health professionals have seen a corresponding increase in use of these compounds among patients with psychiatric disorders. Unfortunately, there is almost no research available in the literature on this topic, and what little exists is based on case reports of individuals without psychiatric disorders. Synthetic cannabinoids are functionally similar to, but structurally different from, delta-9-tetrahydrocannabinol, the active principle in cannabis, and are problematic for many reasons. The psychotropic action of synthetic cannabinoids in patients with schizophrenia is unpredictable, with very diverse clinical presentations. These drugs can be much more potent than delta-9-tetrahydrocannabinol, they are readily available and difficult to detect. The gold standard for identification of synthetic cannabinoids is gas chromatography with mass spectrometry, but even this is difficult because new formulations of these designer drugs are constantly emerging. In this manuscript, we provide an overview and discussion of synthetic cannabinoids and present four cases of patients with synthetic cannabinoid intoxication who were hospitalized in our intensive psychiatric unit at the time of intoxication. All patients had a history of schizophrenia and had been hospitalized several times previously. While hospitalized, they smoked an unknown substance brought in by a visitor, which was then confirmed using gas chromatography with mass spectrometry to be the synthetic cannabinoid AM-2201. Our patients experienced predominantly psychiatric adverse clinical effects. We observed the appearance of new psychotic phenomena, without exacerbation of their previously known psychotic symptoms, as well as the occurrence or marked worsening of mood and anxiety symptoms. Despite several similar reactions, and even though they ingested the same exact substance, the clinical picture

  17. Cannabinoid-Elicited Conditioned Place Preference in a Modified Behavioral Paradigm.

    Science.gov (United States)

    Liu, Tao; Zheng, Qiaohua; Qian, Zhaoqiang; Wang, Haoquan; Liu, Zhiqiang; Ren, Wei; Zhang, Xia; Han, Jing

    2016-05-01

    Cannabinoids are the active ingredients in marijuana, which is among the most widely used addictive drugs despite the well-documented harmfulness related to its abuse. The mechanism underlying cannabinoid addiction remains unclear, which is attributed partially to the difficulty in behavioral testing of high-dose cannabinoids using the conditioned place preference (CPP) model. Here, we optimized conditions for establishing CPP with the synthetic cannabinoid HU210 intraperitoneally administered at a high dose. We found that the natural place preference of rats could be exploited for establishing a biased CPP model, and that the adverse effect of HU210 could be ameliorated by adding four daily pre-injections before the conditioning program. Thus, 0.1 mg/kg HU210 induced CPP when pre-injections were administered before traditional conditioning with HU210 administration paired with the non-preferred compartment. The present study provides a useful CPP model for behavioral measurement of the rewarding effects of cannabinoids. PMID:26935020

  18. Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats.

    Science.gov (United States)

    Zhang, Hai-Ying; Bi, Guo-Hua; Li, Xia; Li, Jie; Qu, Hong; Zhang, Shi-Jian; Li, Chuan-Yun; Onaivi, Emmanuel S; Gardner, Eliot L; Xi, Zheng-Xiong; Liu, Qing-Rong

    2015-03-01

    The discovery of functional cannabinoid receptors 2 (CB2Rs) in brain suggests a potential new therapeutic target for neurological and psychiatric disorders. However, recent findings in experimental animals appear controversial. Here we report that there are significant species differences in CB2R mRNA splicing and expression, protein sequences, and receptor responses to CB2R ligands in mice and rats. Systemic administration of JWH133, a highly selective CB2R agonist, significantly and dose-dependently inhibited intravenous cocaine self-administration under a fixed ratio (FR) schedule of reinforcement in mice, but not in rats. However, under a progressive ratio (PR) schedule of reinforcement, JWH133 significantly increased breakpoint for cocaine self-administration in rats, but decreased it in mice. To explore the possible reasons for these conflicting findings, we examined CB2R gene expression and receptor structure in the brain. We found novel rat-specific CB2C and CB2D mRNA isoforms in addition to CB2A and CB2B mRNA isoforms. In situ hybridization RNAscope assays found higher levels of CB2R mRNA in different brain regions and cell types in mice than in rats. By comparing CB2R-encoding regions, we observed a premature stop codon in the mouse CB2R gene that truncated 13 amino-acid residues including a functional autophosphorylation site in the intracellular C-terminus. These findings suggest that species differences in the splicing and expression of CB2R genes and receptor structures may in part explain the different effects of CB2R-selective ligands on cocaine self-administration in mice and rats. PMID:25374096

  19. Chronologically overlapping occurrences of nicotine-induced anxiety- and depression-related behavioral symptoms: effects of anxiolytic and cannabinoid drugs

    Directory of Open Access Journals (Sweden)

    Hayase Tamaki

    2007-09-01

    Full Text Available Abstract Background Anxiety and depression are among the most frequently-observed psychiatric symptoms associated with nicotine (NC. In addition to the similarity to other addictive drugs, these NC-induced symptoms are characteristic in that the opposite behavioral effects, i.e. anxiolytic and antidepressant effects, which may reinforce the habitual use of NC, have also been reported. In the present study, the time course of anxiety- and depression-related behavioral alterations was examined in mice. Furthermore, based on the reported similarity in the mechanisms responsible for NC-induced anxiety- and depression-related symptoms, as well as the contribution of brain cannabinoid (CB receptors to these behavioral symptoms, the effects of anxiolytics and CB receptor ligands (CBs against these behavioral symptoms were investigated. Results Repeated subcutaneous NC treatments (0.3 mg/kg, 4 days, compared with a single treatment (0.5 mg/kg, caused both prolonged anxiogenic effects in the elevated plus-maze test, and prolonged depressive effects in the forced swimming test, even at 120 min time point after the last NC treatment. A transient anxiolytic preference for open arms was also observed in the elevated plus-maze test. Among the anxiolytics and CBs, the serotonin 1A (5-HT1A antagonist WAY 100135 and the endogenous mixed CB agonist/antagonist virodhamine (VD, when administered intraperitoneally before each NC treatment, provided the strongest antagonistic effects against the anxiety-related symptoms. However, against the depression-related symptoms, only VD provided significant antagonistic effects in both single and repeated treatment groups. Conclusion The present results support the presence of a chronological overlap of NC-induced anxiety- and depression-related behavioral symptoms, and the contribution of brain CB receptors to these behavioral symptoms. The repeated NC-induced prolongation of these behavioral symptoms and the early transient

  20. HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid.

    Science.gov (United States)

    Haj, Christeene G; Sumariwalla, Percy F; Hanuš, Lumír; Kogan, Natalya M; Yektin, Zhana; Mechoulam, Raphael; Feldmann, Mark; Gallily, Ruth

    2015-10-01

    Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas. In contrast to Δ(9)-tetrahydrocannabinol (Δ(9)-THC), it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of tumor necrosis factor (TNF)-α, a proinflammatory cytokine, and was found to be an oral antiarthritic therapeutic in murine collagen-induced arthritis in vivo. However, in acidic media, it can cyclize to the psychoactive Δ(9)-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ(9)-THC-like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-α production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ(9)-THC-like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases. PMID:26272937

  1. Plant-Derived and Endogenous Cannabinoids in Epilepsy.

    Science.gov (United States)

    Verrotti, Alberto; Castagnino, Miriam; Maccarrone, Mauro; Fezza, Filomena

    2016-05-01

    Cannabis is one of the oldest psychotropic drugs and its anticonvulsant properties have been known since the last century. The aim of this reveiw was to analyze the efficacy of cannabis in the treatment of epilepsy in adults and children. In addition, a description of the involvement of the endocannabinoid system in epilepsy is given in order to provide a biochemical background to the effects of endogenous cannabinoids in our body. General tolerability and adverse events associated with cannabis treatment are also investigated. Several anecdotal reports and clinical trials suggest that in the human population cannabis has anticonvulsant properties and could be effective in treating partial epilepsies and generalized tonic-clonic seizures, still known as "grand mal." They are based, among other factors, on the observation that in individuals who smoke marijuana to treat epilepsy, cessation of cannabis use precipitates the re-emergence of convulsive seizures, whereas resuming consumption of this psychotropic drug controls epilepsy in a reproducible manner. In conclusion, there is some anecdotal evidence for the potential efficacy of cannabis in treating epilepsy. Though there has been an increased effort by patients with epilepsy, their caregivers, growers, and legislators to legalize various forms of cannabis, there is still concern about its efficacy, relative potency, availability of medication-grade preparations, dosing, and potential short- and long-term side effects, including those on prenatal and childhood development. PMID:26892745

  2. Fatal intoxication with synthetic cannabinoid MDMB-CHMICA.

    Science.gov (United States)

    Adamowicz, Piotr

    2016-04-01

    MDMB-CHMICA is a synthetic cannabinoid that appeared on the European drug market in September 2014. This substance was found in Poland in the herbal mixture "Mocarz" ("Strongman"), which caused a large outbreak of intoxications at the beginning of July 2015. This paper describes the circumstances of death and toxicological findings in a fatal intoxication with MDMB-CHMICA (in combination with alcohol). Loss of consciousness and asystole occurred a few minutes after smoking the 'legal high'. The man died after 4 days of hospitalisation. The cause of death accepted by the medical examiner was multiple organ failure. MDMB-CHMICA was detected and quantified in blood (ante- and postmortem) and internal organs tissues. The samples were analysed using liquid chromatography with mass spectrometry (LC-MS/MS). The concentration of MDMB-CHMICA in antemortem blood was 5.6ng/mL. Although the death occurred after 4 days from administration a relatively high concentration (2.6ng/g) was estimated in the brain. Traces of this compound were also found in other postmortem materials (blood, stomach, liver, bile, and kidney). The presented case shows the health risks associated with MDMB-CHMICA use. The administration of this substance can lead to the number of organ failures, cardiac arrest and consequently death. PMID:26934903

  3. Cannabinoid hyperemesis syndrome masquerading as an eating disorder.

    Science.gov (United States)

    Brewerton, Timothy D; Anderson, Odette

    2016-08-01

    The case of a 22 year old woman with cannabinoid hyperemesis syndrome (CHS) presenting as an eating disorder is described. The importance of recognizing chronic cannabis use as a cause of episodic vomiting is emphasized, given that CHS can be confused with self-induced purging and cyclic vomiting. This case was further complicated by the well-defined history of anorexia nervosa (binge-purge type), major depressive disorder, obsessive-compulsive disorder, migraine headache, and the initial denial of cannabis use. However, collateral history and a positive drug screen confirmed the diagnosis. The signs, symptoms and pathophysiological mechanisms of CHS are reviewed in light of clinical presentations that mimic eating disorder phenomenology complicated by addiction. Given the trend for increasing legalization of recreational marijuana as well as medical marijuana, CHS is an important and potentially complicating disorder that eating disorder clinicians need to be aware of. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:826-829). PMID:26842268

  4. High Alert For Cannabinoid Hyperemesis Syndrome: A Case Report

    Directory of Open Access Journals (Sweden)

    Madhur Rathi

    2015-10-01

    Full Text Available Background: A 32-year-old Caucasian man presented with intractable nausea, psychogenic vomiting, abdominal pain and compulsive hot-water bathing behaviors following the habitual use of cannabis for years, consistent with the uncommon and frequently overlooked diagnosis of Cannabinoid Hyperemesis Syndrome. This was his third admission to the emergency department with the same complaints and symptoms which had persisted for over two years without a recognizable etiology. All imaging studies done on each visit were unremarkable. Results: The patient was clinically symptomatic with the aforementioned presenting complaints, but disappeared upon discontinuation of the cannabis. Within two days of supportive treatment in addition to temporary relief of symptoms with bathing. To date, no effective cure has been sought for this unique diagnosis other than abstaining from cannabis use. Conclusion: A complete recovery was made three days following admission. The presenting symptoms were attributed to the smoking behaviors. The patient was followed up by his primary care physician once released from the hospital. A very rare diagnosis surfaced a number of times with the same patient in the same setting over the span of a couple years, but was overlooked due to its rarity. Hence, physicians should list it higher on their differentials when dealing with a patient with a history of drug abuse.

  5. Estrogenic effects of marijuana smoke condensate and cannabinoid compounds

    International Nuclear Information System (INIS)

    Chronic exposure to marijuana produces adverse effects on the endocrine and reproductive systems in humans; however, the experimental evidence for this presented thus far has not been without controversy. In this study, the estrogenic effect of marijuana smoke condensate (MSC) was evaluated using in vitro bioassays, viz., the cell proliferation assay, the reporter gene assay, and the ER competitive binding assay. The results of these assays were compared with those of three major cannabinoids, i.e., THC, CBD, and CBN. The estrogenic effect of MSC was further confirmed by the immature female rat uterotrophic assay. MSC stimulated the estrogenicity related to the ER-mediated pathway, while neither THC, CBD, nor CBN did. Moreover, treatment with 10 and 25 mg/kg MSC induced significant uterine response, and 10 mg/kg MSC resulted in an obvious change in the uterine epithelial cell appearance. MSC also enhanced the IGFBP-1 gene expression in a dose-dependent manner. To identify the constituents of MSC responsible for its estrogenicity, the MSC fractionated samples were examined using another cell proliferation assay, and the estrogenic active fraction was analyzed using GC-MS. In the organic acid fraction that showed the strongest estrogenic activity among the seven fractions of MSC, phenols were identified. Our results suggest that marijuana abuse is considered an endocrine-disrupting factor. Furthermore, these results suggest that the phenolic compounds contained in MSC play a role in its estrogenic effect

  6. Minor oxygenated cannabinoids from high potency Cannabis sativa L.

    Science.gov (United States)

    Ahmed, Safwat A; Ross, Samir A; Slade, Desmond; Radwan, Mohamed M; Khan, Ikhlas A; ElSohly, Mahmoud A

    2015-09-01

    Nine oxygenated cannabinoids were isolated from a high potency Cannabis sativa L. variety. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR, HRMS and GC-MS. These minor compounds include four hexahydrocannabinols, four tetrahydrocannabinols, and one hydroxylated cannabinol, namely 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexa-hydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol, Δ(9)-THC aldehyde A, 8-oxo-Δ(9)-THC, 10aα-hydroxy-10-oxo-Δ(8)-THC, 9α-hydroxy-10-oxo-Δ(6a,10a)-THC, and 1'S-hydroxycannabinol, respectively. The latter compound showed moderate anti-MRSa (IC50 10.0 μg/mL), moderate antileishmanial (IC50 14.0 μg/mL) and mild antimalarial activity against Plasmodium falciparum (D6 clone) and P. falciparum (W2 clone) with IC50 values of 3.4 and 2.3 μg/mL, respectively. PMID:26093324

  7. Alcohol and cannabinoids differentially affect HIV infection and function of human monocyte-derived dendritic cells (MDDC

    Directory of Open Access Journals (Sweden)

    Marisela eAgudelo

    2015-12-01

    Full Text Available During human immunodeficiency virus (HIV infection, alcohol has been known to induce inflammation while cannabinoids have been shown to have an anti-inflammatory role. For instance cannabinoids have been shown to reduce susceptibility to HIV-1 infection and attenuate HIV replication in macrophages. Recently, we demonstrated that alcohol induces cannabinoid receptors and regulates cytokine production by monocyte-derived dendritic cells (MDDC. However, the ability of alcohol and cannabinoids to alter MDDC function during HIV infection has not been clearly elucidated yet. In order to study the potential impact of alcohol and cannabinoids on differentiated MDDC infected with HIV, monocytes were cultured for 7 days with GM-CSF and IL-4, differentiated MDDC were infected with HIV-1Ba-L and treated with EtOH (0.1 and 0.2%, THC (5 and 10 uM, or JWH-015 (5 and 10 uM for 4-7 days. HIV infection of MDDC was confirmed by p24 and Long Terminal Repeats (LTR estimation. MDDC endocytosis assay and cytokine array profiles were measured to investigate the effects of HIV and substances of abuse on MDDC function. Our results show the HIV+EtOH treated MDDC had the highest levels of p24 production and expression when compared with the HIV positive controls and the cannabinoid treated cells. Although both cannabinoids, THC and JWH-015 had lower levels of p24 production and expression, the HIV+JWH-015 treated MDDC had the lowest levels of p24 when compared to the HIV+THC treated cells. In addition, MDDC endocytic function and cytokine production were also differentially altered after alcohol and cannabinoid treatments. Our results show a differential effect of alcohol and cannabinoids, which may provide insights into the divergent inflammatory role of alcohol and cannabinoids to modulate MDDC function in the context of HIV infection.

  8. 2012 Division of medicinal chemistry award address. Trekking the cannabinoid road: a personal perspective.

    Science.gov (United States)

    Makriyannis, Alexandros

    2014-05-22

    My involvement with the field of cannabinoids spans close to 3 decades and covers a major part of my scientific career. It also reflects the robust progress in this initially largely unexplored area of biology. During this period of time, I have witnessed the growth of modern cannabinoid biology, starting from the discovery of its two receptors and followed by the characterization of its endogenous ligands and the identification of the enzyme systems involved in their biosynthesis and biotransformation. I was fortunate enough to start at the beginning of this new era and participate in a number of the new discoveries. It has been a very exciting journey. With coverage of some key aspects of my work during this period of "modern cannabinoid research," this Award Address, in part historical, intends to give an account of how the field grew, the key discoveries, and the most promising directions for the future. PMID:24707904

  9. A runner’s high depends on cannabinoid receptors in mice

    Science.gov (United States)

    Fuss, Johannes; Steinle, Jörg; Bindila, Laura; Auer, Matthias K.; Kirchherr, Hartmut; Lutz, Beat; Gass, Peter

    2015-01-01

    Exercise is rewarding, and long-distance runners have described a runner’s high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both β-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner's high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models. PMID:26438875

  10. Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity.

    Science.gov (United States)

    Leussink, Verena Isabell; Husseini, Leila; Warnke, Clemens; Broussalis, Erasmia; Hartung, Hans-Peter; Kieseier, Bernd C

    2012-09-01

    A large proportion of patients with multiple sclerosis (MS) have spasticity, which has a marked impact on their quality of life. Anecdotal evidence suggests a beneficial effect of cannabis on spasticity as well as pain. Recently, randomized, double-blind, placebo-controlled studies have confirmed the clinical efficacy of cannabinoids for the treatment of spasticity in patients with MS. Based on these data, nabiximols (Sativex), a 1:1 mix of Δ-9-tetrahydrocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, received approval for treating MS-related spasticity in various countries around the globe. In this article we review the current understanding of cannabinoid biology and the value of cannabinoids as a symptomatic treatment option addressing spasticity in patients with MS. PMID:22973422

  11. beta2-Agonists at the Olympic Games.

    Science.gov (United States)

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  12. The Effects of Synthetic Cannabinoids on Alveolar-Arterial Oxygen Gradient

    Directory of Open Access Journals (Sweden)

    Egemen Kucuk

    2014-12-01

    Full Text Available Aim: Synthetic cannabinoids are chemicals that produce several marijuana-like effects in humans. Aim of this study is to investigate the effects of synthetic cannabinoids on to alveolar-arterial oxygen gradient. Material and Method: A total of 112 patients, who admitted directly to emergency clinic with synthetic cannabinoid usage, were determined between February 2014 and August 2014. Blood gases of 41 patients were determined as arterial blood gases on room air, and included in to study. Patients were evaluated according to age, sex, decade, partial pressure of arterial oxygen, partial pressure of arterial carbon dioxide, pH, bicarbonate, metabolic status, age consistent expected alveolar-arterial oxygen gradient and calculated alveolar-arterial oxygen gradient. Results: Synthetic cannabinoid using was higher in males, mean age of patients was 23.32±6.14 years. Number of patients in the third decade were significantly higher than the other decades. The calculated alveolar-arterial oxygen gradient value of patients was significantly higher than age consistent expected alveolar-arterial oxygen gradient value. Respiratory acidosis, was significantly higher than the other types of the metabolic disorders. The best cutoff point for calculated alveolar-arterial oxygen gradient was 12.70, with sensitivity of 90% and specifity of 85%. Area under curve was 0.70 for calculated alveolar-arterial oxygen gradient. Discussion: The value of alveolar-arterial oxygen gradient has been increased due to synthetic cannabinoid usage. This can be used as a supportive parameter in the diagnosis of synthetic cannabinoid usage.

  13. The Role of Cannabinoid Transmission in Emotional Memory Formation: Implications for Addiction and Schizophrenia

    Directory of Open Access Journals (Sweden)

    Huibing eTan

    2014-06-01

    Full Text Available Emerging evidence from both basic and clinical research demonstrates an important role for endocannabinoid (ECB signaling in the processing of emotionally salient information, learning and memory. Cannabinoid transmission within neural circuits involved in emotional processing has been shown to modulate the acquisition, recall and extinction of emotionally salient memories and importantly, can strongly modulate the emotional salience of incoming sensory information. Two neural regions in particular, the medial prefrontal cortex (PFC and the basolateral nucleus of the amygdala (BLA, play important roles in emotional regulation and contain high levels of cannabinoid receptors. Furthermore, both regions show profound abnormalities in neuropsychiatric disorders such as addiction and schizophrenia. Considerable evidence has demonstrated that cannabinoid transmission functionally interacts with dopamine (DA, a neurotransmitter system that is of exceptional importance for both addictive behaviours and the neuropsychopathology of disorders like schizophrenia. Research in our laboratory has focused on how cannabinoid transmission both within and extrinsic to the mesolimbic DA system, including the BLAmPFC circuitry, can modulate both rewarding and aversive emotional information. In this review, we will summarize clinical and basic neuroscience research demonstrating the importance of cannabinoid signaling within this neural circuitry. In particular, evidence will be reviewed emphasizing the importance of cannabinoid signaling within the BLAmPFC circuitry in the context of emotional salience processing, memory formation and memory-related plasticity. We propose that aberrant states of hyper or hypoactive ECB signaling within the amygdala-prefrontal cortical circuit may lead to dysregulation of mesocorticolimbic DA transmission controlling the processing of emotionally salient information. These disturbances may in turn lead to emotional processing

  14. Synaptic neurotransmission depression in ventral tegmental dopamine neurons and cannabinoid-associated addictive learning.

    Directory of Open Access Journals (Sweden)

    Zhiqiang Liu

    Full Text Available Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP and long-term depression (LTD. Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses of the midbrain ventral tegmental area (VTA following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses. It is unknown whether chronic exposure of cannabis (marijuana or cannabinoids, the most commonly used illicit drug worldwide, induce LTP or LTD at these synapses. More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed. Here we show in rats that chronic cannabinoid exposure activates VTA cannabinoid CB1 receptors to induce transient neurotransmission depression at VTA local Glu-DA synapses through activation of NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits. A GluR2-derived peptide blocks cannabinoid-induced VTA synaptic depression and conditioned place preference, i.e., learning to associate drug exposure with environmental cues. These data not only provide the first evidence, to our knowledge, that NMDA receptor-dependent synaptic depression at VTA dopamine circuitry requires GluR2 endocytosis, but also suggest an essential contribution of such synaptic depression to cannabinoid-associated addictive learning, in addition to pointing to novel pharmacological strategies for the treatment of cannabis addiction.

  15. [Progress in study on endocannabinoids and cannabinoid receptors in the treatment for neuropathic pain].

    Science.gov (United States)

    Liu, Peng; Zhang, Wei; Zhang, Shaobo; Zhang, Yibao; Wang, Jing

    2016-08-01

    Endocannabinoids and cannabinoid receptors are expressed in various central pain modulation regions. They maintain in dynamic changes in the expression level and distribution under different pathological and physiological conditions. These changes possess advantage as well as disadvantage. Exogenous administration of endocannabinoids exerts analgesic effect in different pain models, which is mainly mediated by the cannabinoid CB1 and CB2 receptors. Inhibition of enzymes for degrading endocannabinoids in different pain models also shows analgesic effect due to the increased local levels of endocannabinoids. PMID:27600019

  16. Mecanismos de la acción neuroprotectora de los cannabinoides en la enfermedad de Alzheimer

    OpenAIRE

    Martín Moreno, Ana María

    2010-01-01

    El papel neuroprotector de los cannabinoides in vivo e in vitro es conocido, pero el mecanismo a través del cual llevan a cabo su acción neuroprotectora, en el contexto de la enfermedad de Alzheimer, no había sido abordado en su conjunto. Los objetivos del presente trabajo son 5: 1. Estudiar el efecto de distintos agonistas cannabinoides, en particular aquellos carentes de efectos psicoactivos, sobre funciones microgliales tales como la generación de nitritos o la migración, que puedan se...

  17. Cannabinoid hyperemesissyndrom som årsag til langvarig kvalme og opkastning hos cannabismisbrugere

    DEFF Research Database (Denmark)

    Vindsand Naver, Astrid; Theede, Klaus

    2015-01-01

    cannabinoid hyperemesis syndrome. Characteristically, the symptoms appear in a cyclical pattern and are relieved by long, hot baths. Physical examination, radiology and endoscopy are often normal. The symptoms resolve with cessation of cannabis abuse. Health professionals must be aware of this syndrome in......Cannabinoid hyperemesis syndrome causing prolonged nausea and vomiting in patients with cannabis abuse Cannabis is one of the most used drugs worldwide. The link between repeated episodes of nausea, vomiting, and cannabis abuse is often missed in patients with prolonged cannabis abuse and is named...

  18. WINNING HEARTS AND MINDS IN THE NAMIBIAN BORDER WAR

    Directory of Open Access Journals (Sweden)

    Lieneke Eloff de Visser

    2011-08-01

    Full Text Available During the Namibian border war, South African counterinsurgency doctrine acknowledged the importance of securing the allegiance and cooperation of the population. This article demonstrates that, in the operational zone, the responsibility of winning the hearts and minds of the Namibian people largely fell to the SADF (South African Defence Force. Although the SADF dedicated considerable resources to this task, these efforts were often at cross-purposes with those of institutions in the political, police and administrative domains. In addition, there was a lack of unity and purpose within the SADF. This article argues that lack of unity between and within the different domains undermined the effort at winning the hearts and minds of the Namibian population, and must at least partly have contributed to SWAPO´s victory in the 1989 elections.

  19. Identification of Selective ERRγ Inverse Agonists

    Directory of Open Access Journals (Sweden)

    Jina Kim

    2016-01-01

    Full Text Available GSK5182 (4 is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively. Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

  20. Reciprocity of agonistic support in ravens.

    Science.gov (United States)

    Fraser, Orlaith N; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  1. FXR agonist activity of conformationally constrained analogs of GW 4064

    Energy Technology Data Exchange (ETDEWEB)

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce; (GSKNC)

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  2. Preclinical evaluation and quantification of [18F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain

    International Nuclear Information System (INIS)

    [18F]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [18F]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain. Dynamic small-animal PET scans with [18F]MK-9470 were performed in Wistar rats on a FOCUS-220 system for up to 10 h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Displacement and blocking experiments were done using cold MK-9470 and another inverse agonist, SR141716A. The distribution volume (VT) of [18F]MK-9470 was used as a quantitative measure and compared to the use of brain uptake, expressed as SUV, a simplified method of quantification. The percentage of intact [18F]MK-9470 in arterial plasma samples was 80 ± 23 % at 10 min, 38 ± 30 % at 40 min and 13 ± 14 % at 210 min. A polar radiometabolite fraction was detected in plasma and brain tissue. The brain radiometabolite concentration was uniform across the whole brain. Displacement and pretreatment studies showed that 56 % of the tracer binding was specific and reversible. VT values obtained with a one-tissue compartment model plus constrained radiometabolite input had good identifiability (≤10 %). Ignoring the radiometabolite contribution using a one-tissue compartment model alone, i.e. without constrained radiometabolite input, overestimated the [18F]MK-9470 VT, but was correlated. A correlation between [18F]MK-9470 VT and SUV in the brain was also found (R 2 = 0.26-0.33; p ≤ 0.03). While the presence of a brain-penetrating radiometabolite fraction complicates the quantification of [18F]MK-9470 in the rat brain, its tracer kinetics can be modelled using a one-tissue compartment model with and without constrained radiometabolite input. (orig.)

  3. Antidepressant-like effects of the cannabinoid receptor ligands in the forced swimming test in mice: mechanism of action and possible interactions with cholinergic system.

    Science.gov (United States)

    Kruk-Slomka, Marta; Michalak, Agnieszka; Biala, Grazyna

    2015-05-01

    The purpose of the experiments was to explore the role of the endocannabinoid system, through cannabinoid (CB) receptor ligands, nicotine and scopolamine, in the depression-related responses using the forced swimming test (FST) in mice. Our results revealed that acute injection of oleamide (10 and 20 mg/kg), a CB1 receptor agonist, caused antidepressant-like effect in the FST, while AM 251 (0.25-3 mg/kg), a CB1 receptor antagonist, did not provoke any effect in this test. Moreover, acute administration of both CB2 receptor agonist, JWH 133 (0.5 and 1 mg/kg) and CB2 receptor antagonist, AM 630 (0.5 mg/kg), exhibited antidepressant action. Antidepressant effects of oleamide and JWH 133 were attenuated by acute injection of both non-effective dose of AM 251, as well as AM 630. Among the all CB compounds used, only the combination of non-effective dose of oleamide (2.5 mg/kg) with non-effective dose of nicotine (0.5 mg/kg) caused an antidepressant effect. However, none of the CB receptor ligands, had influence on the antidepressant effects provoked by nicotine (0.2 mg/kg) injection. In turn, the combination of non-effective dose of oleamide (2.5 mg/kg); JWH (2 mg/kg) or AM 630 (2 mg/kg), but not of AM 251 (0.25 mg/kg), with non-effective dose of scopolamine (0.1 mg/kg), exhibited antidepressant properties. Indeed, all of the CB compounds used, intensified the antidepressant-like effects induced by an acute injection of scopolamine (0.3 mg/kg). Our results provide clear evidence that the endocannabinoid system participates in the depression-related behavior and through interactions with cholinergic system modulate these kind of responses. PMID:25660201

  4. Increased brain metabolism after acute administration of the synthetic cannabinoid HU210: a small animal PET imaging study with 18F-FDG.

    Science.gov (United States)

    Nguyen, Vu H; Verdurand, Mathieu; Dedeurwaerdere, Stefanie; Wang, Hongqin; Zahra, David; Gregoire, Marie-Claude; Zavitsanou, Katerina

    2012-02-10

    Cannabis use has been shown to alter brain metabolism in both rat models and humans although the observations between both species are conflicting. In the present study, we examined the short term effects of a single-dose injection of the synthetic cannabinoid agonist HU210 on glucose metabolism in the rat brain using small animal (18)F-2-fluoro-deoxyglucose (FDG) Positron Emission Tomography (PET) 15 min (Day 1) and 24h (Day 2) post-injection of the agonist in the same animal. Young adult male Wistar rats received an intra-peritoneal injection of HU210 (100 μg/kg, n=7) or vehicle (n=5) on Day 1. Approximately 1mCi of (18)F-FDG was injected intravenously into each animal at 15 min (Day 1) and 24h (Day 2) post-injection of HU210. A 5-min Computer Tomography (CT) scan followed by a 20-min PET scan was performed 40 min after each (18)F-FDG injection. Standardised Uptake Values (SUVs) were calculated for 10 brain regions of interest (ROIs). Global increased SUVs in the whole brain, hence global brain metabolism, were observed following HU210 treatment on Day 1 compared to the controls (21%, PHU210 treated group returned to control levels (21-30% decrease compared to Day 1), in all ROIs investigated (PHU210 increases brain glucose metabolism in the rat brain shortly after administration, in line with normalised human in vivo studies, an effect that was no longer apparent 24 h later. PMID:22155282

  5. Goal! Profit maximization and win maximization in football leagues

    OpenAIRE

    Pedro Garcia-del-Barrio; Stefan Szymanski

    2006-01-01

    In this paper we estimate the best responses of football clubs to the choices of other clubs in Spanish and English leagues over the period 1994-2004. We find that choices are more closely approximated by win maximization than by profit maximization in both the short term and the long term. We examine club characteristics that might explain variations in choices between Spanish clubs.

  6. Does it pay to win the Stanley Cup?

    OpenAIRE

    Derek Lanoue

    2015-01-01

    Yes, it does indeed pay to win the Stanley Cup (SC). Professional sports offer a unique opportunity to examine the relationship between a player’s salary and their performance. Salary statistics have become widely available and enable individual performance scrutiny in relation to remuneration level. There is an extensive literature explaining which factors in‡uence the players’ salary in the National Hockey League (NHL), using data sets from different seasons and including various performanc...

  7. Winning end users active support to demand side response

    Energy Technology Data Exchange (ETDEWEB)

    Osorio, Jose [Rede Electrica Nacional, S.A., Lisbon (Portugal); Estanqueiro, Ana [Laboratorio Nacional de Energia e Geologia (LNEG), Lisbon (Portugal)

    2012-07-01

    While objectives proposed for Smart Grids and Smart metering may seem to be able to win easily end user's supports, a considerable amount of studies on social behavior concerning energy efficiency and sustainability show the gap between the values people would like to fulfill and their real life performance. As TSOs envision here a source of System Ancillary Services, measures to make the source really dependable, so that an adequate market design may really work are pointed out. (orig.)

  8. Optimizing Distribution Problems using WinQSB Software

    Directory of Open Access Journals (Sweden)

    Daniel Mihai Amariei

    2015-07-01

    Full Text Available In the present paper we are presenting a problem of distribution using the Network Modeling Module of the WinQSB software, were we have 5 athletes which we must assign the optimal sample, function of the obtained time, so as to obtain the maximum output of the athletes. Also we analyzed the case of an accident of 2 athletes, the coupling of 3 athletes with 5 various athletic events causing the maximum coupling, done using the Hungarian algorithm.

  9. Winning end users active support to demand side response

    OpenAIRE

    Osório, José; Estanqueiro, Ana

    2012-01-01

    While objectives proposed for Smart Grids and Smart metering may seem to be able to win easily end user’s supports, a considerable amount of studies on social behavior concerning energy efficiency and sustainability show the gap between the values people would like to fulfill and their real life performance. As TSOs envision here a source of System Ancillary Services, measures to make the source really dependable, so that an adequate market design may really work are pointed out.

  10. Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development.

    Science.gov (United States)

    Sharma, Charu; Sadek, Bassem; Goyal, Sameer N; Sinha, Satyesh; Kamal, Mohammad Amjad; Ojha, Shreesh

    2015-01-01

    The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ(9)-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics. PMID:26664449

  11. Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

    Directory of Open Access Journals (Sweden)

    Charu Sharma

    2015-01-01

    Full Text Available The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2 which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.

  12. Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

    Science.gov (United States)

    Sharma, Charu; Sadek, Bassem; Goyal, Sameer N.; Sinha, Satyesh; Ojha, Shreesh

    2015-01-01

    The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics. PMID:26664449

  13. [Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis].

    Science.gov (United States)

    Goullé, Jean-Perre; Guerbet, Michel

    2014-03-01

    Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11-OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself. PMID:26427296

  14. Cannabinoid modulation of functional connectivity within regions processing attentional salience.

    Science.gov (United States)

    Bhattacharyya, Sagnik; Falkenberg, Irina; Martin-Santos, Rocio; Atakan, Zerrin; Crippa, Jose A; Giampietro, Vincent; Brammer, Mick; McGuire, Philip

    2015-05-01

    There is now considerable evidence to support the hypothesis that psychotic symptoms are the result of abnormal salience attribution, and that the attribution of salience is largely mediated through the prefrontal cortex, the striatum, and the hippocampus. Although these areas show differential activation under the influence of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), the two major derivatives of cannabis sativa, little is known about the effects of these cannabinoids on the functional connectivity between these regions. We investigated this in healthy occasional cannabis users by employing event-related functional magnetic resonance imaging (fMRI) following oral administration of delta-9-THC, CBD, or a placebo capsule. Employing a seed cluster-based functional connectivity analysis that involved using the average time series from each seed cluster for a whole-brain correlational analysis, we investigated the effect of drug condition on functional connectivity between the seed clusters and the rest of the brain during an oddball salience processing task. Relative to the placebo condition, delta-9-THC and CBD had opposite effects on the functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Delta-9-THC reduced fronto-striatal connectivity, which was related to its effect on task performance, whereas this connection was enhanced by CBD. Conversely, mediotemporal-prefrontal connectivity was enhanced by delta-9-THC and reduced by CBD. Our results suggest that the functional integration of brain regions involved in salience processing is differentially modulated by single doses of delta-9-THC and CBD and that this relates to the processing of salient stimuli. PMID:25249057

  15. Exploring prospects of β3-adrenoceptor agonists and inverse agonists for colon mobility control

    Directory of Open Access Journals (Sweden)

    Maria Grazia Perrone

    2013-07-01

    Full Text Available Inverse agonists are useful active ingredient of drugs clinically used to treat diseases mainly involving receptors endowed with non-endogenous agonist induced activity (constitutive or basal activity. SP-1e and SP-1g are the first two potent and highly selective β3-adrenoceptor inverse agonists [EC50=181 nM (IA=- 64% and 136 nM (IA=-73%, respectively], which their peculiar activity seems due to the absolute configurations of the two stereogenic centres present in each molecule. Rat proximal colon motility measurements allowed their further pharmacological characterization and pA2 values determination by Schild analysis (7.89 and 8.16, respectively. The purpose of our work is a further characterization of our novel β3-adrenoceptor agonists (SP-1a-d, SP-1f,1h and inverse agonists (SP-1e and SP-1g on rat proximal colon motility and a confirmation of their inverse agonist nature in a more complex system like the functional test on rat proximal colon. Male Wistar rats segment of the proximal colon were placed in organ baths containing Krebs solution. Muscle tension was recorded isotonically. Cumulative β3-AR agonists doses experiments were performed for each test compound: isoprenaline, BRL37344, SP-1a-d, SP-1f and SP-1h were dissolved in Krebs. The EC50 values of each agonists and pA2 of inverse agonists were determined. SP- 1a-d, SP-1f and SP-1h in rat colon have a muscle relaxing effect thus confirming their partial agonist activity found in CHO-K1 cell line. SP-1e and SP-1g behaved as antagonists with pA2 values of 7.89 and 8.16, respectively. In conclusion, experiments carried out by using isolated rat proximal colon allowed us to determine the pA2 values of the two β3-AR inverse agonists and add knowledge on the behavior of a novel set of compounds and their possible value as agents useful whenever is necessary to also control the colon motility.

  16. Gonadotropin releasing hormone agonists: Expanding vistas

    Directory of Open Access Journals (Sweden)

    Navneet Magon

    2011-01-01

    Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

  17. Cannabinoid CB1 receptor inhibition blunts adolescent-typical increased binge alcohol and sucrose consumption in male C57BL/6J mice

    Science.gov (United States)

    Agoglia, Abigail E.; Holstein, Sarah E.; Eastman, Vallari R.; Hodge, Clyde W.

    2016-01-01

    Increased binge alcohol consumption has been reported among adolescents as compared to adults in both humans and rodent models, and has been associated with serious long-term health consequences. However, the neurochemical mechanism for age differences in binge drinking between adolescents and adults has not been established. The present study was designed to evaluate the mechanistic role of the cannabinoid CB1 receptor in adolescent and adult binge drinking. Binge consumption was established in adolescent and adult male C57BL/6J mice by providing access to 20% alcohol or 1% sucrose for 4 h every other day. Pretreatment with the CB1 antagonist/inverse agonist AM-251 (0, 1, 3, and 10 mg/kg) in a Latin square design dose-dependently reduced adolescent alcohol consumption to adult levels without altering adult intake. AM-251 (3 mg/kg) also reduced adolescent but not adult sucrose consumption. Adolescent reductions in alcohol and sucrose were not associated with alterations in open-field locomotor activity or thigmotaxis. These findings point to age differences in CB1 receptor activity as a functional mediator of adolescent-typical increased binge drinking as compared to adults. Developmental alterations in endocannabinoid signaling in the adolescent brain may therefore be responsible for the drinking phenotype seen in this age group. PMID:26800788

  18. In vivo labeling of cocaine receptors with 3H-(-) cocaine, 3H-WIN 35,065-2 and 3H-WIN 35,428

    International Nuclear Information System (INIS)

    11C-(-)cocaine (-COC) has recently been employed to image -COC binding sites in vivo using PET. Two analogs of -COC, WIN 35,065-2 (WIN-2) and WIN 35,428 (CFT), have been shown in vitro to exhibit higher affinity for the -COC receptor than -COC. The present study evaluates 3H-WIN-2 and 3H-CFT as in vivo receptor labels in mice with a view towards the use of these compounds as PET ligands for -COC receptors in the living human brain. 3H-labeled -COC, WIN-2 and CFT were injected i.v. into mice and their specific binding in the CNS determined. Peak striatal/cerebellar (S/C) ratios were reached at 5 minutes post injection with -COC (1.56), at 45 minutes with 3H-WIN-2 (3.30) and 60 minutes with 3H-CFT (4.0). The specificity of in vivo binding of 3H-WIN-2 and 3H-CFT was tested by pre-injection of various drugs. Binding of 3H-WIN-2 and 3H-CFT was dose-dependently blocked by cold WIN-2 and CFT, and by dopamine uptake site inhibitors (mazindol, GBR 12,909, nomifensine), but not by (+)COC, paroxetine and desipramine. The data indicate that 3H-WIN-2 and 3H-CFT exhibit improved in vivo binding (higher S/C ratios, longer retention time at the -COC receptor/dopamine transporter) compared to -COC and support their testing in PET studies

  19. A win-win marginal rent analysis for operator and consumer under battery leasing mode in China electric vehicle market

    International Nuclear Information System (INIS)

    Recently battery leasing has been introduced into the market by automobile manufacturers and power suppliers due to its potential to reduce the purchase cost of electric vehicles (EVs). However, the profit prospect of battery leasing is still uncertain. This paper takes the views of both the operators and consumers and calculates the 'win-win' marginal rent, which not only ensures the profitability of operators, but also allows consumers a lower expenditure than using Internal combustion engine vehicles (ICVs) and EVs with embedded batteries. Battery cost, vehicle weight, gasoline and electricity price, and the discount rate have impacts on the rent. Battery cost plays a dominant role and a battery cost >5 Yen /W h fails to enable the survival of battery leasing to all types of EVs. Battery leasing would be more competitive when focusing on heavier EVs. At least one of the three thresholds is required for the existence of rent pricing range for a 1000 kg EV: gasoline retail price >6 Yen /L, electricity price <0.6 Yen /kW h, or the discount rate <7%. Typically, the feasible battery rent range is 0.34-0.38 Yen /W h/year for a 1000 kg EV under the present battery cost 2 Yen /W h and China current gasoline and electricity prices. - Highlights: → Rent pricing for EV battery leasing must obey win-win rule for BLO and consumers. → Rent is affected by battery cost, vehicle weight, energy price and discount rate. → Battery cost plays dominant role for the BLO survival as described in '5-3-2' Law. → Heavier EVs are more suitable for battery leasing when battery cost is high. → The profitability of BLO is sensitive to the price of gasoline and electricity.

  20. CB1 Cannabinoid Receptors Modulate Kinase and Phosphatase Activity during Extinction of Conditioned Fear in Mice

    Science.gov (United States)

    Kamprath, Kornelia; Hermann, Heike; Lutz, Beat; Marsicano, Giovanni; Cannich, Astrid; Wotjak, Carsten T.

    2004-01-01

    Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and…