412 results on '"WIN 55,212-2"'
Search Results
402. Repeated administration of a synthetic cannabinoid receptor agonist differentially affects cortical and accumbal neuronal morphology in adolescent and adult rats.
- Author
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Carvalho AF, Reyes BA, Ramalhosa F, Sousa N, and Van Bockstaele EJ
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- Age Factors, Animals, Behavior, Animal drug effects, Cell Shape drug effects, Conditioning, Psychological drug effects, Dendritic Spines drug effects, Dendritic Spines metabolism, Drug Administration Schedule, Male, Nucleus Accumbens cytology, Nucleus Accumbens metabolism, Prefrontal Cortex cytology, Prefrontal Cortex metabolism, Pyramidal Cells metabolism, Rats, Sprague-Dawley, Receptors, Cannabinoid metabolism, Benzoxazines administration & dosage, Cannabinoid Receptor Agonists administration & dosage, Morpholines administration & dosage, Naphthalenes administration & dosage, Nucleus Accumbens drug effects, Prefrontal Cortex drug effects, Pyramidal Cells drug effects, Receptors, Cannabinoid drug effects
- Abstract
Recent studies demonstrate a differential trajectory for cannabinoid receptor expression in cortical and sub-cortical brain areas across postnatal development. In the present study, we sought to investigate whether chronic systemic exposure to a synthetic cannabinoid receptor agonist causes morphological changes in the structure of dendrites and dendritic spines in adolescent and adult pyramidal neurons in the medial prefrontal cortex (mPFC) and medium spiny neurons (MSN) in the nucleus accumbens (Acb). Following systemic administration of WIN 55,212-2 in adolescent (PN 37-40) and adult (P55-60) male rats, the neuronal architecture of pyramidal neurons and MSN was assessed using Golgi-Cox staining. While no structural changes were observed in WIN 55,212-2-treated adolescent subjects compared to control, exposure to WIN 55,212-2 significantly increased dendritic length, spine density and the number of dendritic branches in pyramidal neurons in the mPFC of adult subjects when compared to control and adolescent subjects. In the Acb, WIN 55,212-2 exposure significantly decreased dendritic length and number of branches in adult rat subjects while no changes were observed in the adolescent groups. In contrast, spine density was significantly decreased in both the adult and adolescent groups in the Acb. To determine whether regional developmental morphological changes translated into behavioral differences, WIN 55,212-2-induced aversion was evaluated in both groups using a conditioned place preference paradigm. In adult rats, WIN 55,212-2 administration readily induced conditioned place aversion as previously described. In contrast, adolescent rats did not exhibit aversion following WIN 55,212-2 exposure in the behavioral paradigm. The present results show that synthetic cannabinoid administration differentially impacts cortical and sub-cortical neuronal morphology in adult compared to adolescent subjects. Such differences may underlie the disparate development effects of cannabinoids on behavior.
- Published
- 2016
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403. Influence of WIN 55,212-2 on the anticonvulsant and acute neurotoxic potential of clobazam and lacosamide in the maximal electroshock-induced seizure model and chimney test in mice.
- Author
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Florek-Luszczki M, Zagaja M, and Luszczki JJ
- Subjects
- Acetamides toxicity, Animals, Anticonvulsants toxicity, Benzodiazepines toxicity, Benzoxazines toxicity, Clobazam, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Synergism, Electroshock, Injections, Intraperitoneal, Lacosamide, Male, Mice, Morpholines toxicity, Naphthalenes toxicity, Random Allocation, Seizures physiopathology, Acetamides pharmacology, Anticonvulsants pharmacology, Benzodiazepines pharmacology, Benzoxazines pharmacology, Morpholines pharmacology, Motor Activity drug effects, Naphthalenes pharmacology, Seizures drug therapy
- Abstract
Unlabelled: The influence of WIN 55,212-2 mesylate (WIN) on the anticonvulsant activity and acute neurotoxic potential of clobazam (CLB) and lacosamide (LCM) was studied in the maximal electroshock-induced seizure (MES) model and chimney test in mice., Results: indicate that WIN administered intraperitoneally, at doses of 2.5 and 5 mg/kg significantly enhanced the anticonvulsant action of CLB in the MES test by reducing its median effective dose (ED50) from 20.80 mg/kg to 12.05 mg/kg (P<0.05), and 8.22 mg/kg (P<0.001), respectively. In contrast, WIN (1.25 mg/kg) did not significantly potentiate the anticonvulsant activity of CLB against MES-induced seizures. Similarly, WIN at doses of 1.25, 2.5 and 5 mg/kg had no significant impact on the anticonvulsant action of LCM in the MES test. On the other hand, WIN (5 mg/kg) had no impact on the acute neurotoxic effects of CLB and LCM in the chimney test and the median toxic doses (TD50) for CLB and LCM were almost unchanged. Thus, WIN (5 mg/kg) elevated the protective index values for CLB (from 1.41 to 3.07) and LCM (from 3.60 to 4.91). In conclusion, WIN potentiates suppression of tonic-clonic seizures produced by CLB in the mouse MES model, without affecting acute neurotoxic adverse effects of CLB in the chimney test in mice, which is favorable from a preclinical point of view., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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404. Cannabinoid-induced changes in respiration of brain mitochondria.
- Author
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Fišar Z, Singh N, and Hroudová J
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- Animals, Arachidonic Acids pharmacology, Benzoxazines pharmacology, Brain metabolism, Cannabidiol pharmacology, Cell Respiration drug effects, Dose-Response Relationship, Drug, Dronabinol pharmacology, Drug Inverse Agonism, Endocannabinoids pharmacology, Mitochondria metabolism, Morpholines pharmacology, Naphthalenes pharmacology, Piperidines pharmacology, Polyunsaturated Alkamides pharmacology, Pyrazoles pharmacology, Receptor, Cannabinoid, CB1 metabolism, Signal Transduction drug effects, Swine, Brain drug effects, Cannabinoid Receptor Agonists pharmacology, Cannabinoids pharmacology, Energy Metabolism drug effects, Mitochondria drug effects, Receptor, Cannabinoid, CB1 drug effects
- Abstract
Cannabinoids exert various biological effects that are either receptor-mediated or independent of receptor signaling. Mitochondrial effects of cannabinoids were interpreted either as non-receptor-mediated alteration of mitochondrial membranes, or as indirect consequences of activation of plasma membrane type 1 cannabinoid receptors (CB1). Recently, CB1 receptors were confirmed to be localized to the membranes of neuronal mitochondria, where their activation directly regulates respiration and energy production. Here, we performed in-depth analysis of cannabinoid-induced changes of mitochondrial respiration using both an antagonist/inverse agonist of CB1 receptors, AM251 and the cannabinoid receptor agonists, Δ(9)-tetrahydrocannabinol (THC), cannabidiol, anandamide, and WIN 55,212-2. Relationships were determined between cannabinoid concentration and respiratory rate driven by substrates of complex I, II or IV in pig brain mitochondria. Either full or partial inhibition of respiratory rate was found for the tested drugs, with an IC50 in the micromolar range, which verified the significant role of non-receptor-mediated mechanism in inhibiting mitochondrial respiration. Effect of stepwise application of THC and AM251 evidenced protective role of AM251 and corroborated the participation of CB1 receptor activation in the inhibition of mitochondrial respiration. We proposed a model, which includes both receptor- and non-receptor-mediated mechanisms of cannabinoid action on mitochondrial respiration. This model explains both the inhibitory effect of cannabinoids and the protective effect of the CB1 receptor inverse agonist., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
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405. THE CANNABINOID RECEPTOR AGONIST WIN 55, 212???2 POTENTLY STIMULATES DOPAMINERGIC NEURONAL ACTIVITY IN THE MESOLIMBIC SYSTEM
- Author
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A Argiolas, S Succu, and M R Melis
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Pharmacology ,Agonist ,Psychiatry and Mental health ,Cannabinoid receptor ,Chemistry ,medicine.drug_class ,Dopaminergic ,medicine ,Cannabinoid receptor type 2 ,Premovement neuronal activity ,WIN 55,212-2 ,Neuroscience ,medicine.drug - Published
- 1996
406. Calcium regulation by temperature-sensitive transient receptor potential channels in human uveal melanoma cells.
- Author
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Mergler S, Derckx R, Reinach PS, Garreis F, Böhm A, Schmelzer L, Skosyrski S, Ramesh N, Abdelmessih S, Polat OK, Khajavi N, and Riechardt AI
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- Benzoxazines pharmacology, Capsaicin pharmacology, Cell Line, Tumor, Gene Expression Regulation, Neoplastic drug effects, Humans, Immunohistochemistry, Ion Channel Gating drug effects, Models, Biological, Morpholines pharmacology, Naphthalenes pharmacology, Pyrimidinones pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, Receptor, Cannabinoid, CB1 metabolism, Transient Receptor Potential Channels agonists, Transient Receptor Potential Channels metabolism, Calcium metabolism, Melanoma genetics, Melanoma pathology, Temperature, Transient Receptor Potential Channels genetics, Uveal Neoplasms genetics, Uveal Neoplasms pathology
- Abstract
Uveal melanoma (UM) is both the most common and fatal intraocular cancer among adults worldwide. As with all types of neoplasia, changes in Ca(2+) channel regulation can contribute to the onset and progression of this pathological condition. Transient receptor potential channels (TRPs) and cannabinoid receptor type 1 (CB1) are two different types of Ca(2+) permeation pathways that can be dysregulated during neoplasia. We determined in malignant human UM and healthy uvea and four different UM cell lines whether there is gene and functional expression of TRP subtypes and CB1 since they could serve as drug targets to either prevent or inhibit initiation and progression of UM. RT-PCR, Ca(2+) transients, immunohistochemistry and planar patch-clamp analysis probed for their gene expression and functional activity, respectively. In UM cells, TRPV1 and TRPM8 gene expression was identified. Capsaicin (CAP), menthol or icilin induced Ca(2+) transients as well as changes in ion current behavior characteristic of TRPV1 and TRPM8 expression. Such effects were blocked with either La(3+), capsazepine (CPZ) or BCTC. TRPA1 and CB1 are highly expressed in human uvea, but TRPA1 is not expressed in all UM cell lines. In UM cells, the CB1 agonist, WIN 55,212-2, induced Ca(2+) transients, which were suppressed by La(3+) and CPZ whereas CAP-induced Ca(2+) transients could also be suppressed by CB1 activation. Identification of functional TRPV1, TRPM8, TRPA1 and CB1 expression in these tissues may provide novel drug targets for treatment of this aggressive neoplastic disease., (© 2013.)
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- 2014
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407. Pretreatment with clonidine caused desensitization to WIN 55,212-2 in guinea pig ileum.
- Author
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Rezania F, Mohaghegh Shalmani L, Rahimian R, Dehpour AR, and Ejtemaei Mehr S
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- Animals, Dose-Response Relationship, Drug, Electric Stimulation, Enteric Nervous System physiology, Guinea Pigs, Ileum physiology, In Vitro Techniques, Male, Muscle Contraction drug effects, Muscle Contraction physiology, Benzoxazines antagonists & inhibitors, Benzoxazines pharmacology, Clonidine pharmacology, Drug Tolerance, Enteric Nervous System drug effects, Ileum drug effects, Morpholines antagonists & inhibitors, Morpholines pharmacology, Naphthalenes antagonists & inhibitors, Naphthalenes pharmacology
- Abstract
Considering the existence of cross-tolerance between clonidine and morphine besides the same interaction between morphine and WIN 55,212-2 persuaded us to verify this fact between WIN 55,212-2 and clonidine in guinea pig ileum, which is a well-known model to examine the mode of action of cannabinoids and α2 -adenoceptor agonists The rectangular pulses were passed to the 0.5 g stretched ileum segments that were fixed in 20-ml organ bath. PowerLab system and Graphpad Prism were applied to record twitches and analyse the data. Electrically evoked contractions were dose-dependently inhibited by WIN 55,212-2 and clonidine (pD2 = 8.56 ± 0.41 and 7.65 ± 0.15, respectively). Tolerance to this effect could be induced by 4-h incubation with WIN 55,212-2 (3 × IC50 ) (pD2 = 6.36 ± 0.26, degree of tolerance: 159.32) (P < 0.01) but not with clonidine (2 × IC50 and 4 × IC50 ) for different time courses. Dose-response curve for inhibitory action of WIN 55,212-2 was shifted to the right after 4-h incubation with clonidine (3 × 10(-10) m) comparing to the untreated tissues (pD2 = 5.26 ± 0.69, degree of tolerance: 2000) (P < 0.001). This observation provides the evidence for the cannabinoid-noradrenergic systems interaction in the enteric nervous system as a simplified representative for central nervous system., (© 2014 John Wiley & Sons Ltd.)
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- 2014
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408. Cholinergic modulation of primary afferent glutamatergic transmission in rat medullary dorsal horn neurons.
- Author
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Jeong SG, Choi IS, Cho JH, and Jang IS
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- Anesthetics, Local pharmacology, Animals, Animals, Newborn, Cholinergic Agents pharmacology, Drug Interactions, Excitatory Amino Acid Agents pharmacology, Excitatory Amino Acid Antagonists pharmacology, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials physiology, Female, In Vitro Techniques, Male, Rats, Rats, Sprague-Dawley, Receptor, Muscarinic M2 genetics, Receptor, Muscarinic M2 metabolism, Synaptic Transmission drug effects, Tetrodotoxin pharmacology, Valine analogs & derivatives, Valine pharmacology, Acetylcholine metabolism, Glutamic Acid metabolism, Medulla Oblongata cytology, Posterior Horn Cells drug effects, Synaptic Transmission physiology
- Abstract
Although muscarinic acetylcholine (mACh) receptors are expressed in trigeminal ganglia, it is still unknown whether mACh receptors modulate glutamatergic transmission from primary afferents onto medullary dorsal horn neurons. In this study, we have addressed the cholinergic modulation of primary afferent glutamatergic transmission using a conventional whole cell patch clamp technique. Glutamatergic excitatory postsynaptic currents (EPSCs) were evoked from primary afferents by electrical stimulation of trigeminal tract and monosynaptic EPSCs were recorded from medullary dorsal horn neurons of rat horizontal brain stem slices. Muscarine and ACh reversibly and concentration-dependently decreased the amplitude of glutamatergic EPSCs and increased the paired-pulse ratio. In addition, muscarine reduced the frequency of miniature EPSCs without affecting the current amplitude, suggesting that muscarine acts presynaptically to decrease the probability of glutamate release onto medullary dorsal horn neurons. The muscarine-induced decrease of glutamatergic EPSCs was significantly occluded by methoctramine or AF-DX116, M2 receptor antagonists, but not pirenzepine, J104129 and MT-3, selective M1, M3 and M4 receptor antagonists. The muscarine-induced decrease of glutamatergic EPSCs was highly dependent on the extracellular Ca2+ concentration. Physostigmine and clinically available acetylcholinesterase inhibitors, such as rivastigmine and donepezil, significantly shifted the concentration-inhibition relationship of ACh for glutamatergic EPSCs. These results suggest that muscarine acts on presynaptic M2 receptors to inhibit glutamatergic transmission by reducing the Ca2+ influx into primary afferent terminals, and that M2 receptor agonists and acetylcholinesterase inhibitors could be, at least, potential targets to reduce nociceptive transmission from orofacial tissues., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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409. BML-190 and AM251 act as inverse agonists at the human cannabinoid CB2 receptor: signalling via cAMP and inositol phosphates
- Author
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David C. New and Yung Hou Wong
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AM251 ,Cannabinoid receptor ,Inositol Phosphates ,Morpholines ,Receptors, Drug ,medicine.medical_treatment ,Indomethacin ,Biophysics ,Ligands ,Second Messenger Systems ,Biochemistry ,Cell Line ,Piperidines ,Structural Biology ,Cyclic AMP ,Genetics ,Enzyme-linked receptor ,medicine ,Cannabinoid receptor type 2 ,Humans ,Receptors, Cannabinoid ,Inositol phosphate ,WIN 55,212-2 ,Molecular Biology ,Cannabinoid ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Chemistry ,BML-190 ,Colforsin ,Drug Synergism ,Cell Biology ,CB2 ,Pyrazoles ,Estrogen-related receptor gamma ,lipids (amino acids, peptides, and proteins) ,medicine.drug ,Inverse agonist - Abstract
The aminoalkylindole BML-190 and diarylpyrazole AM251 ligands have previously been shown to bind to cannabinoid CB(2) and CB(1) receptors, respectively. In HEK-293 cells stably expressing the human CB(2) receptor, BML-190 and AM251 potentiated the forskolin-stimulated accumulation of cAMP. Moreover, the CB(2) receptor can interact productively with 16z44, a promiscuous G alpha(16/z) chimera. BML-190 and AM251 reduce the basal levels of inositol phosphate production in cells expressing the CB(2) receptor and 16z44. These results demonstrate that BML-190 and AM251 act as inverse agonists at the human CB(2) receptor acting via G alpha(i/o) and G alpha(q) family-coupled pathways.
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410. 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
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Magdalena Florek-Luszczki, Maria W. Kondrat-Wróbel, Jarogniew J. Luszczki, Piotr Tutka, and Aleksandra Wlaz
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Male ,Agonist ,Clobazam ,medicine.drug_class ,Morpholines ,medicine.medical_treatment ,Translational Neurosciences - Original Article ,Antiepileptic drugs ,Biophysics ,Clinical Neurology ,Naphthalenes ,Pharmacology ,Drug interactions ,6 Hz psychomotor seizure model ,Mice ,Epilepsy, Complex Partial ,WIN 55,212-2 ,Avoidance Learning ,medicine ,Animals ,Muscle Strength ,Biological Psychiatry ,Analysis of Variance ,Electroshock ,Dose-Response Relationship, Drug ,Cannabinoids ,Clonazepam ,Benzoxazines ,Disease Models, Animal ,Psychiatry and Mental health ,Neuroprotective Agents ,Anticonvulsant ,Neurology ,Pharmacodynamics ,Anticonvulsants ,Phenobarbital ,Neurology (clinical) ,Cannabinoid ,Psychology ,Psychomotor Performance ,medicine.drug - Abstract
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 ascertained by use of the chimney test (evaluating motor performance), step-through passive avoidance task (assessing learning) and grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5 mg/kg, administered intraperitoneally) significantly enhanced the anticonvulsant action of clonazepam (P
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411. [Untitled]
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0301 basic medicine ,medicine.medical_specialty ,Multidisciplinary ,Cannabinoid receptor ,Microglia ,business.industry ,Multiple sclerosis ,medicine.disease ,Neuroprotection ,Endocannabinoid system ,03 medical and health sciences ,Myelin ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,medicine ,Remyelination ,WIN 55,212-2 ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Dysfunctions in the endocannabinoid system have been associated with experimental animal models and multiple sclerosis patients. Interestingly, the endocannabinoid system has been reported to confer neuroprotection against demyelination. The present study aims to assess the effects of the cannabinoid agonist WIN-55,212-2 in cuprizone fed animals on myelin repair capacity. Animals exposed to cuprizone were simultaneously treated withWIN-55,212-2, behaviorally tested and finally the corpus callosum was exhaustively studied by Western blotting, qRT-PCR and a myelin staining procedure. We report that the long-term administration of WIN-55,212-2 reduced the global amount of CB1 protein. Histological analysis revealed clear demyelination after being fed cuprizone for three weeks. However, cuprizone-fed mice subjected to 0.5 mg/Kg of WIN-55,212-2 displayed no differences when compared to controls during demyelination, although there was a robust increase in the myelinated axons during the remyelination phase. These animals displayed better performance on contextual fear conditioning which was in turn non-attributable to an antinociceptive effect. In contrast, a 1 mg/Kg dosage caused a remarkable demyelination accompanied by limited potential for myelin repair. Upon drug administration while mice ongoing demyeliniation, the expression of Aif1 (microglia) and Gfap (astrocytes) followed a dose-dependent manner whereas the expression of both markers was apparently attenuated during remyelination. Treatment with vehicle or 0.5 mg/Kg of the drug during demyelination increased the expression of Pdgfra (oligodendrocyte precursor cells) but this did not occur when 1 mg/Kg was administered. In conclusion, the drug at 0.5 mg/Kg did not alter myelin architecture while 1 mg/Kg had a deleterious effect in this model.
412. MOLECULAR CHARACTERIZATION OF A PERIPHERAL RECEPTOR FOR CANNABINOIDS
- Author
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Kerrie L. Thomas, Muna Abu-Shaar, and Sean Munro
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Cannabinoid receptor ,Polyunsaturated Alkamides ,Morpholines ,Receptors, Drug ,medicine.medical_treatment ,Molecular Sequence Data ,Arachidonic Acids ,Naphthalenes ,Biology ,Pharmacology ,Rimonabant ,Cannabinoid receptor type 1 ,Tumor Cells, Cultured ,medicine ,Cannabinoid receptor type 2 ,Animals ,Humans ,Amino Acid Sequence ,Cloning, Molecular ,Receptors, Cannabinoid ,WIN 55,212-2 ,Multidisciplinary ,Base Sequence ,Cannabinoids ,Macrophages ,Brain ,DNA ,Amides ,Benzoxazines ,Rats ,GPR55 ,Immunology ,Fatty Acids, Unsaturated ,Cannabinoid receptor binding ,RNA ,Cannabinoid ,Spleen ,Endocannabinoids ,medicine.drug - Abstract
The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
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