Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A broad range of therapeutic applications has been suggested for cannabis or its pharmacologically active compound (tetrahydrocannabinol; THC) in many publications. Psychotropic side effects and the anecdotal character of the research have limited the pharmacotherapeutic use of THC until now. Therefore, the Netherlands Health Council recently decided negatively on this matter. Besides several cannabinoid receptor subtypes present in the central nervous system and peripheral tissues endogenous cannabinoids have been detected. These endogenous cannabinoids appear to play an important role in signal transduction, which may be starting points for therapy regarding: cardiovascular diseases, multiple sclerosis and spinal cord disorders. cerebrovascular accident and brain trauma, neurodegenerative diseases, epilepsy, pain management, glaucoma, oncologic and aids-related disorders such as nausea, vomiting and appetite problems.
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PMID:[Therapeutic applications and biomedical effects of cannabinoids; pharmacological starting points]. 954 85

The effects of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), a specific cannabinoid receptor antagonist, were assessed in the dog static ataxia test after either acute treatment with two cannabinoid receptor agonists, delta9-tetrahydrocannabinol and arachidonylethanolamide (anandamide), or chronic treatment with delta9-tetrahydrocannabinol. As previously reported, acute intravenous (i.v.) injected delta9-tetrahydrocannabinol produced dose-dependent cannabinoid effects, including marked static ataxia, prancing, loss of muscle tone, and incoordination. The behavioral profile of anandamide was distinctly different in that it produced a loss of muscle tone and considerable sedation with little static ataxia, prancing, or incoordination. Despite these qualitative differences between the two agonists, SR 141716A blocked the acute behavioral effects of both drugs indicating a cannabinoid receptor mechanism of action. Interestingly, SR 141716A was able to precipitate a withdrawal syndrome in delta9-tetrahydrocannabinol-tolerant dogs, but failed to produce any observable effects in dogs receiving chronic vehicle injections. Acute toxicity caused by anandamide, which was not blocked by SR 141716A, precluded conducting dependence studies with this drug. The delta9-tetrahydrocannabinol precipitated withdrawal syndrome included diarrhea, vomiting, excessive salivation, decreases in social behavior, and increases in restless behavior and trembling. This is the first demonstration of a precipitated withdrawal syndrome in a non-rodent species.
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PMID:Effects of SR 141716A after acute or chronic cannabinoid administration in dogs. 979 29

We have recently shown that the cannabinoid CB(1) receptor antagonist, SR 141716A, produces emesis in the least shrew (Cryptotis parva) in a dose- and route-dependent manner. This effect was blocked by delta-9-tetrahydrocannabinol (Delta(9)-THC). The present study investigates the cannabinoid receptor mechanisms by which Delta(9)-THC produces its antiemetic effects against cisplatin (20 mg/kg, i.p.)-induced emesis as well as its cannabimimetic activity profile (motor reduction) in the least shrew. Intraperitoneal administration of Delta(9)-THC (1, 2.5, 5 and 10 mg/kg) dose-dependently reduced both the percentage of animals vomiting (ID(50)=1.8+/-1.6 mg/kg) and the frequency of vomits (ID(50)=0.36+/-1.18 mg/kg) in a potent manner. The lowest significantly effective antiemetic dose of Delta(9)-THC for the latter emesis parameters was 2.5 mg/kg. Although Delta(9)-THC reduced the frequency of vomits up to 98%, it failed to completely protect all tested shrews from vomiting (80% protection). The cannabinoid CB(1) antagonist (SR 141716A) and not the CB(2) antagonist (SR 144528), reversed the antiemetic effects of Delta(9)-THC in a dose-dependent fashion. Delta(9)-THC (1, 5, 10 and 20 mg/kg, ip) suppressed locomotor parameters (spontaneous locomotor activity, duration of movement and rearing frequency) in a biphasic manner and only the 20-mg/kg dose simultaneously suppressed the triad of locomotor parameters to a significant degree. Subcutaneous (1-10 mg/kg) and intraperitoneal (0.05-40 mg/kg) injection of some doses of SR 141716A caused significant reductions in one or more components of the triad of locomotor parameters but these reductions were not dose dependent. Subcutaneous injection of SR 141716A (0.2, 1, 5 and 10 mg/kg) reversed the motor suppressant effects of a 20-mg/kg dose of Delta(9)-THC (ip) in a dose-dependent manner. Relative to its motor suppressant effects, Delta(9)-THC is a more potent antiemetic agent. Both effects are probably mediated via CB(1) receptors in distinct loci.
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PMID:Delta-9-tetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB(1) receptors in the least shrew. 1142 92

The active principle in marijuana, Delta(9)-tetrahydrocannabinol (THC), has been shown to have wide therapeutic application for a number of important medical conditions, including pain, anxiety, glaucoma, nausea, emesis, muscle spasms, and wasting diseases. Delta(9)-THC binds to and activates two known cannabinoid receptors found in mammalian tissue, CB1 and CB2. The development of cannabinoid-based therapeutics has focused predominantly on the CB1 receptor, based on its predominant and abundant localization in the CNS. Like most of the known cannabinoid agonists, Delta(9)-THC is lipophilic and relatively nonselective for both receptor subtypes. Clinical studies show that nonselective cannabinoid agonists are relatively safe and provide therapeutic efficacy, but that they also induce psychotropic side effects. Recent studies of the biosynthesis, release, transport, and disposition of anandamide are beginning to provide an understanding of the role of lipid transmitters in the CNS. This review attempts to link current understanding of the basic biology of the endocannabinoid nervous system to novel opportunities for therapeutic intervention. This new knowledge may facilitate the development of cannabinoid receptor-targeted therapeutics with improved safety and efficacy profiles.
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PMID:The endocannabinoid nervous system: unique opportunities for therapeutic intervention. 1144 25

The dibenzopyran cannabinoids (delta-9 (Delta9)-tetrahydrocannabinol and nabilone) are clinically used to suppress nausea and vomiting produced by chemotherapeutic agents such as cisplatin. The purpose of this investigation was to investigate the antiemetic potential of the aminoalkylindole cannabinoid receptor agonist WIN 55, 212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl) methyl] pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate] against cisplatin-induced vomiting. Different doses of WIN 55, 212-2 (0, 1, 2.5 and 5 mg/kg, i.p.) reduced both the frequency of cisplatin (20 mg/kg, i.p.)-induced emesis (ID(50)=0.5 mg/kg) as well as the percentage of shrews vomiting (ID50=1.2 mg/kg) in a dose-dependent manner. Significant reductions in emesis frequency occurred from 2.5 mg/kg dose of WIN 55, 212-2, whereas significant total protection from vomiting was afforded at its 5 mg/kg dose. The antiemetic actions of a 5-mg/kg dose of WIN 55, 212-2 against cisplatin (20 mg/kg, i.p.)-induced vomiting were reversed by nonemetic subcutaneous doses (0, 0.25, 0.5 and 1 mg/kg) of the cannabinoid CB1 receptor antagonist/inverse agonist SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] (ID50=0.27 and 0.47 mg/kg, respectively) but not by a 5-mg/kg dose of the cannabinoid CB2 receptor antagonist SR 144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1] heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methybenzyl) pyrazole-3-carboxamide]. The effects of the cited doses of WIN 55, 212-2 were also investigated on several motor parameters (spontaneous locomotor activity, duration of movement and rearing frequency). Significant reductions in motor parameters were only observed at its highest tested dose (ID50=1.97, 2.75 and 2.8 mg/kg; respectively). SR 141716A (0, 0.5, 1, 5 and 10 mg/kg) also reversed the motor suppressant effects of a 5-mg/kg dose of WIN 55, 212-2 (ID50=0.39, 0.1 and 0.3 mg/kg, respectively) and significant reversals were seen from its 0.5 and 1 mg/kg doses. These results suggest that WIN 55, 212-2 reduces both emesis and indeces of locomotion via the stimulation of cannabinoid CB1 receptors. However, cannabinoid CB1 receptors in different loci are most likely responsible for the antiemetic and motor suppressive effects of WIN 55, 212-2 since reduction in the frequency of vomiting occurred at lower doses relative to its sedative actions.
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PMID:The cannabinoid CB1 receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55, 212-2. 1169 62

Lower esophageal sphincter (LES) tone is decreased during swallowing, during transient LES relaxations (TLESRs), and before emesis, and this decrease is due primarily to increasing inhibitory vagal output to the LES. Reflex-evoked relaxation of the LES is mediated by long-loop vagovagal reflexes that are coordinated by the dorsal vagal complex in the hindbrain medulla. A sequence of events occurs. Central control of TLESRs has not been studied directly; the information on how drugs may work centrally to reduce TLESRs is extrapolated from knowledge of how the brain evokes LES relaxation. Reduction of the frequency of TLESRs by a GABAB agonist, baclofen, is due to inhibition of vagal afferents, information transfer between the nucleus tractus solitarius and dorsal motor nucleus of the vagus, and vagal efferent outflow. Preliminary data show that cannabinoid receptor activation reduces information transfer between the nucleus tractus solitarius and dorsal motor nucleus of the vagus. The potential therapeutic usefulness of these types of agents that reduce TLESRs by acting centrally is promising.
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PMID:Central mechanisms of lower esophageal sphincter control. 1248 67

The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.
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PMID:Therapeutic potential of cannabinoids in CNS disease. 1261 97

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.
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PMID:Pharmacology of cannabinoids. 1515 77

Many patients with life-threatening diseases such as cancer experience severe symptoms that compromise their health status and deny them quality of life. Patients with cancer often experience cachexia, pain, and depression,which translate into an unacceptable quality of life. The discovery of the endocannabinoid system has led to a renewed interest in the use of cannabinoids for the management of nausea, vomiting, and weight loss arising either from cancer or the agents used to treat cancer. The endocannabinoid system has been found to be a key modulator of systems involved in pain perception, emesis, and reward pathways. As such, it represents a target for development of new medications for controlling the symptoms associated with cancer. Although the cannabinoid receptor agonist tetrahydrocannabinol and one of its analogs are currently the only agents approved for clinical use, efforts are under way to devise other strategies for activating the endocannabinoid system for therapeutic uses.
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PMID:Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. 1535 14

The principal psychoactive component of marijuana, delta-9-tetrahydrocannabinol (Delta9-THC), suppresses nausea and vomiting in cancer patients caused by chemotherapeutics such as cisplatin. Cisplatin induces vomiting via a number of emetic stimuli, including dopamine. Currently, there is controversy as to whether Delta9-THC can prevent emesis produced by dopaminergic agonists such as apomorphine. The present investigation utilizes the least shrew to evaluate the antiemetic potential and the cannabinoid receptor by which Delta9-THC may prevent emesis produced by four dopamine receptor agonists with differing selectivity for D2 and D3 receptors, i.e., a nonselective dopamine receptor agonist (apomorphine), a D2-preferring receptor agonist (quinpirole), and two D3-preferring receptor agonists (quinelorane and 7-OH DPAT). In addition, relative to its antiemetic doses, the motor suppressive doses of Delta9-THC in dopamine D2/D3-receptor-agonist-treated shrews were also evaluated. Thus, different groups of shrews were injected with either vehicle (V) or varying doses of Delta9-THC [0.5, 1, 2.5, 5, or 10 mg/kg, intraperitoneal (i.p.)] 10 min prior to administration of a 2 mg/kg dose of one of the four cited D2/D3 agonists. Immediately after the last injection, the frequency of vomiting for each shrew was recorded for the next 30 min. To investigate which cannabinoid receptor is involved in the antiemetic action of Delta9-THC, various doses of the CB1 receptor antagonist SR 141716A [0, 5, 10, and 20 mg/kg, subcutaneous (s.c.)] were administered to shrews 10 min prior to an injection of a fully effective antiemetic dose of Delta9-THC (5 mg/kg, i.p.). Ten minutes later, each treated shrew was administered with a 2 mg/kg dose of apomorphine. The emesis frequency was recorded for the next 30 min. For locomotor studies, different groups of shrews received either vehicle or various doses of Delta9-THC (0, 5, 10, 20, or 30 mg/kg) 10 min prior to an injection of vehicle or a 2 mg/kg dose of one of the four D2/D3 receptor agonists. The triad of motor behaviors (spontaneous locomotor activity, total duration of movement, and rearing frequency) were recorded for the next 30 min by a computerized video tracking system. Delta9-THC dose-dependently attenuated the frequency of emesis as well as fully protecting shrews from vomiting produced by each one of the four cited dopamine D2/D3 receptor agonists with ID50s ranging from 1 to 4 mg/kg. SR 141716A reversed the antiemetic activity of Delta9-THC against apomorphine-induced emesis. Delta9-THC also differentially suppressed the triad of motor activities in dopamine D2/D3-receptor-agonist-treated shrews with ID50s ranging from 7 to 21 mg/kg. The results suggest that Delta9-THC prevents emesis via cannabinoid CB1 receptors in a potent and dose-dependent manner in D2/D3-receptor-agonist-treated shrews at doses well below those which cause significant motor depression.
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PMID:Delta-9-tetrahydrocannabinol differentially suppresses emesis versus enhanced locomotor activity produced by chemically diverse dopamine D2/D3 receptor agonists in the least shrew (Cryptotis parva). 1565 78


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