PMC:3951193 / 74809-83531 JSONTXT

{"project":"2_test","denotations":[{"id":"24622769-9831287-95790447","span":{"begin":276,"end":279},"obj":"9831287"},{"id":"24622769-9813289-95790448","span":{"begin":631,"end":634},"obj":"9813289"},{"id":"24622769-8987831-95790449","span":{"begin":772,"end":775},"obj":"8987831"},{"id":"24622769-8987831-95790450","span":{"begin":1069,"end":1072},"obj":"8987831"},{"id":"24622769-10582605-95790451","span":{"begin":1076,"end":1079},"obj":"10582605"},{"id":"24622769-20357755-95790452","span":{"begin":1083,"end":1086},"obj":"20357755"},{"id":"24622769-10737621-95790453","span":{"begin":1454,"end":1457},"obj":"10737621"},{"id":"24622769-17222515-95790454","span":{"begin":1527,"end":1530},"obj":"17222515"},{"id":"24622769-21747398-95790455","span":{"begin":1735,"end":1738},"obj":"21747398"},{"id":"24622769-22948261-95790456","span":{"begin":2306,"end":2309},"obj":"22948261"},{"id":"24622769-16157354-95790457","span":{"begin":2575,"end":2578},"obj":"16157354"},{"id":"24622769-10428044-95790458","span":{"begin":2715,"end":2718},"obj":"10428044"},{"id":"24622769-7996450-95790459","span":{"begin":2882,"end":2885},"obj":"7996450"},{"id":"24622769-15148260-95790460","span":{"begin":3008,"end":3011},"obj":"15148260"},{"id":"24622769-12235230-95790461","span":{"begin":3147,"end":3150},"obj":"12235230"},{"id":"24622769-20417220-95790462","span":{"begin":3312,"end":3315},"obj":"20417220"},{"id":"24622769-8987831-95790469","span":{"begin":3658,"end":3661},"obj":"8987831"},{"id":"24622769-9882692-95790470","span":{"begin":3665,"end":3668},"obj":"9882692"},{"id":"24622769-17641667-95790471","span":{"begin":4014,"end":4016},"obj":"17641667"},{"id":"24622769-15148260-95790472","span":{"begin":4330,"end":4333},"obj":"15148260"},{"id":"24622769-10779390-95790473","span":{"begin":4337,"end":4340},"obj":"10779390"},{"id":"24622769-9285589-95790474","span":{"begin":4343,"end":4346},"obj":"9285589"},{"id":"24622769-11752094-95790475","span":{"begin":4426,"end":4429},"obj":"11752094"},{"id":"24622769-15146190-95790476","span":{"begin":4535,"end":4538},"obj":"15146190"},{"id":"24622769-14996548-95790477","span":{"begin":4542,"end":4545},"obj":"14996548"},{"id":"24622769-19118122-95790478","span":{"begin":4567,"end":4570},"obj":"19118122"},{"id":"24622769-9384246-95790479","span":{"begin":4944,"end":4947},"obj":"9384246"},{"id":"24622769-15148260-95790480","span":{"begin":4976,"end":4979},"obj":"15148260"},{"id":"24622769-9808686-95790481","span":{"begin":5080,"end":5083},"obj":"9808686"},{"id":"24622769-8593598-95790482","span":{"begin":5087,"end":5090},"obj":"8593598"},{"id":"24622769-9864268-95790483","span":{"begin":5203,"end":5206},"obj":"9864268"},{"id":"24622769-10570066-95790484","span":{"begin":5411,"end":5414},"obj":"10570066"},{"id":"24622769-7853184-95790485","span":{"begin":5496,"end":5499},"obj":"7853184"},{"id":"24622769-8306090-95790486","span":{"begin":5503,"end":5506},"obj":"8306090"},{"id":"24622769-20357755-95790487","span":{"begin":5526,"end":5529},"obj":"20357755"},{"id":"24622769-22051632-95790488","span":{"begin":5797,"end":5800},"obj":"22051632"},{"id":"24622769-17714742-95790489","span":{"begin":6486,"end":6489},"obj":"17714742"},{"id":"24622769-19918051-95790490","span":{"begin":7613,"end":7616},"obj":"19918051"},{"id":"24622769-18021759-95790491","span":{"begin":7857,"end":7860},"obj":"18021759"},{"id":"24622769-11606325-95790492","span":{"begin":8086,"end":8089},"obj":"11606325"},{"id":"24622769-21175579-95790493","span":{"begin":8093,"end":8096},"obj":"21175579"},{"id":"24622769-21175579-95790494","span":{"begin":8484,"end":8487},"obj":"21175579"},{"id":"24622769-21175579-95790495","span":{"begin":8717,"end":8720},"obj":"21175579"}],"text":"Cannabis\nCannabis and cannabis products are complex polypharmaceuticals, consisting of THC, cannabidiol (CBD), dozens of minor cannabinoids, as well as terpenoids, flavonoids, and other compounds. Fundamentally, THC mimics AEA and 2-AG by acting as an agonist at CB1 and CB2 [279]. But rather than simply substituting for AEA and 2-AG, McPartland and Guy [280] proposed that Cannabis and its many constituents work, in part, by “kick-starting” the eCB system. The acute administration of THC increased CB1 density in rodent brains [281], [282]. Acute upregulation of CB1 mRNA continued for up to 14 days in some rat brain regions [283]. Acute THC also increased the sensitivity of CB1 to cannabinoids, measured by WIN-55,212-2-stimulated [35S]GTPγS binding in rat brains [284]. Lastly, acute THC stimulated AEA biosynthesis [285].\nChronic, high dosing of THC causes a predictable desensitization and downregulation of CB1 and CB2, accompanied by drug tolerance. Chronic THC decreased CB1 density in rodent brains, and dampened cannabinoid-stimulated [35S]GTPγS [282], [284], [286], [287]. CB1 in different regions of the brain downregulate and desensitize at unequal rates and magnitudes, with greatest decreases in the hippocampus and little or no change in the nucleus accumbens and basolateral amygdala. Chronic THC elicited few changes in AEA or 2-AG levels in rat brains, except for a significant augmentation of AEA levels in the limbic forebrain [288].\nSimilar results have been reported in two human studies. Villares [289] collected postmortem brain tissues from known cannabis smokers; [3H]SR141716A binding and CB1 mRNA was downregulated in several brain regions, compared to non-smoking control autopsies. Hirvonen et al. [290] employed PET scan imaging in living subjects. The degree of CB1 downregulation correlated with years of chronic cannabis smoking. CB1 densities returned to normal after four weeks of abstinence. Variable downregulation in different brain regions may explain why frequent users of cannabis develop tolerance to some effects of THC, such as anxiogenesis and cognitive impairment, but not to its euphoric effects [291]. Downregulation is partially epigenetic—the CB1 promoter region in chronic marijuana smokers is hypermethylated, reducing CB1 mRNA expression levels [292].\nTHC acts as a partial agonist of CB1, compared to synthetic cannabinoids which act as full agonists (Table 5). Partial agonism likely explains why exposure to THC caused half as much CB1 desensitization as the full agonist WIN55,212-2 in rat hippocampal neurons [293]. In a study of rat CB1 transfected into AtT20 cells, THC caused less downregulation and internalization than WIN55,212-2 or CP-55,940 [294]. In agreement, drug tolerance studies utilizing the behavioral “tetrad” test show that chronic THC caused less tolerance than the full agonist CP-55,940 in mice [295]. In a study of human CB1 transfected into Xenopus oocytes, the desensitization rate of THC was half that of WIN55,212-2 [296]. However, one [35S]GTPγS autoradiography study of rat brains suggested that chronic THC and WIN55,212-2 caused equal desensitization [297]. Another study indicated that THC acts as a full agonist at mouse GABAergic synapses, with efficacy equal to WIN55,212-2, albeit at fairly high concentrations [298].\n10.1371/journal.pone.0089566.t005 Table 5 Partial agonism of THC at CB1, based on assays of cannabinoid-stimulated signal transduction. If THC is a partial agonist, then THC might functionally antagonize the effects of a full agonist when the two drugs are added together. THC antagonized the effects of WIN55,212-2 in rat brain sections [284], [299], and mouse autaptic hippocampal neurons [300].\nThe capacity of THC to antagonize a full agonist depends, in part, upon ligand affinity—its ability to occupy and hold the CB1 binding site. A meta-analysis of affinity studies calculated a mean Ki = 42.6 nM for THC in rat membranes—much less affinity than that of WIN-55,940, with a Kd = 2.4 nM [22]. This indicates that high concentrations of THC relative to WIN-55,940 are required to antagonize the full agonist. There are species differences—in human membranes, CB1 affinity of THC (Ki = 25.1 nM) is much closer to that of WIN-55,940 (Kd = 16.7).\n2-AG acts as a full agonist at rodent and human CB1 and CB2 [296], [301]–[303]. The emetogenic effects of exogenously-administered 2-AG were blocked by THC [304]. THC dampened or occluded eCB-mediated retrograde signaling of CB1, presumable mediated by 2-AG [300], [305], [306]. Roloff and Thayer [307] demonstrated another complexity in the relationship between THC and 2-AG: neuron firing rate in response to stimulus in rat hippocampal neurons. At low firing rates, THC mimicked 2-AG and behaved like an agonist; at high firing rates, THC antagonized endogenous 2-AG signaling.\nAEA is a partial agonist like THC, with an efficacy somewhat greater than THC in mouse brain [308] and transfected human CB1 [296]. Consistent with partial agonism, exogenously-administered AEA caused little tolerance in rodents [309], [310]. Agonist trafficking adds further complexity—THC and AEA preferentially activate different G-protein subtypes [311]. At transfected human CB1, AEA acted as a full agonist via Gαi subunits, and a partial agonist via Gαo subunits, with agonist efficacy much greater than THC at Gαi, and slightly greater than THC at Gαo [312].\nAEA and THC can antagonize each other; this in part is due to cross-tolerance [313], [314]. Falenski et al. [287] demonstrated that subchronic administration of THC in FAAH−/− knockout mice caused greater tolerance to THC than did subchronic administration of THC in wildtype mice. Thus elevated levels of AEA in FAAH−/− knockouts produced additive effects with THC. Vann et al. [315] trained rats to discriminate THC; trained rats injected with PMSF, which inhibits FAAH, showed 2.7-fold greater discrimination than rats injected with vehicle. In other words, inhibiting AEA degradation led to an increase in the potency of THC. Further, THC was more potent at producing antinociception, decreasing spontaneous activity, and increasing ring immobility when co-administered with PMSF as compared to vehicle.\nIn summary, the effects of THC upon the eCB system oscillate between potentiation and suppression, depending on acute versus chronic dosage. The dividing line between “acute” and “chronic” is a gray zone, and likely differs amongst individuals. Suplita et al. [316] summarized the situation: they studied “stress antinociception,” where rodents become less responsive to painful stimuli following exposure to an environmental stressor. Stress antinociception is mediated, in part, by the coordinated release of 2-AG and AEA. Acute administration of THC potentiated eCB-mediated stress antinociception. The converse was also true: animals exposed acutely to foot shock, which elicits eCB-mediated stress antinociception, became sensitized to the effects of THC. Chronic administration of THC predictably dampened stress antinociception. The converse was not true: chronic exposure to foot shock (3 min/day for 15 days) failed to dampen antinociception induced by either WIN-55,212-2 or by further footshocks.\nThe potential synergy between THC and the eCB system is analogous to the potential synergy between AEA and 2-AG: Rodent studies that combined FAAH and MAGL inhibitors indicated that AEA and 2-AG may activate CB1 receptors in different parts of the central nervous system. Each causes unique behavioral effects, and when both are enhanced, new effects emerge. Long and colleagues [317] showed that AEA and 2-AG independently dampen pain sensation, but together their effects are dramatically enhanced.\nCannabis is more than THC [318], [319]. Adding CBD to THC in mice enhanced CB1 expression in hippocampus and hypothalamus [320]. CBD increased hippocampal cell survival and neurogenesis, whereas THC had the opposite effect; the CBD response was absent in CB1 −/− knockout mice [321]. CBD inhibited the cellular uptake of AEA and its breakdown by FAAH [322], [323]. A separate systematic review regarding the effects of CBD on THC is currently underway (McPartland, unpublished). Several other non-THC cannabinoids interact with enzymes of the eCB system. For example, cannabidivarin and cannabidiolic acid are moderately potent inhibitors of DAGLα, and cannabigerol and cannabichromene are relatively potent inhibitors of anandamide cellular uptake [323]. Interestingly, cannabis extracts (“botanical drug substances,” BDS) enriched in cannabinoids, such as THC-acid BDS and CBD-BDS, were more potent than the corresponding pure compounds at inhibiting MAGL and AEA cellular uptake [323]."}

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I_67194"},{"id":"T4903","span":{"begin":8570,"end":8582},"obj":"CHEBI_67194"},{"id":"T4904","span":{"begin":8362,"end":8372},"obj":"CHEBI_35222"},{"id":"T4905","span":{"begin":8442,"end":8452},"obj":"CHEBI_35222"},{"id":"T4906","span":{"begin":8387,"end":8399},"obj":"CHEBI_69477"},{"id":"T4907","span":{"begin":8404,"end":8419},"obj":"CHEBI_3357"},{"id":"T4908","span":{"begin":8535,"end":8539},"obj":"CHEBI_23888"},{"id":"T4909","span":{"begin":8553,"end":8556},"obj":"CHEBI_72752"},{"id":"T4910","span":{"begin":8601,"end":8604},"obj":"CHEBI_72752"},{"id":"T4911","span":{"begin":8613,"end":8616},"obj":"CHEBI_72752"},{"id":"T4912","span":{"begin":8596,"end":8600},"obj":"CHEBI_37527"},{"id":"T4913","span":{"begin":8596,"end":8600},"obj":"CHEBI_32806"}],"text":"Cannabis\nCannabis and cannabis products are complex polypharmaceuticals, consisting of THC, cannabidiol (CBD), dozens of minor cannabinoids, as well as terpenoids, flavonoids, and other compounds. Fundamentally, THC mimics AEA and 2-AG by acting as an agonist at CB1 and CB2 [279]. But rather than simply substituting for AEA and 2-AG, McPartland and Guy [280] proposed that Cannabis and its many constituents work, in part, by “kick-starting” the eCB system. The acute administration of THC increased CB1 density in rodent brains [281], [282]. Acute upregulation of CB1 mRNA continued for up to 14 days in some rat brain regions [283]. Acute THC also increased the sensitivity of CB1 to cannabinoids, measured by WIN-55,212-2-stimulated [35S]GTPγS binding in rat brains [284]. Lastly, acute THC stimulated AEA biosynthesis [285].\nChronic, high dosing of THC causes a predictable desensitization and downregulation of CB1 and CB2, accompanied by drug tolerance. Chronic THC decreased CB1 density in rodent brains, and dampened cannabinoid-stimulated [35S]GTPγS [282], [284], [286], [287]. CB1 in different regions of the brain downregulate and desensitize at unequal rates and magnitudes, with greatest decreases in the hippocampus and little or no change in the nucleus accumbens and basolateral amygdala. Chronic THC elicited few changes in AEA or 2-AG levels in rat brains, except for a significant augmentation of AEA levels in the limbic forebrain [288].\nSimilar results have been reported in two human studies. Villares [289] collected postmortem brain tissues from known cannabis smokers; [3H]SR141716A binding and CB1 mRNA was downregulated in several brain regions, compared to non-smoking control autopsies. Hirvonen et al. [290] employed PET scan imaging in living subjects. The degree of CB1 downregulation correlated with years of chronic cannabis smoking. CB1 densities returned to normal after four weeks of abstinence. Variable downregulation in different brain regions may explain why frequent users of cannabis develop tolerance to some effects of THC, such as anxiogenesis and cognitive impairment, but not to its euphoric effects [291]. Downregulation is partially epigenetic—the CB1 promoter region in chronic marijuana smokers is hypermethylated, reducing CB1 mRNA expression levels [292].\nTHC acts as a partial agonist of CB1, compared to synthetic cannabinoids which act as full agonists (Table 5). Partial agonism likely explains why exposure to THC caused half as much CB1 desensitization as the full agonist WIN55,212-2 in rat hippocampal neurons [293]. In a study of rat CB1 transfected into AtT20 cells, THC caused less downregulation and internalization than WIN55,212-2 or CP-55,940 [294]. In agreement, drug tolerance studies utilizing the behavioral “tetrad” test show that chronic THC caused less tolerance than the full agonist CP-55,940 in mice [295]. In a study of human CB1 transfected into Xenopus oocytes, the desensitization rate of THC was half that of WIN55,212-2 [296]. However, one [35S]GTPγS autoradiography study of rat brains suggested that chronic THC and WIN55,212-2 caused equal desensitization [297]. Another study indicated that THC acts as a full agonist at mouse GABAergic synapses, with efficacy equal to WIN55,212-2, albeit at fairly high concentrations [298].\n10.1371/journal.pone.0089566.t005 Table 5 Partial agonism of THC at CB1, based on assays of cannabinoid-stimulated signal transduction. If THC is a partial agonist, then THC might functionally antagonize the effects of a full agonist when the two drugs are added together. THC antagonized the effects of WIN55,212-2 in rat brain sections [284], [299], and mouse autaptic hippocampal neurons [300].\nThe capacity of THC to antagonize a full agonist depends, in part, upon ligand affinity—its ability to occupy and hold the CB1 binding site. A meta-analysis of affinity studies calculated a mean Ki = 42.6 nM for THC in rat membranes—much less affinity than that of WIN-55,940, with a Kd = 2.4 nM [22]. This indicates that high concentrations of THC relative to WIN-55,940 are required to antagonize the full agonist. There are species differences—in human membranes, CB1 affinity of THC (Ki = 25.1 nM) is much closer to that of WIN-55,940 (Kd = 16.7).\n2-AG acts as a full agonist at rodent and human CB1 and CB2 [296], [301]–[303]. The emetogenic effects of exogenously-administered 2-AG were blocked by THC [304]. THC dampened or occluded eCB-mediated retrograde signaling of CB1, presumable mediated by 2-AG [300], [305], [306]. Roloff and Thayer [307] demonstrated another complexity in the relationship between THC and 2-AG: neuron firing rate in response to stimulus in rat hippocampal neurons. At low firing rates, THC mimicked 2-AG and behaved like an agonist; at high firing rates, THC antagonized endogenous 2-AG signaling.\nAEA is a partial agonist like THC, with an efficacy somewhat greater than THC in mouse brain [308] and transfected human CB1 [296]. Consistent with partial agonism, exogenously-administered AEA caused little tolerance in rodents [309], [310]. Agonist trafficking adds further complexity—THC and AEA preferentially activate different G-protein subtypes [311]. At transfected human CB1, AEA acted as a full agonist via Gαi subunits, and a partial agonist via Gαo subunits, with agonist efficacy much greater than THC at Gαi, and slightly greater than THC at Gαo [312].\nAEA and THC can antagonize each other; this in part is due to cross-tolerance [313], [314]. Falenski et al. [287] demonstrated that subchronic administration of THC in FAAH−/− knockout mice caused greater tolerance to THC than did subchronic administration of THC in wildtype mice. Thus elevated levels of AEA in FAAH−/− knockouts produced additive effects with THC. Vann et al. [315] trained rats to discriminate THC; trained rats injected with PMSF, which inhibits FAAH, showed 2.7-fold greater discrimination than rats injected with vehicle. In other words, inhibiting AEA degradation led to an increase in the potency of THC. Further, THC was more potent at producing antinociception, decreasing spontaneous activity, and increasing ring immobility when co-administered with PMSF as compared to vehicle.\nIn summary, the effects of THC upon the eCB system oscillate between potentiation and suppression, depending on acute versus chronic dosage. The dividing line between “acute” and “chronic” is a gray zone, and likely differs amongst individuals. Suplita et al. [316] summarized the situation: they studied “stress antinociception,” where rodents become less responsive to painful stimuli following exposure to an environmental stressor. Stress antinociception is mediated, in part, by the coordinated release of 2-AG and AEA. Acute administration of THC potentiated eCB-mediated stress antinociception. The converse was also true: animals exposed acutely to foot shock, which elicits eCB-mediated stress antinociception, became sensitized to the effects of THC. Chronic administration of THC predictably dampened stress antinociception. The converse was not true: chronic exposure to foot shock (3 min/day for 15 days) failed to dampen antinociception induced by either WIN-55,212-2 or by further footshocks.\nThe potential synergy between THC and the eCB system is analogous to the potential synergy between AEA and 2-AG: Rodent studies that combined FAAH and MAGL inhibitors indicated that AEA and 2-AG may activate CB1 receptors in different parts of the central nervous system. Each causes unique behavioral effects, and when both are enhanced, new effects emerge. Long and colleagues [317] showed that AEA and 2-AG independently dampen pain sensation, but together their effects are dramatically enhanced.\nCannabis is more than THC [318], [319]. Adding CBD to THC in mice enhanced CB1 expression in hippocampus and hypothalamus [320]. CBD increased hippocampal cell survival and neurogenesis, whereas THC had the opposite effect; the CBD response was absent in CB1 −/− knockout mice [321]. CBD inhibited the cellular uptake of AEA and its breakdown by FAAH [322], [323]. A separate systematic review regarding the effects of CBD on THC is currently underway (McPartland, unpublished). Several other non-THC cannabinoids interact with enzymes of the eCB system. For example, cannabidivarin and cannabidiolic acid are moderately potent inhibitors of DAGLα, and cannabigerol and cannabichromene are relatively potent inhibitors of anandamide cellular uptake [323]. Interestingly, cannabis extracts (“botanical drug substances,” BDS) enriched in cannabinoids, such as THC-acid BDS and CBD-BDS, were more potent than the corresponding pure compounds at inhibiting MAGL and AEA cellular uptake [323]."}