123I-labeled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors

Gatley, S. John; Gifford, Andrew N.; Volkow, Nora D.; Lan, Ruoxi; Makriyannis, Alexandros

doi:10.1016/0014-2999(96)00279-8

Cited by 234 publications

(136 citation statements)

References 5 publications

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“…AM630 is a CB 2 receptor-selective antagonist with 70-to 165-fold selectivity for binding to the CB 2 receptor in vitro (18,19). AM251 is a 300-fold selective CB 1 receptor antagonist (20,21). Drugs were administered i.p.…”

Section: Methodsmentioning

confidence: 99%

Activation of CB ₂ cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

Ibrahim

Deng

Zvonok

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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438

308

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We designed AM1241, a selective CB2 cannabinoid receptor agonist, and used it to test the hypothesis that CB2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB 2 receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB 2 but not by a CB1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB 2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB 1 receptors (CB1 ؊/؊ mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB 1 receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB 2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB 2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications. N europathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (1). It affects Ϸ1% of the population and results from a variety of etiologies including trauma, infection, diabetes, immune deficiencies, ischemic disorders, and toxic neuropathies (1, 2). It can be excruciating, and some patients are unable to work or to perform normal daily activities. Neuropathic pain often responds poorly to medical therapy (3,4). This may be due, in part, to adverse side effects of available medications that limit drug dosage (5). Medications currently used for the treatment of neuropathic pain act on neurotransmitter systems or ion channels and typically produce significant CNS side effects. For example, gabapentin, a drug commonly used to treat neuropathic pain because of its modest side effect profile compared with other therapeutic options, produces somnolence in 19% of patients and dizziness in 17% (Neurontin prescribing information, Parke-Davis). A therapy directed at targets not found in the CNS would avoid these problems. CB 2 cannabinoid receptors are one such potential target.CB 2 receptor mRNA is not detected in brain (6, 7). In addition, the CB 2 receptor-selective antagonist SR144528 did not displace the nonselective cannabinoid ligand [ 3 H]CP55,940 from binding to rat brain (7). Finally, binding of [ 3 H]CP55,940 to mouse brain was eliminated by disruption of the CB 1 receptor gene (8) but was not affected by disruption of the CB 2 receptor gene (9). These studies suggest that CB 2 receptors are not found in the normal CNS, although they do not fully exclude the possibility that CB 2 receptors are expressed in the CNS in small, but functionally signi...

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Section: Methodsmentioning

confidence: 99%

Activation of CB ₂ cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

Ibrahim

Deng

Zvonok

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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438

308

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“…Interestingly, when cognitive performance was tested, most cannabinoids demonstrated certain impairing effects on a diverse array of learning and memory tests [5,6]. On the other hand, the generation of selective antagonists for different cannabinoid receptors, such as SR141716A (rimonabant) [7] and AM251 [8] for the CB1 cannabinoid receptor (CB1R) subtype, and SR144528 [9] and AM630 [10] for the CB2 cannabinoid receptor (CB2R) subtype, represents excellent tools to characterize the role of specific components of the endocannabinoid system (ECS) in cognition. In this regard, several of these antagonists have shown memory-improving capabilities in spatial and operant paradigms, further supporting the role of the ECS in cognitive function [11,12].…”

Section: Natural and Synthetic Cannabinoids Affecting Cognitionmentioning

confidence: 99%

Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

Puighermanal

Busquets-García

Maldonado

et al. 2012

Phil. Trans. R. Soc. B

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Exogenous cannabinoids, such as delta9-tetrahydrocannabinol (THC), as well as the modulation of endogenous cannabinoids, affect cognitive function through the activation of cannabinoid receptors. Indeed, these compounds modulate a number of signalling pathways critically implicated in the deleterious effect of cannabinoids on learning and memory. Thus, the involvement of the mammalian target of rapamycin pathway and extracellular signal-regulated kinases, together with their consequent regulation of cellular processes such as protein translation, play a critical role in the amnesic-like effects of cannabinoids. In this study, we summarize the cellular and molecular mechanisms reported in the modulation of cognitive function by the endocannabinoid system.

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“…with 30 mg/kg of the CB1 antagonist, AM-251(Tocris Bioscience, Ellisville, MO), dissolved in DMSO, Tween-80, ethanol and 0.9% saline or vehicle as previously described [2,59]. AM-251 peak brain concentrations have previously been observed at 30 minutes post injection and 30 mg/kg is a dosage at which a plateau in brain to plasma ratio is reached [17,59].…”

Section: Pretreatment With the Cb1 Receptor Antagonist Am-251mentioning

confidence: 99%

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

Toscano

Ueda

Tomita

et al. 2008

Brain Research Bulletin

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Excitotoxicity involves over activation of brain excitatory glutamate receptors and has been implicated in neurological, neurodegenerative and neuropsychiatric diseases. Metabolism of arachidonic acid (AA) through the phospholipase A 2 (PLA 2 )/ prostaglandin-endoperoxide synthase (PTGS) pathway is increased after excitotoxic stimulation. However, the individual roles of the PTGS isoforms in this process are not well established. We assessed the role of the PTGS isoforms in the process of excitotoxicity by exposing mice deficient in either PTGS-1 (PTGS-1 -/-) or PTGS-2 (PTGS-2 -/-) to the rototypic excitotoxin, kainic acid (KA). Seizure intensity and neuronal damage were significantly elevated in KA-exposed PTGS-2 -/-, but not in PTGS-1 -/-, mice. The increased susceptibility was not associated with an alteration in KA receptor binding activity or mediated through the CB1 endocannabinoid receptor. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was decreased in the CA1 pyramidal neurons of PTGS-2 -/-mice, suggesting an alteration of GABAergic function. In wild-type mice, six weeks treatment with the PTGS-2 selective inhibitor celecoxib recapitulated the increased susceptibility to KA-induced excitotoxicity observed in PTGS-2 -/-mice, further supporting the role of PTGS-2 in the excitotoxic process. The increased susceptibility to KA was also associated with decreased brain levels of PGE 2 , a biomarker of PTGS-2 activity. Our results suggest that PTGS-2 activity and its specific products may modulate neuronal excitability by affecting GABAergic neurotransmission. Further, inhibition of PTGS-2 but not PTGS-1, may increase the susceptibility to seizures.

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123I-labeled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors

Cited by 234 publications

References 5 publications

Activation of CB ₂ cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

Activation of CB ₂ cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

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123I-labeled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors

Cited by 234 publications

References 5 publications

Activation of CB 2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

Activation of CB 2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

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Activation of CB ₂ cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

Activation of CB ₂ cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS