Binding of the non-classical cannabinoid CP 55,940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors

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

doi:10.1016/s0024-3205(97)00690-5

Cited by 132 publications

(90 citation statements)

References 11 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.

Self Cite

438

308

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“…Indeed, in a detailed hemodynamic study in anesthetized rats (Bátkai et al, 2004b), the acute hypotensive effect of LPS could be attributed to decreased cardiac contractility rather than decreased TPR, and it could be inhibited by SR141716, but not by AM251, an antagonist equipotent with SR141716 at CB 1 receptors (Gatley et al, 1997) but lacking inhibitory potency at SR141716-sensitive endothelial and myocardial receptors (Fig. 3) (Ford et al, 2002;Ho and Hiley, 2003;O'Sullivan et al, 2004).…”

Section: Role Of the Endocannabinergic System In The Hypotension Assomentioning

confidence: 99%

Blood pressure regulation by endocannabinoids and their receptors

2005

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Cannabinoids and their endogenous and synthetic analogs exert powerful hypotensive and cardiodepressor effects by complex mechanisms involving direct and indirect effects on myocardium and vasculature. On the one hand, endocannabinoids and cannabinoid receptors have been implicated in the hypotensive state associated with hemorrhagic, endotoxic and cardiogenic shock, and advanced liver cirrhosis. On the other hand, there is emerging evidence suggesting that the endocannabinergic system plays an important role in the cardiovascular regulation in hypertension. This review is aimed to discuss the in vivo hypotensive and cardiodepressant effects of cannabinoids mediated by cannabinoid and TRPV 1 receptors, and focuses on the novel therapeutical strategies offered by targeting the endocannabinoid system in the treatment of hypertension.

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“…Next, we investigated the effects of the cannabinoid inverse agonist AM281 (23), an analog of SR141716A (Rimonabant). AM281 is able to antagonize endocytosis induced by the agonist WIN (Fig.…”

Section: Cb1-egfp Is Functional and Displays A Predominantly Intracelmentioning

confidence: 99%

Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor

Leterrier

Bonnard

Carrel

et al. 2004

Journal of Biological Chemistry

216

234

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The CB1 cannabinoid receptor (CB1R) displays a significant level of ligand-independent (i.e. constitutive) activity, either when heterologously expressed in nonneuronal cells or in neurons where CB1Rs are endogenous. The present study investigates the consequences of constitutive activity on the intracellular trafficking of CB1R. When transfected in HEK-293 cells, CB1R is present at the plasma membrane, but a substantial proportion (ϳ85%) of receptors is localized in intracellular vesicles. Detailed analysis of CB1-EGFP expressed in HEK-293 cells shows that the intracellular CB1R population is mostly of endocytic origin and that treatment with inverse agonist AM281 traps CB1R at the plasma membrane through a monensin-sensitive recycling pathway. Co-transfection with dominant positive or dominant negative mutants of the small GTPases Rab5 and Rab4, but not Rab11, profoundly modifies the steady-state and ligand-induced intracellular distribution of CB1R, indicating that constitutive endocytosis is Rab5-dependent, whereas constitutive recycling is mediated by Rab4. In conclusion, our results indicate that, due to its natural constitutive activity, CB1R permanently and constitutively cycles between plasma membrane and endosomes, leading to a predominantly intracellular localization at steady state.

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Binding of the non-classical cannabinoid CP 55,940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors

Cited by 132 publications

References 11 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

Blood pressure regulation by endocannabinoids and their receptors

Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor

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Binding of the non-classical cannabinoid CP 55,940, and the diarylpyrazole AM251 to rodent brain cannabinoid receptors

Cited by 132 publications

References 11 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

Blood pressure regulation by endocannabinoids and their receptors

Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor

Contact Info

Product

Resources

About

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