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Antiemetic and motor-depressive actions of CP55,940: cannabinoid CB1 receptor characterization, distribution, and G-protein activation.

Abstract

Dibenzopyran (Delta(9)-tetrahydrocannabinol) and aminoalkylindole [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate; (WIN55,212-2)] cannabinoids suppress vomiting produced by cisplatin via cannabinoid CB(1) receptors. This study investigates the antiemetic potential of the "nonclassical" cannabinoid CP55,940 [1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol] against cisplatin-induced vomiting and assesses the presence and functionality of cannabinoid CB(1) receptors in the least shrew (Cryptotis parva) brain. CP55,940 (0.025-0.3 mg/kg) reduced both the frequency of cisplatin-induced emesis (ID(50)=0.025 mg/kg) and the percentage of shrews vomiting (ID(50)=0.09 mg/kg). CP55,940 also suppressed shrew motor behaviors (ID(50)=0.06- 0.21 mg/kg) at such doses. The antiemetic and motor-suppressant actions of CP55,940 were countered by SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], indicating both effects are cannabinoid CB(1) receptor-mediated. Autoradiographic studies with [3H]-SR141716A and [35S]-GTPgammaS binding revealed that the distribution of the cannabinoid CB(1) receptor and its activation pattern are similar to rodent brain and significant levels are present in brain loci (e.g., nucleus tractus solitarius (NTS)) that control emesis. The affinity rank order of structurally diverse cannabinoid ligands for cannabinoid CB(1) receptor in shrew brain is similar to rodent brain: HU-210=CP55,940=SR141716A>/=WIN55,212-2>/=delta-9-tetrahydrocannabinol>methanandamide=HU-211=cannabidiol=2-arachidonoylglycerol. This affinity order is also similar and is highly correlated to the cannabinoid EC(50) potency rank order for GTPgammaS stimulation except WIN55,212-2 and delta-9-tetrahydrocannabinol potency order were reversed. The affinity and the potency rank order of tested cannabinoids were significantly correlated with their antiemetic ID(50) potency order against cisplatin-induced vomiting (CP55,940>WIN55,212-2=delta-9-tetrahydrocannabinol) as well as emesis produced by 2-arachidonoylglycerol or SR141716A (CP55,940>WIN55,212-2>delta-9-tetrahydrocannabinol).

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, Kirksville College of Osteopathic Medicine, 800 W. Jefferson Street, Kirksville, MO 63501, USA. ndarmani@kcom.edu

    , , , , ,

    Source

    European journal of pharmacology 459:1 2003 Jan 10 pg 83-95

    MeSH

    Animals
    Antiemetics
    Benzoxazines
    Binding, Competitive
    Brain
    Cisplatin
    Cyclohexanols
    Dose-Response Relationship, Drug
    Dronabinol
    Female
    GTP-Binding Proteins
    Guanosine 5'-O-(3-Thiotriphosphate)
    Injections, Intraperitoneal
    Injections, Subcutaneous
    Male
    Morpholines
    Motor Activity
    Naphthalenes
    Piperidines
    Pyrazoles
    Radioligand Assay
    Receptors, Cannabinoid
    Receptors, Drug
    Rimonabant
    Shrews
    Sulfur Radioisotopes
    Tritium
    Vomiting

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    12505537

    Citation

    Darmani, Nissar A., et al. "Antiemetic and Motor-depressive Actions of CP55,940: Cannabinoid CB1 Receptor Characterization, Distribution, and G-protein Activation." European Journal of Pharmacology, vol. 459, no. 1, 2003, pp. 83-95.
    Darmani NA, Sim-Selley LJ, Martin BR, et al. Antiemetic and motor-depressive actions of CP55,940: cannabinoid CB1 receptor characterization, distribution, and G-protein activation. Eur J Pharmacol. 2003;459(1):83-95.
    Darmani, N. A., Sim-Selley, L. J., Martin, B. R., Janoyan, J. J., Crim, J. L., Parekh, B., & Breivogel, C. S. (2003). Antiemetic and motor-depressive actions of CP55,940: cannabinoid CB1 receptor characterization, distribution, and G-protein activation. European Journal of Pharmacology, 459(1), pp. 83-95.
    Darmani NA, et al. Antiemetic and Motor-depressive Actions of CP55,940: Cannabinoid CB1 Receptor Characterization, Distribution, and G-protein Activation. Eur J Pharmacol. 2003 Jan 10;459(1):83-95. PubMed PMID: 12505537.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Antiemetic and motor-depressive actions of CP55,940: cannabinoid CB1 receptor characterization, distribution, and G-protein activation. AU - Darmani,Nissar A, AU - Sim-Selley,Laura J, AU - Martin,Billy R, AU - Janoyan,Jano J, AU - Crim,Jennifer L, AU - Parekh,Bavita, AU - Breivogel,Christopher S, PY - 2002/12/31/pubmed PY - 2003/5/6/medline PY - 2002/12/31/entrez SP - 83 EP - 95 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 459 IS - 1 N2 - Dibenzopyran (Delta(9)-tetrahydrocannabinol) and aminoalkylindole [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate; (WIN55,212-2)] cannabinoids suppress vomiting produced by cisplatin via cannabinoid CB(1) receptors. This study investigates the antiemetic potential of the "nonclassical" cannabinoid CP55,940 [1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol] against cisplatin-induced vomiting and assesses the presence and functionality of cannabinoid CB(1) receptors in the least shrew (Cryptotis parva) brain. CP55,940 (0.025-0.3 mg/kg) reduced both the frequency of cisplatin-induced emesis (ID(50)=0.025 mg/kg) and the percentage of shrews vomiting (ID(50)=0.09 mg/kg). CP55,940 also suppressed shrew motor behaviors (ID(50)=0.06- 0.21 mg/kg) at such doses. The antiemetic and motor-suppressant actions of CP55,940 were countered by SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], indicating both effects are cannabinoid CB(1) receptor-mediated. Autoradiographic studies with [3H]-SR141716A and [35S]-GTPgammaS binding revealed that the distribution of the cannabinoid CB(1) receptor and its activation pattern are similar to rodent brain and significant levels are present in brain loci (e.g., nucleus tractus solitarius (NTS)) that control emesis. The affinity rank order of structurally diverse cannabinoid ligands for cannabinoid CB(1) receptor in shrew brain is similar to rodent brain: HU-210=CP55,940=SR141716A>/=WIN55,212-2>/=delta-9-tetrahydrocannabinol>methanandamide=HU-211=cannabidiol=2-arachidonoylglycerol. This affinity order is also similar and is highly correlated to the cannabinoid EC(50) potency rank order for GTPgammaS stimulation except WIN55,212-2 and delta-9-tetrahydrocannabinol potency order were reversed. The affinity and the potency rank order of tested cannabinoids were significantly correlated with their antiemetic ID(50) potency order against cisplatin-induced vomiting (CP55,940>WIN55,212-2=delta-9-tetrahydrocannabinol) as well as emesis produced by 2-arachidonoylglycerol or SR141716A (CP55,940>WIN55,212-2>delta-9-tetrahydrocannabinol). SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/12505537/Antiemetic_and_motor_depressive_actions_of_CP55940:_cannabinoid_CB1_receptor_characterization_distribution_and_G_protein_activation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014299902028157 DB - PRIME DP - Unbound Medicine ER -