Abstract
There is substantial clinical evidence that Δ9-tetrahydrocannabinol (Δ9-THC) and its synthetic analogs (nabilone and levonantradol) can prevent emesis in cancer patients receiving chemotherapy. Limited available animal studies also support the antiemetic potential of these cannabinoids. The present study investigates the mechanism of antiemetic action of cannabinoids in an established animal model of emesis, the least shew (Cryptotis parva). Since cannabinoid agonists prevent emesis, it was hypothesized that blockade of either the cannabinoid CB1 receptor or the cannabinoid CB2 receptor would induce vomiting. Thus, the emetic potential of SR 141716A (CB1 receptor antagonist) or SR 144528 (CB2 receptor antagonist) was investigated. Both intraperitoneal (0, 1, 2.5, 5, 10 and 20 mg/kg, n = 7–15 per group) and subcutaneous (0, 10, 20 and 40 mg/kg, n = 6–9 per group) administration of SR 141716A caused emesis (ED50 = 5.52 ± 1.23 and 20.2 ± 1.02 mg/kg, respectively) in the least shrew in a dose-dependent manner. Indeed, both the frequency of emesis and the percentage of animals vomiting increased with increasing doses of SR 141716A. Significant effects were seen at the 10- and 20-mg/kg doses for the IP route, while only the 40-mg/kg dose produced significant emesis via the SC route. The CB2 antagonist failed to produce emesis via either route of administration. SR 141716A at an IP dose of 20 mg/kg was used to induce emesis for drug interaction studies. Thus, varying doses of three different classes of cannabinoid agonists [CP 55, 940 (0, 0.1, 0.5 and 1 mg/kg), WIN 55, 212-2 (0, 1, 5 and 10 mg/kg), and Δ9-THC (0, 5, 10 and 20 mg/kg)], were administered IP to different groups of shrews 10 min prior to SR 141716A injection. The frequency of emesis was recorded for 30 min following the administration of SR 141716A. The order of potency for redcing both the frequency of emesis and the percentage of shrews vomiting was CP 55, 940 > WIN 55, 212-2 > Δ9-THC which is consistent with an action on the CB1 receptor. These results suggest that the antiemetic activity of Δ9-THC and its synthetic analogs reside in their ability to stimulate the cannabinoid CB1 receptor. Furthermore, the antiemetic potency of CP 55, 940 is 45 times greater than Δ9-THC. On the other hand, blockade of CB1 receptors can induce vomiting, which implicates an important role for endogenous cannabinoids in emetic circuits.
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References
Abood ME, Martin BR . (1992): Neurobiology of marijuana abuse. Trends Pharmacol Sci 13: 201–206
Abrahamov AS, Abrahamov A, Mechoulam R . (1995): An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci 56: 2097–2102
Aceto MD, Scates SM, Razdan RJ, Martin BR . (1998): Anandamide, an endogenous cannabinoid, has very low physical dependence potential. J Pharmacol Exp Therap 287: 598–605
Calignano A, La Rana G, Makriyannis A, Lyn SY, Betramo M, Piomelli D . (1997): Inhibition of intestinal motility by anandamide, an endogenous cannabinoid. Eur J Pharmacol 340: R7–R8
Chan HSL, Correia JA, Macleod SM . (1987): Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: A double blind, crossover trial. Pediatrics 79: 946–952
Churchfield S . (1990): The Natural History of Shrews. Ithaca NY, Cornell University Press, Comstock Publishing Associates.
Colombo G, Agabio R, Lobina C, Reali R, Gessa GL . (1998): Cannabinoid modulation of intestinal propulsion in mice. Eur J Pharmacol 344: 67–69
Compton DR, Aceto MD, Lowe J, Martin BR . (1996): In vivo characterization of a specific cannabinoid receptor antagonist (SR 141716A). Inhibition of Δ9-tetrahydrocannabinol-induced responses and apparent agonist activity. J Pharmacol Exp Therap 277: 586–594
Cook SA, Lowe JA, Martin BR . (1998): CB1 receptor antagonist precipitates withdrawal in mice exposed to Δ9-tetrahydrocannabinol. J Pharmacol Exp Therap 285: 1150–1156
Dalzell AM, Bartlett H, Lilleyman JS . (1986): Nabilone: an alternative antiemetic for cancer chemotherapy. Arch Disease Childhood 161: 502–505
Darmani NA . (2000): Δ9-Tetrahydrocannabinol prevents chemotherapy-induced vomiting via activation of cannabinoid CB1 receptors. Soc Neurosci Abs 26 (part 2): P2160
Darmani NA . (1998): Serotonin 5-HT3 receptor antagonists prevent cisplatin-induced emesis in Cryptotis parva: A new experimental model of emesis. J Neural Transm 105: 1143–1154
Darmani NA, Pandya DK . (2000): Involvement of other neurotransmitters in behaviors induced by the cannabinoid CB1 receptor antagonist SR 141716A in naive mice. J Neural Transm 107: 931–945
Darmani NA, Zhao W, Ahmad B . (1999): The role of D2 and D3 dopamine receptors in the mediation of emesis in Cryptotis parva (the least shew). J Neural Transm 106: 1045–1061
Feigenbaum JJ, Richmond SA, Weissman Y, Mechoulam R . (1989): Inhibition of cisplatin-induced emesis in the pegeon by a nonpsychotropic synthetic cannabinoid. Eur J Pharmacol 169: 159–165
Gralla RA . (1999): Cannabinoids and the control of chemotherapy-induced nausea and vomiting. In Nahas GG, Sutin KM, Harvey DJ, Agurell S (eds), Marijuana and Medicine. Totowa, NJ, Humana Press, pp 599–610
Izzo AA, Mascolo N, Borrelli F, Capasso F . (1999): Defecation, intestinal fluid accumulation and motility in rodents: Implications of cannabinoid CB1 receptors. Naunyn-Schmied Arch Pharmacol 359: 65–70
Krowicki ZK, Moerschbaecher JM, Winsauer PJ, Digavalli SV, Hornby PJ . (1999): Δ9-Tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB1 receptors. Eur J Pharmacol 371: 187–196
Lehmann A, Karrberg L . (1996): Effects of N-methyl-D-aspartate receptor antagonists on cisplatin-induced emesis in the ferret. Neuropharmacology 35: 475–481
London SW, McCarthy LE, Borison HL . (1979): Suppression of cancer chemotherapy-induced vomiting in the cat by nabilone, a synthetic cannabinoid. Pro Soc Exp Biol Med 160: 437–440
Lucot JB . (1998): Effects of N-methyl-D-aspartate antagonists on different measures of motion sickness in cats. Brain Res 47: 407–411
Matsuda LA . (1997): Molecular aspects of cannabinoid receptors. Critical Rev Neurobiology 11: 143–166
Matsuki N, Ueno S, Kaji T, Ishihara A, Wang C-H, Saito H . (1988): Emesis induced by cancer chemotherapeutic agents in the Suncus murinus: A new experimental model. Jpn J Pharmacol 48: 303–306
McCarthy LE, Borison HL . (1981): Antiemetic activity of N-methyllevonantradol and nabilone in cisplatin-treated cats. J Clin Pharmacol 21: 30S–37S
McCarthy LE, Flora KP, Vishnuvajjala R . (1984): Antiemetic properties and plasma concentrations of delta-9-tetrahydrocannabinol against cisplatin vomiting in cats. In Agurell S, Dewey WL, Willette RD (eds), The Cannabinoids: Chemical, Pharmacological and Therapeutic Aspects. London, Academic Press, pp 895–902
Naylor RJ, Rudd JA . (1996): Mechanisms of chemotherapy/radiotherapy-induced emesis in animal models. Oncology 53(Suppl 1): 8–17
Pertwee RG . (1997): Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Therap 74: 129–180
Rinaldi-Carmona M, Barth F, Healume M, Shire D, Calandra G, Congy C, Martinez S, Maruani J, Néliat G, Caput D, Ferrara P, Soubrie P, Breliere J-C, Le Fur G . (1994): SR 141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350: 240–244
Rinaldi-Carmona M, Barth F, Millan J, Derocq JM, Casellas P, Congy C, Oustric D, Sanran M, Bouaboula M, Calandra P, Portier M, Shire D, Breliere IC, Le Fur JL . (1998): SR 144528, the first potent and selective antagonist of CB2 cannabinoid receptor. J Pharmacol Exp Therap 284: 644–650
Rubino T, Patrini G, Massi P, Fuzio D, Vigano D, Giagnoni G, Parolaro D . (1998): Cannabinoid-precipitated withdrawal: A time-course study of the behavioral aspect and its correlation with cannabinoid receptors and G-protein expression. J Pharmacol Exp Therap 285: 813–819
Shook JE, Burks TF . (1989): Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents. J Pharmacol Exp Therap 249: 444–449
Stark P . (1982): The pharmacologic profile of nabilone: A new antiemetic agent. Cancer Treat Rev 9(Suppl B): 11–16
Torii Y, Saito H, Matsuki N . (1991): Selective blockade of cytotoxic drug-induced emesis by 5-HT3 receptor antagonists in Suncus murinus. Jpn J Pharmacol 55: 107–113
Voth EA, Schwartz RH . (1997): Medicinal application of delta-9-tetrahydrocannabinol and marijuana. Annals Inter Med 126: 791–798
Acknowledgements
This work was supported by a grant from the National Institute on Drug Abuse (DA 0767). The author would like to thank R. Chronister for typing the manuscript.
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Darmani, N. Δ9-Tetrahydrocannabinol and Synthetic Cannabinoids Prevent Emesis Produced by the Cannabinoid CB1 Receptor Antagonist/Inverse Agonist SR 141716A. Neuropsychopharmacol 24, 198–203 (2001). https://doi.org/10.1016/S0893-133X(00)00197-4
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DOI: https://doi.org/10.1016/S0893-133X(00)00197-4
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