Abstract
The endogenous ligand for the cannabinoid receptor, arachidonylethanolamide (anandamide), has been shown to produce antinociception using the tail-flick test following intrathecal administration. Anandamide was administered i.p. (40 mg kg) to mice four times per day for 3 days. Tolerance developed to anandamide: the ED50 for anandamide (i.t.) was shifted from 40 (26-61) to 139 (79-248) micrograms/mouse. Anandamide-tolerant mice were cross-tolerant to delta 9-THC and CP55,940, but not cross-tolerant to mu-, delta- or kappa- opioids, including dynorphins. Conversely, delta 9-THC-tolerant mice are cross-tolerant to anandamide, CP55,940 and kappa agonists. Our data indicate that anandamide and delta 9-THC differ in the mechanisms by which they induce tolerance, in particular the interaction with endogenous dynorphinergic systems.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Analgesics / pharmacology*
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Animals
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Arachidonic Acids / administration & dosage
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Arachidonic Acids / pharmacology*
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Cannabinoids / administration & dosage
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Cannabinoids / pharmacology*
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Cyclohexanols / pharmacology
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Dose-Response Relationship, Drug
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Dronabinol / pharmacology*
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Drug Tolerance
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Dynorphins / metabolism*
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Endocannabinoids
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Injections, Intraperitoneal
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Injections, Spinal
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Mice
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Naltrexone / analogs & derivatives
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Naltrexone / pharmacology
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Narcotic Antagonists / pharmacology
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Pain Measurement / drug effects
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Polyunsaturated Alkamides
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Receptors, Cannabinoid
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Receptors, Drug / drug effects*
Substances
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Analgesics
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Arachidonic Acids
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Cannabinoids
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Cyclohexanols
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Endocannabinoids
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Narcotic Antagonists
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Polyunsaturated Alkamides
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Receptors, Cannabinoid
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Receptors, Drug
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norbinaltorphimine
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Naltrexone
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Dynorphins
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Dronabinol
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3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
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anandamide