Abstract
Painful peripheral neuropathy is a dose-limiting complication of chemotherapy. Cisplatin produces a cumulative toxic effect on peripheral nerves, and 30-40% of cancer patients receiving this agent experience pain. By modeling cisplatin-induced hyperalgesia in mice with daily injections of cisplatin (1 mg/kg, i.p.) for 7 d, we investigated the anti-hyperalgesic effects of anandamide (AEA) and cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597), an inhibitor of AEA hydrolysis. Cisplatin-induced mechanical and heat hyperalgesia were accompanied by a decrease in the level of AEA in plantar paw skin. No changes in motor activity were observed after seven injections of cisplatin. Intraplantar injection of AEA (10 μg/10 μl) or URB597 (9 μg/10 μl) transiently attenuated hyperalgesia through activation of peripheral CB₁ receptors. Co-injections of URB597 (0.3 mg/kg daily, i.p.) with cisplatin decreased and delayed the development of mechanical and heat hyperalgesia. The effect of URB597 was mediated by CB₁ receptors since AM281 (0.33 mg/kg daily, i.p.) blocked the effect of URB597. Co-injection of URB597 also normalized the cisplatin-induced decrease in conduction velocity of Aα/Aβ-fibers and reduced the increase of ATF-3 and TRPV1 immunoreactivity in dorsal root ganglion (DRG) neurons. Since DRGs are a primary site of toxicity by cisplatin, effects of cisplatin were studied on cultured DRG neurons. Incubation of DRG neurons with cisplatin (4 μg/ml) for 24 h decreased the total length of neurites. URB597 (100 nM) attenuated these changes through activation of CB₁ receptors. Collectively, these results suggest that pharmacological facilitation of AEA signaling is a promising strategy for attenuating cisplatin-associated sensory neuropathy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Activating Transcription Factor 3 / metabolism
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Animals
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / antagonists & inhibitors
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Arachidonic Acids / pharmacokinetics
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Arachidonic Acids / pharmacology
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Arachidonic Acids / therapeutic use*
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Benzamides / antagonists & inhibitors
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Benzamides / pharmacology
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Benzamides / therapeutic use*
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Cannabinoid Receptor Modulators / pharmacokinetics
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Cannabinoid Receptor Modulators / pharmacology
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Cannabinoid Receptor Modulators / therapeutic use
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Carbamates / antagonists & inhibitors
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Carbamates / pharmacology
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Carbamates / therapeutic use*
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Cells, Cultured
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Cisplatin / adverse effects
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Cisplatin / antagonists & inhibitors*
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Disease Models, Animal
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Drug Interactions
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Endocannabinoids
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / metabolism
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Hyperalgesia / chemically induced
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Hyperalgesia / drug therapy*
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Male
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Mice
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Mice, Inbred C3H
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Morpholines / pharmacology
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Motor Activity / drug effects
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Neurites / drug effects
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Neurotoxicity Syndromes / drug therapy*
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Peripheral Nervous System Diseases / chemically induced
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Peripheral Nervous System Diseases / drug therapy*
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Polyunsaturated Alkamides / pharmacokinetics
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Polyunsaturated Alkamides / pharmacology
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Polyunsaturated Alkamides / therapeutic use*
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Pyrazoles / pharmacology
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Receptor, Cannabinoid, CB1 / agonists*
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TRPV Cation Channels / metabolism
Substances
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Activating Transcription Factor 3
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Antineoplastic Agents
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Arachidonic Acids
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Atf3 protein, mouse
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Benzamides
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Cannabinoid Receptor Modulators
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Carbamates
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Endocannabinoids
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Enzyme Inhibitors
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Morpholines
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Polyunsaturated Alkamides
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Pyrazoles
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Receptor, Cannabinoid, CB1
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TRPV Cation Channels
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TRPV1 protein, mouse
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cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
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Cisplatin
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AM 281
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anandamide