title: Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy.
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.
authors.affiliation: Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Iryna A
authors.initials: IA
authors.lastname: Khasabova
authors.forename: Sergey
authors.initials: S
authors.lastname: Khasabov
authors.forename: Justin
authors.initials: J
authors.lastname: Paz
authors.forename: Catherine
authors.initials: C
authors.lastname: Harding-Rose
authors.forename: Donald A
authors.initials: DA
authors.lastname: Simone
authors.forename: Virginia S
authors.initials: VS
authors.lastname: Seybold
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors; D001095:Arachidonic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D063385:Cannabinoid Receptor Modulators / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002219:Carbamates / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004347:Drug Interactions; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D016501:Neurites / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000188:drug therapy*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy*; D053284:Polyunsaturated Alkamides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; D001095:Arachidonic Acids; C103002:Atf3 protein, mouse; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D009025:Morpholines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D002945:Cisplatin; C109925:AM 281; C078814:anandamide