Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy

Iryna Khasabova, Sergey Khasabov, Justin Paz, Catherine A Harding-Rose, Donald A Simone, Virginia S Seybold

Research output: Contribution to journalArticle

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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 cyclohexylcar-bamic 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 (9μg/10μl) transiently attenuated hyperalgesia through activation of peripheral CB 1 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 CB 1 receptors. Collectively, these results suggest that pharmacological facilitation of AEA signaling is a promising strategy for attenuating cisplatin-associated sensory neuropathy.

Original languageEnglish (US)
Pages (from-to)7091-7101
Number of pages11
JournalJournal of Neuroscience
Volume32
Issue number20
DOIs
StatePublished - May 16 2012

Fingerprint

Cannabinoid Receptors
Cisplatin
Drug Therapy
Pain
Hyperalgesia
Spinal Ganglia
Injections
Neurons
Hot Temperature
Cannabinoid Receptor CB1
Poisons
Diagnosis-Related Groups
Proxy
Peripheral Nervous System Diseases
Neurites
cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
Peripheral Nerves
Esters
Motor Activity
Hydrolysis

Cite this

Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. / Khasabova, Iryna; Khasabov, Sergey; Paz, Justin; Harding-Rose, Catherine A; Simone, Donald A; Seybold, Virginia S.

In: Journal of Neuroscience, Vol. 32, No. 20, 16.05.2012, p. 7091-7101.

Research output: Contribution to journalArticle

Khasabova, Iryna ; Khasabov, Sergey ; Paz, Justin ; Harding-Rose, Catherine A ; Simone, Donald A ; Seybold, Virginia S. / Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 20. pp. 7091-7101.
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