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- Title
Cannabinoid Type-1 Receptor Reduces Pain and Neurotoxicity Produced by Chemotherapy.
- Authors
Khasabova, Iryna A.; Khasabov, Sergey; Paz, Justin; Harding-Rose, Catherine; Simone, Donald A.; Seybold, Virginia S.
- 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 (10µg/10µl) or URB597 (9µg/10µl) 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 (4µg/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.
- Subjects
CANNABINOID receptors; PAIN; NEUROTOXICOLOGY; NEUROPATHY; CANCER chemotherapy; CANCER patients; CISPLATIN
- Publication
Journal of Neuroscience, 2012, Vol 32, Issue 20, p7091
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0403-12.2012