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 days, we investigated the antihyperalgesic effects of anandamide (AEA) and 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 7 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 TRPV-1 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.

Organ-specific antitoxic effects of N-stearoilethanolamine male mice with lewis carcinoma under indoxorubicin intoxication

“…Так, один із представників ендоканабіноїдів -анандамід -здатен зменшувати нейро-токсичність цитостатиків [18]. У попередніх роботах нашого відділу було показано, що N-стеароїлетаноламін (NSE), насичений пред-ставник ендоканабіноїдів, гальмує ріст та метастазування карциноми Льюїс у мишей в умовах його введення на різних стадіях роз-витку пухлини [19,20].…”

Assessment and Treatment of Chemotherapy-induced Peripheral Neuropathy- a Physical Therapy Perspective

“…Acety-L-Carnitine [65], Alpha-lipoic acid [66], Amifostine [67], cholest-4-en-3-one, oxime (TRO19622) [68], Cannabinoid type-1 receptor [69], Gabapentin [70], Glutamine [71], Lamotrigine [72], recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) [73], Neurosteroids [74], Palmitoylethanolamide [75] and Retinoic acid [76] were studied individually for their efficacy in randomized clinical trials.…”

Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications

“…been several investigations in which a selective CB 1 or CB 2 receptor antagonist (17,23,24,50,51) , or genetic deletion of the CB 1 receptor (52) , has been found to attenuate signs of antinociception induced by URB597, PF3845 or ST4070 in rodent models of visceral, inflammatory or neuropathic pain. In two of these investigations, however, the TRPV1 antagonist, 5…”