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Cancer pain seriously affects the life quality of patients. Morphine is commonly used for cancer pain, but tolerance development limits its clinical administration. Central immune signaling is important in the development of cancer pain and morphine tolerance. Cannabinoid receptor 2 (CB2) inhibits cancer pain and morphine tolerance by regulating central immune signaling. In the present study, we investigated the mechanisms of central immune signaling involved in morphine tolerance inhibition by the CB2 agonist AM1241 in cancer pain treatment. Rats were implanted with tumor cells and divided into 4 groups: Vehicle (PBS), 0.07 μg AM1241, 0.03 μg AM1241, and AM630 (10 μg) + AM1241 (0.07 μg). All groups received morphine (20 μg/day, i.t.) for 8 days. AM630 (CB2 antagonist) was intrathecally injected 30 min before AM1241, and AM1241 was intrathecally injected 30 min before morphine. The spinal cord (SC) and dorsal root ganglion (DRG) were collected to determine the expression of Toll-like receptor 4 (TLR4), the p38 mitogen-activated protein kinase (MAPK), microglial markers, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α. The expression of TLR4, p38 MAPK, microglial markers, IL-1β, and TNF-α was significantly higher in AM1241-pretreated groups than in the vehicle group (P < 0.05). No difference in microglial markers, IL-1β, and TNF-α expression was detected in the AM630 + AM1241 group compared with the vehicle group. Our results suggest that in a cancer pain-morphine tolerance model, an i.t. non-analgesic dose of AM1241 induces microglial activation and IL-1β TNF-α upregulation in SC and DRG via the CB2 receptor pathway. Copyright © 2020 Elsevier Inc. All rights reserved.


Chao Ma, Mingyue Zhang, Li Liu, Pinyi Zhang, Dandan Liu, Xiaoyu Zheng, Xuelai Zhong, Guonian Wang. Low-dose cannabinoid receptor 2 agonist induces microglial activation in a cancer pain-morphine tolerance rat model. Life sciences. 2021 Jan 01;264:118635

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PMID: 33131746

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