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This research was supported by MCIN/AEI/10.13039/501100011033 (PID2019-111510RB-I00), Asociacion Espanola de Gastroenterologia-Asociacion Espanola de Neurogastroenterologia y Motilidad (Beca AEG-ASENEM, 2021), and the Irish Research Council (IRCL/2017/78). MAH was supported by a grant to ALB from Enterprise Ireland (Programme H2020 Proposal Preparation Support, CS20192034).

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The Endocannabinoid System of the Nervous and Gastrointestinal Systems Changes after a Subnoxious Cisplatin Dose in Male Rats

Publicado en:Pharmaceuticals. 17 (10): 1256- - 2024-10-01 17(10), DOI: 10.3390/ph17101256

Autores: Lopez-Tofino, Yolanda; Hopkins, Mary A; Bagues, Ana; Boullon, Laura; Abalo, Raquel; Llorente-Berzal, Alvaro

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Background/Objectives: Cisplatin, a common chemotherapy agent, is well known to cause severe side effects in the gastrointestinal and nervous systems due to its toxic and pro-inflammatory effects. Although pharmacological manipulation of the endocannabinoid system (ECS) can alleviate these side effects, how chemotherapy affects the ECS components in these systems remains poorly understood. Our aim was to evaluate these changes. Methods: Male Wistar rats received cisplatin (5 mg/kg, i.p.) or saline on day 0 (D0). Immediately after, serial X-rays were taken for 24 h (D0). Body weight was recorded (D0, D1, D2 and D7) and behavioural tests were performed on D4. On D7, animals were euthanized, and gastrointestinal tissue, dorsal root ganglia (DRGs) and brain areas were collected. Expression of genes related to the ECS was assessed via Rt-PCR, while LC-MS/MS was used to analyse endocannabinoid and related N-acylethanolamine levels in tissue and plasma. Results: Animals treated with cisplatin showed a reduction in body weight. Cisplatin reduced gastric emptying during D0 and decreased MAGL gene expression in the antrum at D7. Despite cisplatin not causing mechanical or heat sensitivity, we observed ECS alterations in the prefrontal cortex (PFC) and DRGs similar to those seen in other chronic pain conditions, including an increased CB1 gene expression in L4/L5 DRGs and a decreased MAGL expression in PFC. Conclusions: A single dose of cisplatin (5 mg/kg, i.p.), subnoxious, but capable of inducing acute gastrointestinal effects, caused ECS changes in both gastrointestinal and nervous systems. Modulating the ECS could alleviate or potentially prevent chemotherapy-induced toxicity.

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