PMID- 34792764 OWN - NLM STAT- MEDLINE DCOM- 20220330 LR - 20220330 IS - 1476-3524 (Electronic) IS - 1029-8428 (Linking) VI - 39 IP - 6 DP - 2021 Dec TI - Endocannabinoid System Attenuates Oxaliplatin-Induced Peripheral Sensory Neuropathy Through the Activation of CB1 Receptors. PG - 1782-1799 LID - 10.1007/s12640-021-00442-x [doi] AB - Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy. CI - (c) 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Pereira, Anamaria Falcao AU - Pereira AF AD - Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil. FAU - Lisboa, Mario Roberto Pontes AU - Lisboa MRP AD - Department of Morphology, Faculty of Medicine, Morpho-Functional Sciences Post Graduation Program, Federal University of Ceara, Fortaleza, CE, Brazil. FAU - de Freitas Alves, Bruno Wesley AU - de Freitas Alves BW AD - Department of Morphology, Faculty of Medicine, Morpho-Functional Sciences Post Graduation Program, Federal University of Ceara, Fortaleza, CE, Brazil. FAU - da Silva, Cristiane Maria Pereira AU - da Silva CMP AD - Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil. FAU - Dias, Diego Bernarde Souza AU - Dias DBS AD - Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil. FAU - de Menezes, Karoline Luanne Santos AU - de Menezes KLS AD - Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil. FAU - Cesario, Francisco Rafael Alves Santana AU - Cesario FRAS AD - Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil. FAU - de Franca, Jonas Costa AU - de Franca JC AD - Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil. FAU - de Oliveira, Amanda Rocha AU - de Oliveira AR AD - Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil. FAU - Hallak, Jaime Eduardo Cecilio AU - Hallak JEC AD - Department of Neuroscience and Behavior, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil. AD - National Institute of Science and Technology in Translational Medicine (INCT-TM), CNPq/FAPESP/CAPES, Ribeirao Preto, Brazil. FAU - Zuardi, Antonio Waldo AU - Zuardi AW AD - Department of Neuroscience and Behavior, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil. AD - National Institute of Science and Technology in Translational Medicine (INCT-TM), CNPq/FAPESP/CAPES, Ribeirao Preto, Brazil. FAU - Crippa, Jose Alexandre AU - Crippa JA AD - Department of Neuroscience and Behavior, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil. AD - National Institute of Science and Technology in Translational Medicine (INCT-TM), CNPq/FAPESP/CAPES, Ribeirao Preto, Brazil. FAU - de Alencar, Nylane Maria Nunes AU - de Alencar NMN AD - Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil. AD - Drug Research and Development Center, Federal University of Ceara, R. Cel. Nunes de Melo, 1000, Rodolfo Teofilo, Fortaleza, CE, 60430-275, Brazil. FAU - Lima-Junior, Roberto Cesar Pereira AU - Lima-Junior RCP AD - Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil. AD - Drug Research and Development Center, Federal University of Ceara, R. Cel. Nunes de Melo, 1000, Rodolfo Teofilo, Fortaleza, CE, 60430-275, Brazil. FAU - Vale, Mariana Lima AU - Vale ML AD - Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil. marianavale@ufc.br. AD - Drug Research and Development Center, Federal University of Ceara, R. Cel. Nunes de Melo, 1000, Rodolfo Teofilo, Fortaleza, CE, 60430-275, Brazil. marianavale@ufc.br. AD - Department of Morphology, Faculty of Medicine, Morpho-Functional Sciences Post Graduation Program, Federal University of Ceara, Fortaleza, CE, Brazil. marianavale@ufc.br. LA - eng GR - PR2-0101-00054.01.00/15/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ GR - PR2-0101-00054.01.00/15/Fundacao Cearense de Apoio ao Desenvolvimento Cientifico e Tecnologico/ GR - 2008/09009-2/Instituto Nacional de Ciencia e Tecnologia Translacional em Medicina/ PT - Journal Article DEP - 20211118 PL - United States TA - Neurotox Res JT - Neurotoxicity research JID - 100929017 RN - 0 (Endocannabinoids) RN - 0 (Receptor, Cannabinoid, CB1) RN - 04ZR38536J (Oxaliplatin) SB - IM MH - Animals MH - Endocannabinoids/*metabolism MH - Fluorescent Antibody Technique MH - Ganglia, Spinal/drug effects/pathology/physiopathology MH - Male MH - Mice MH - Nociception/*drug effects MH - Oxaliplatin/*adverse effects/antagonists & inhibitors MH - Pain Measurement MH - Peripheral Nervous System Diseases/*chemically induced/metabolism MH - Receptor, Cannabinoid, CB1/*agonists/metabolism MH - Rotarod Performance Test OTO - NOTNLM OT - Cannabidiol OT - Cannabinoid receptors OT - Endocannabinoid system OT - Neuropathy OT - Oxaliplatin EDAT- 2021/11/19 06:00 MHDA- 2022/03/31 06:00 CRDT- 2021/11/18 12:30 PHST- 2021/04/07 00:00 [received] PHST- 2021/11/05 00:00 [accepted] PHST- 2021/11/03 00:00 [revised] PHST- 2021/11/19 06:00 [pubmed] PHST- 2022/03/31 06:00 [medline] PHST- 2021/11/18 12:30 [entrez] AID - 10.1007/s12640-021-00442-x [pii] AID - 10.1007/s12640-021-00442-x [doi] PST - ppublish SO - Neurotox Res. 2021 Dec;39(6):1782-1799. doi: 10.1007/s12640-021-00442-x. Epub 2021 Nov 18.