Endocannabinoid System Attenuates Oxaliplatin-Induced Peripheral Sensory Neuropathy Through the Activation of CB1 Receptors

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 nin...

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Bibliographic Details
Published in:	Neurotoxicity research Vol. 39; no. 6; pp. 1782 - 1799
Main Authors:	Pereira, Anamaria Falcão, Lisboa, Mario Roberto Pontes, de Freitas Alves, Bruno Wesley, da Silva, Cristiane Maria Pereira, Dias, Diego Bernarde Souza, de Menezes, Karoline Luanne Santos, Cesário, Francisco Rafael Alves Santana, de França, Jonas Costa, de Oliveira, Amanda Rocha, Hallak, Jaime Eduardo Cecilio, Zuardi, Antonio Waldo, Crippa, José Alexandre, de Alencar, Nylane Maria Nunes, Lima-Júnior, Roberto César Pereira, Vale, Mariana Lima
Format:	Journal Article
Language:	English
Published:	New York Springer US 01-12-2021
Subjects:	Animals Biomedical and Life Sciences Biomedicine Cell Biology Endocannabinoids - metabolism Fluorescent Antibody Technique Ganglia, Spinal - drug effects Ganglia, Spinal - pathology Ganglia, Spinal - physiopathology Male Mice Neurobiology Neurochemistry Neurology Neurosciences Nociception - drug effects Original Article Oxaliplatin - adverse effects Oxaliplatin - antagonists & inhibitors Pain Measurement Peripheral Nervous System Diseases - chemically induced Peripheral Nervous System Diseases - metabolism Pharmacology/Toxicology Receptor, Cannabinoid, CB1 - agonists Receptor, Cannabinoid, CB1 - metabolism Rotarod Performance Test Cannabidiol Endocannabinoid system Oxaliplatin Neuropathy Cannabinoid receptors
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Summary:	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.
ISSN:	1029-8428 1476-3524
DOI:	10.1007/s12640-021-00442-x