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

Author(s):Show less -

Pereira, Anamaria Falcao ^[1] ; Pontes Lisboa, Mario Roberto ^[2] ; de Freitas Alves, Bruno Wesley ^[2] ; Pereira da Silva, Cristiane Maria ^[1] ; Souza Dias, Diego Bernarde ^[1] ; Santos de Menezes, Karoline Luanne ^[1] ; Santana Cesario, Francisco Rafael Alves ^[1] ; de Franca, Jonas Costa ^[1] ; de Oliveira, Amanda Rocha ^[1] ; Cecilio Hallak, Jaime Eduardo ^{[3, 4]} ; Zuardi, Antonio Waldo ^{[3, 4]} ; Crippa, Jose Alexandre ^{[3, 4]} ; Nunes de Alencar, Nylane Maria ^{[1, 5]} ; Pereira Lima-Junior, Roberto Cesar ^{[1, 5]} ; Vale, Mariana Lima ^{[1, 5, 2]}

Affiliation

^[1] Univ Fed Ceara, Fac Med, Dept Physiol & Pharmacol, Fortaleza, Ceara - Brazil

^[2] Univ Fed Ceara, Fac Med, Dept Morphol, Morpho Funct Sci Post Grad Program, Fortaleza, Ceara - Brazil

^[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Neurosci & Behav, Ribeirao Preto, SP - Brazil

^[4] CNPq FAPESP CAPES, Natl Inst Sci & Technol Translat Med INCT TM, Ribeirao Preto - Brazil

^[5] Univ Fed Ceara, Drug Res & Dev Ctr, R Cel Nunes de Melo 1000, BR-60430275 Fortaleza, Ceara - Brazil

• Document type: Journal article
• Source: NEUROTOXICITY RESEARCH; v. 39, n. 6 NOV 2021.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 08/09009-2 - Crack/cocaine chronic use: dopamine transporters availability, genetic factors, and executive functioning
• Grantee: Acioly Luiz Tavares de Lacerda
• Support Opportunities: Regular Research Grants