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.
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Abbreviations
- 2-AG:
-
2-Arachidonoylglycerol
- AEA:
-
Anandamide
- AM251:
-
Cannabinoid CB1 receptor antagonist
- AM630:
-
Cannabinoid CB2 receptor antagonist
- ATF3:
-
Activating transcription factor 3
- CB1:
-
Cannabinoid CB1 receptor
- CB2:
-
Cannabinoid CB2 receptor
- CBD:
-
Cannabidiol
- DRG:
-
Dorsal root ganglia
- Iba-1:
-
Ionized calcium-binding adapter molecule 1
- iNOS:
-
Inducible nitric oxide synthase
- OXL:
-
Oxaliplatin
- PAG:
-
Periaqueductal gray
- PFA:
-
Paraformaldehyde
- PSN:
-
Peripheral sensory neuropathy
- SC:
-
Spinal cord
- Sp5C:
-
Spinal trigeminal nucleus caudalis
- TG:
-
Trigeminal ganglia
- TRPV1:
-
Transient receptor potential vanilloid 1
- vlPAG:
-
Ventrolateral periaqueductal gray
- WIN:
-
WIN 55, 212–2
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Acknowledgements
The authors would like to thank the Multi-User Facility of Drug Research and Development Center of Federal University of Ceará and the Central Analítica-UFC/CT-INFRA/MCTI-SISANO/Pró-Equipamentos CAPES for the technical support.
Funding
This study was funded by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP) (Process PR2-0101–00054.01.00/15). This work was also partially supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), and by the Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM; CNPq/FAPESP; 2008/09009–2); JAC received a grant from the University Global Partnership Network (UGPN) – Global Priorities in Cannabinoid Research Excellence Program. JEH, AWZ, JAC, RCPLJ, and MLV are recipients of CNPq research fellowships.
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All procedures conducted in studies involving animals were in accordance with the ethical standards of the institution where the studies were performed. The study was approved by the Ethics Committee on the Use of Animals of the Federal University of Ceará (number: 41/2016).
Conflict of Interest
JAC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) – National Health and Medical Research Council (NHMRC). JAC and JEH have received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm. JAC, JEH, and AWZ are coinventors of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023,” Def. US number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimarães FS, Crippa JAS, Breuer A). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JAC, JEH, and AWZ are coinventors of the patent “Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same,” INPI on September 16, 2016 (BR 112018005423–2). The other authors declare that they have no competing interests.
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12640_2021_442_MOESM1_ESM.tif
Supplementary file1 (TIF 16550 KB). Suppl. Fig. 1. Evaluation of cannabimimetic effects of cannabidiol. Catalepsy, hot plate, and rotarod tests were performed until the 56th experimental day to investigate the cannabimimetic effects of cannabidiol. Results are presented as mean ± SEM. n = 6. *P < 0.05 versus C + V (Two-way ANOVA, Tukey’s post-test). C: Control; CBD: Cannabidiol; OXL: Oxaliplatin; V: Vehicle.
12640_2021_442_MOESM2_ESM.tif
Supplementary file2 (TIF 16560 KB). Suppl. Fig. 2. The pharmacological modulation of cannabinoid receptors does not affect animals’ performance on the rota-rod test. Effect of WIN (a), AM251 (b), and AM630 (c) on the rota-rod test. Results are presented as mean ± SEM. n = 6. *P < 0.05 versus C + V (Two-way ANOVA, Tukey’s post-test). AM251: Cannabinoid CB1 receptor antagonist; AM630: Cannabinoid CB2 receptor antagonist; C: Control; OXL: Oxaliplatin; V: Vehicle; WIN: WIN 55,212-2.
12640_2021_442_MOESM3_ESM.tif
Supplementary file3 (TIF 70179 KB). Suppl. Fig. 3. Effect of cannabinoid receptor agonists or antagonists on CB2 expression in the dorsal root ganglia (DRG). Green: NeuN (neuronal marker); red: CB2; blue: DAPI (nuclear marker). Magnification: 200 ×. Scale bar: 50 μm. CB2 expression in DRG (a, b) on the 28th (28D) and 56th (56D) experimental days. The bar graphs present the mean ± SEM of the percentage of CB2 positive neurons compared to total neuronal cells. n = 6. *P < 0.05 versus control; §P < 0.05 versus OXL 28D; ^P < 0.05 versus OXL 56D (One-way ANOVA, Tukey’s post-test). AM251: Cannabinoid CB1 receptor antagonist; AM630: Cannabinoid CB2 receptor antagonist; CB1: Cannabinoid CB1 receptor; CB2: Cannabinoid CB2 receptor; CBD: Cannabidiol; OXL: oxaliplatin; WIN: WIN 55,212-2.
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Pereira, A.F., Lisboa, M.R.P., de Freitas Alves, B.W. et al. Endocannabinoid System Attenuates Oxaliplatin-Induced Peripheral Sensory Neuropathy Through the Activation of CB1 Receptors. Neurotox Res 39, 1782–1799 (2021). https://doi.org/10.1007/s12640-021-00442-x
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DOI: https://doi.org/10.1007/s12640-021-00442-x