135: CB2 Agonist Restores Fascial Hyaluronan Synthase in Chemotherapy-Induced Peripheral Neuropathy

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic cancer related pain, , , , , , , Pharmacological interventions, ,

Background and Aims: Chemotherapy-induced peripheral neuropathy (CIPN) impairs quality of life and may require dose reduction or discontinuation of anticancer therapy. Although neuronal damage has been the primary focus, emerging evidence, including our findings, suggests fascial dysfunction contributes to nociceptive transmission in CIPN. Hyaluronan (HA), synthesized by hyaluronan synthase (HAS), is essential for fascial structure and may play a role in pain modulation. Cannabinoid receptor 2 (CB2) agonists exert anti-inflammatory and analgesic effects; however, their impact on fascial HA metabolism in CIPN remains unclear. We investigated whether CB2 agonist administration modulates fascial HAS expression in a rat CIPN model.

Methods: A CIPN model (n = 8) was established in rats by intraperitoneal administration of vincristine (VCR 0.2mg/kg). Mechanical hypersensitivity of the hind limbs was assessed as 50% paw withdrawal threshold (PWT) using von Frey filaments. The rat fascia of the tibialis anterior muscle was excised and incubated in medium supplemented with CB2 agonist. HAS mRNA expression in the fascia of the tibialis anterior muscle was quantified by RT-PCR. In addition, HA distribution was evaluated using Alcian Blue staining, and hyaluronan synthase 2 (HAS2) expression was assessed by immunohistochemistry.

Results: Rats treated with VCR exhibited a significant decrease in PWT, downregulation of HAS mRNA expression in the fascia, and a reduction in HAS2-positive cells. Administration of a CB2 agonist to the harvested fascia significantly attenuated the downregulation of HAS mRNA expression and the reduction in HAS2-positive cells.

Conclusions: CB2 agonist treatment may mitigate CIPN-associated downregulation of HAS2 and fascial impairment. These findings suggest the involvement of fascia as the non-neuronal mechanisms of CIPN-related pain and the possibility of CB2 agonists as a novel therapeutic strategy for CIPN.

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Guenther K, et al. The cannabinoid CB2 agonist LY2828360 suppresses neuropathic pain behaviour in rodent models including paclitaxel-induced mechanical hypersensitivity. Neuropharmacology. 2025. PMID:39644993.

Stecco C, Fede C, Macchi V, Porzionato A, Petrelli L, Biz C, Stern R, De Caro R. The fasciacytes: A new cell devoted to fascial gliding regulation. Clin Anat. 2018;31(5):667-676. doi:10.1002/ca.23072. PMID:29575206.

Fede C, Pirri C, Petrelli L, Guidolin D, Fan C, De Caro R, Stecco C. Sensitivity of the fasciae to the endocannabinoid system: production of hyaluronan-rich vesicles and potential peripheral effects of cannabinoids in fascial tissue. Int J Mol Sci. 2020;21(8):2936. doi:10.3390/ijms21082936. PMID:32331297

Presenting Author: Chika Tsuboi
Submitting Author: Chika Tsuboi

Senior Author: Yoshikazu Matsuoka

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Yoshikazu Matsuoka - Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
• Mizuki Tanaka - Okayama University
• Nobutaka Sue - Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
• Kyosuke Arakawa - Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
• Hiroshi Morimatsu - Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences