905 - Targeting Inflammatory Arthralgia via Non-psychoactive Cannabinoid Mechanisms

Objectives: To understand novel management of painful arthropathy by evaluating the co-activation of transient receptor potential vanilloid-1 (TRPV1) with cannabinoid 2 receptor (CB2R) in knee osteoarthritis (KOA). Prior to testing the reported anti-inflammatory and anti-fibrotic potential of CB2R activation with CB2R-specific agonists that can also desensitize TRPV1 in KOA synoviocytes, we aim to determine the differential distribution of these receptors in human KOA synovium to identify potential patient responders versus non-responders to local delivery of targeted CB2R pharmacotherapy.

Design: Synovium samples from end-stage KOA patients (n=59) were collected during arthroplasty, preserved for paraffin sectioning, and categorized into high and low pain groups based on knee injury and osteoarthritis outcome scores. Indirect immunofluorescence labels for TRPV1, PGP9.5, and CB2R were captured from synovium sections by confocal microscopy and distribution calculated relative to cell number or tissue area. Student's t-test (𝛼=0.05) was used to compare mean expression of all targets between high and low pain groups.

Results: Significant increases in TRPV1 and PGP9.5 content were observed in the high pain group compared to the low pain group (p< 0.0001). TRPV1 and PGP9.5 were predominantly localized to nerve fibers in the subintima, with synoviocytes in the intima and subintima also expressing TRPV1. The high pain group averaged 136.90% higher TRPV1 expression and 84.11% higher PGP9.5 expression than those reporting low pain. CB2R was primarily detected in intimal synoviocytes and with 118.70% higher expression in the low pain group compared to the high pain group (p< 0.0001).

Conclusions: The differential distribution of CB2R and TRPV1 relative to KOA-attributable synovitis and self-reported pain suggests that targeted exposure of the synovium to CB2R analogs may result in differential anti-inflammatory and analgesic responses among patient groups. Considering the dynamics of CB2 and pain receptor distribution, endocannabinoids, and endovanilloids relative to self-reported pain will inform individualized approaches for managing inflammatory arthralgia.