Targeting arthralgia in knee osteoarthritis via non-psychoactive cannabinoid mechanisms

Location

LSUHSC Center for Advanced Learning and Simulation (CALS)

Document Type

Presentation

Start Date

22-6-2024 10:30 AM

End Date

22-6-2024 11:25 AM

Publication Date

2024-06-22

Description

Introduction: Non-surgical management of painful knee osteoarthritis (KOA) involves NSAIDs, corticosteroids, and opioids, which provide short-term relief and may worsen disease progression. Hence, our overarching goal is to evaluate novel, targeted analgesics that also provide effective, longer lasting anti-inflammatory relief for KOA. Activation of the polymodal transient receptor potential vanilloid 1 (TRPV1) cation channel can cause nociceptive arthralgia. TRPV1 is expressed in articular sensory afferents and some neuroendocrine-like synoviocytes. External or endogenous ligands, such as capsaicin and hydroxyeicosatetraenoic acid derivatives, can bind TRPV1 to trigger the release of calcitonin gene-related peptide (CGRP) that contributes to neurogenic inflammation. Endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and exogenous cannabidiol (CBD) share chemical features that can activate and, after prolonged activity, desensitize TRPV1 by interacting with its capsaicin-binding pocket, as well as mildly trigger anti-inflammatory cascades through cross-interaction with the cannabinoid 2 receptor (CB2R). CBD analogs such as JWH133 have been developed to have a 200-fold higher binding affinity for CB2R than conventional CBD. Before testing the analgesic and anti-inflammatory effects of such analogsin KOA-attributable arthralgia and inflammation, it is crucial to identify responders to treatment from a diverse KOA patient population. This study aims to identify the differential distribution of CB2R and activated TRPV1 in the synovial tissues and fluid of KOA patients grouped by reported pain. Methods: Specimens were collected from 40 patients with end-stage KOA. The patients were divided into two groups of 20 individuals each based on their KOOS pain scores. The first group reported the lowest pain scores, while the second group reported the highest pain scores. Synovial tissue and fluid were collected during total knee arthroplasty, preserved, and banked. Formalin-fixed synovial tissues were processed for paraffin sectioning and staining by H&E and for detection of TRPV1 and CB2R by indirect immunofluorescence. H&E sections were evaluated microscopically for synovitis and scored. Distribution of TRPV1 and CB2R relative to synovial tissue layer and area were calculated using Slidebook™ (3i) software-assisted morphometry of confocal photomicrographs. Synovial fluid was cleared, digested, and analyzed for CGRP by sandwich ELISA (Cusabio®). Prism (Graphpad) software was used to compare groups or correlate by Student’s t or Spearman rho with α=0.05. Results: Compared to the low pain group, patients reporting high pain presented with higher inflammation based on synovitis scores (p ≤ 0.0002) and a higher percentage of synovial TRPV1 (p ≤ 0.0004) with correspondingly high concentrations of CGRP (p=0.0547) in synovial fluid. Patients reporting low pain had a significantly higher distribution of CB2R than the high pain group (p ≤ 0.0001) and altogether, CB2R expression inversely correlated with synovitis severity (R = -0.51; p ≤ 0.0001). Discussion: Increased TRPV1 expression in the synovium of patients reporting high pain could be used to predict patient responsiveness to intra-articular supplementation with CB2R-specific analogs like JWH133 in the comodulation of arthralgia and inflammation. The lower expression of CB2R in patients reporting high pain may indicate internalization due to ligand deficiency or tolerance following chronic upregulation. It can be predicted that a more significant expression of CB2R may indicate higher endocannabinoid production, which would allow for increased TRPV1 crosstalk and, thus, greater desensitization in the patients reporting low pain. Significance/Clinical relevance: Patient-centric co-targeting of CB2R and TRPV1 by local delivery of higher affinity CBD analogs can provide a safe but potent alternative to alleviate painful inflammatory arthropathy.

This document is currently not available here.

Share

COinS
 
Jun 22nd, 10:30 AM Jun 22nd, 11:25 AM

Targeting arthralgia in knee osteoarthritis via non-psychoactive cannabinoid mechanisms

LSUHSC Center for Advanced Learning and Simulation (CALS)

Introduction: Non-surgical management of painful knee osteoarthritis (KOA) involves NSAIDs, corticosteroids, and opioids, which provide short-term relief and may worsen disease progression. Hence, our overarching goal is to evaluate novel, targeted analgesics that also provide effective, longer lasting anti-inflammatory relief for KOA. Activation of the polymodal transient receptor potential vanilloid 1 (TRPV1) cation channel can cause nociceptive arthralgia. TRPV1 is expressed in articular sensory afferents and some neuroendocrine-like synoviocytes. External or endogenous ligands, such as capsaicin and hydroxyeicosatetraenoic acid derivatives, can bind TRPV1 to trigger the release of calcitonin gene-related peptide (CGRP) that contributes to neurogenic inflammation. Endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and exogenous cannabidiol (CBD) share chemical features that can activate and, after prolonged activity, desensitize TRPV1 by interacting with its capsaicin-binding pocket, as well as mildly trigger anti-inflammatory cascades through cross-interaction with the cannabinoid 2 receptor (CB2R). CBD analogs such as JWH133 have been developed to have a 200-fold higher binding affinity for CB2R than conventional CBD. Before testing the analgesic and anti-inflammatory effects of such analogsin KOA-attributable arthralgia and inflammation, it is crucial to identify responders to treatment from a diverse KOA patient population. This study aims to identify the differential distribution of CB2R and activated TRPV1 in the synovial tissues and fluid of KOA patients grouped by reported pain. Methods: Specimens were collected from 40 patients with end-stage KOA. The patients were divided into two groups of 20 individuals each based on their KOOS pain scores. The first group reported the lowest pain scores, while the second group reported the highest pain scores. Synovial tissue and fluid were collected during total knee arthroplasty, preserved, and banked. Formalin-fixed synovial tissues were processed for paraffin sectioning and staining by H&E and for detection of TRPV1 and CB2R by indirect immunofluorescence. H&E sections were evaluated microscopically for synovitis and scored. Distribution of TRPV1 and CB2R relative to synovial tissue layer and area were calculated using Slidebook™ (3i) software-assisted morphometry of confocal photomicrographs. Synovial fluid was cleared, digested, and analyzed for CGRP by sandwich ELISA (Cusabio®). Prism (Graphpad) software was used to compare groups or correlate by Student’s t or Spearman rho with α=0.05. Results: Compared to the low pain group, patients reporting high pain presented with higher inflammation based on synovitis scores (p ≤ 0.0002) and a higher percentage of synovial TRPV1 (p ≤ 0.0004) with correspondingly high concentrations of CGRP (p=0.0547) in synovial fluid. Patients reporting low pain had a significantly higher distribution of CB2R than the high pain group (p ≤ 0.0001) and altogether, CB2R expression inversely correlated with synovitis severity (R = -0.51; p ≤ 0.0001). Discussion: Increased TRPV1 expression in the synovium of patients reporting high pain could be used to predict patient responsiveness to intra-articular supplementation with CB2R-specific analogs like JWH133 in the comodulation of arthralgia and inflammation. The lower expression of CB2R in patients reporting high pain may indicate internalization due to ligand deficiency or tolerance following chronic upregulation. It can be predicted that a more significant expression of CB2R may indicate higher endocannabinoid production, which would allow for increased TRPV1 crosstalk and, thus, greater desensitization in the patients reporting low pain. Significance/Clinical relevance: Patient-centric co-targeting of CB2R and TRPV1 by local delivery of higher affinity CBD analogs can provide a safe but potent alternative to alleviate painful inflammatory arthropathy.