Background & Aims
Osteoarthritis (OA) affects over 500 million globally, causing joint deterioration, pain, swelling and impacting quality of life. Current treatments are oral NSAIDs or opioids but offer short-term relief with significant side effects. Intraarticular injectables like corticosteroids provide limited relief but are associated with cartilage damage. Safer, more effective pain relief is needed for OA patients. Transient receptor potential vanilloid 1 (TRPV1) is a calcium-permeable channel present in sensory neurons implicated in chronic pain conditions. High doses of TRPV1 agonists induce desensitization of TRPV1 and lead to axonal degeneration and long-term pain relief. Repeated application of low doses may induce a similar effect without side effects and presents a promising approach for pain therapy. This study investigates the efficacy of a biopolymer with controlled release of a TRPV1 agonist in vitro, aiming to induce axonal terminal ablation for long-term pain relief in OA patients
Methods
The release kinetics of a TRPV1 agonist from in house synthesised prototypes were assessed using Automated Patch Clamp (APC) in TRPV1-expressing CHO cells. Effects of temperature (37 ºC, 4 ºC), formulation, excipient, pH and the presence or absence of synovial fluid were tested. The release kinetic profile was examined using ND7/23 cells stably transfected with human TRPV1 using APC. TRPV1 desensitisation was measured as a reduction in calcium-induced currents in voltage-clamp mode. Axonal ablation was studied in primary isolated rat dorsal root ganglia in vitro, at different time points using immunohistochemistry. Axonal ablation was quantified and analysed, focusing on the presence of beading, blebbing or swelling on neurites.
Results
Kinetic release analysis reveals a controlled release of a TRPV1 agonist, exhibiting initial rapid release within the first 24 hours and subsequent stabilization. The solvent pH and temperature notably influence the kinetic release profile. The release of TRPV1 agonist was further enhanced in the presence of the enzymes found in synovial fluid. Desensitisation of TRPV1 in ND7/23 cells was concentration-dependent. Slower release profiles were associated with a more gradual desensitisation response compared to the faster-release prototypes. Preliminary findings from primary rat DRG demonstrate a marked increase in TRPV1-positive ablated axons that is both agonist concentration- and time-dependent.
Conclusions
Our studies demonstrate promising findings regarding the controlled release of a TRPV1 agonist from the biopolymer. The synthesized prototypes exhibit an initial rapid release phase followed by stabilization, suggesting their potential utility for desensitisation and sustained pain relief. Additionally, preliminary experiments on rat DRG cells reveal a selective and significant increase in TRPV1-positive axons showing ablation characteristics in response to TRPV1 activation, confirming the potential for axonal terminal ablation in chronic pain management. These findings highlight the opportunity for further investigation of the controlled release of TRPV1 agonists and long-term pain relief.
References
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Presenting Author
Jara Maria Baena Montes
Poster Authors
Jara Maria Baena Montes
BSc, MSc
University of Galway
Lead Author
Yajaira Fellez Sánchez
Bsc
University of Galway
Lead Author
Sahar Avazzadeh
BSc (Hons) MSc PhD
Relevium Medical
Lead Author
Simona Cacciapouti
BSc MSc
University of Galway
Lead Author
Christophe Labriere
PhD
University of Galway
Lead Author
Barry McDermott
BSc (Pharm) MPSI MVB BEng PhD
Relevium Medical
Lead Author
Leo Quinlan
PhD
University of Galway
Lead Author
Topics
- Models: Chronic Pain - Neuropathic