Trpv1 Antagonist for Oa Pain: Preclinical in Vivo Results Predict Clinical Outcome

Purpose: Chronic joint pain with pain at walking as major complaint affects a large portion of an aging population. Treatment options for this pain are insufficient, with side effects and less than full efficacy. Many hopes arose after discovery of the TRP channels, especially the TRPV1 receptor which reacts to increases in temperature but also to other stimuli such as acid environment and capsaicin. This lead to research for new drugs, and between 2006 and 2010 more than 20 patents/applications related to TRPV1 blockers for e.g., pain, inflammation and osteoarthritis were filed each year. The TRPV1 inhibitor AZD1386 was one of those, reducing capsaicin-evoked nocifensive response and reversing heat hyperalgesia in models of inflammatory and neuropathic pain, but showed no effect on pain when tested in patients with knee OA. Lack of predictive power for drug effects has been a major criticism against animal pain models and readouts. It is therefore important to define their utility and limitations. The aim of this study was to use gait analysis as a tool to measure effects in a rat model of monoarthritis induced by Freund’s complete adjuvant (FCA), and compare efficacy between AZD1386 and drugs targeting cyclooxygenase and nerve growth factor pathways. Methods: Male rats (Sprague-Dawley or Lewis) injected intra-articularly into one ankle joint with FCA (1.0 mg/mL) were used. Starting one day after monoarthritis induction, they were treated twice daily p.o. over three days with AZD1386, COX inhibitors or pan-Trk inhibitors, or once i.v. with the NGF antibody MEDI-578. Using a walkway with a glass floor where a light source was projected into the long edge, each paw’s relative contribution to weight bearing during locomotion was automatically calculated by the PawPrint software, giving the guarding index - difference in percent weight bearing between the hind paws. Results: Both hind paws had similar weight bearing before monoarthritis, thus giving guarding index ranging from −1.7 to 6.0 %. One day after FCA injection less weight was put on the injected paw and more on the contra-lateral paw, and the guarding index ranged between 25.2 and 39.8 %. The TRPV1 antagonist was without effect during the entire test period of three days. In contrast, the COX inhibitors reduced the guarding index to values between 18.4 and 18.7 % while the NGF antibody and Trk inhibitors normalized the guarding index to values between 8.0 and 13.2 %. Conclusions: Our results support the use of gait analysis to assess movement-related anti-nociceptive efficacy of drugs, a measurement readout which resembles a major complaint in patients with joint pain.