Effects of an acid-sensing ion channel modulator on inflammatory pain

Purpose The objective of this study was to evaluate GL-001 as an anti-nociceptive compound in an animal model of thermal and inflammatory pain. Acid-sensing ion channels (ASICs) are membrane-bound ion channels that are sensitive to protons and non-proton ligands. In particular, the ASIC3 channel subtype is highly sensitive to decreases in extracellular pH and is found predominantly in peripheral sensory neurons, making it a potential modulator of pain sensation. Non-proton ligand activators and blockers of ASIC3 have been documented to affect nociception in both humans and animal models. As the compound GL-001 shares structural similarity with the non-proton ligands of ASIC3, the hypothesis is that GL-001 will interact with the channel in a similar manner leading to decreased nociception. Materials and methods Sixty male and female C57BL/6J mice (2-3 months old) were fed either a control diet or the control diet supplemented with 6.25g of GL-001 per kg of diet for one week prior to and throughout the nociceptive tests. To assess thermal hyperalgesia, the distal portion of the tail of the mice was dipped in a water bath set at 52°C and the latency to withdraw their tails was used as a measure of pain sensitivity. To induce inflammatory pain, the mice were injected with 4% formalin in their right hindpaw, and their nociceptive behavior (licking the injected paw) was recorded and timed. Statistical analyses (t-test for the thermal hyperalgesia, and ANOVAs for the formalin test) were performed with alpha set at 0.05. Results Preliminary results indicated that neither sex nor treatment affected the latency to withdraw the tail in the thermal hyperalgesia test, even though the treated mice took 10% longer latencies than the controls. For the formalin test, males and females seemed to respond differently to the stimulus. The female mice treated with GL-001 seemed to recover faster than the controls, which was supported by main effects of treatment in the last 30 minutes of the test. Conclusion Our preliminary data suggest a potential effect of GL-001 on nociception, especially related to inflammation. Further, females seemed to be more responsive to GL-001 than males. Further studies will be required to determine the preferred dose of GL-001 for beneficial effects, and identify which ASIC subtypes might be involved in its mechanism of action.