Exploitation of novel transduction targets for pain relief (Christiane Wetzel und Gary Lewin)

There is an unmet need for more effective analgesics and novel strategies for analgesic drug development. With Stomatin-like protein-3 (STOML3) we have identified a potential molecular target that directly participates in the transduction of noxious and innocuous mechanical stimuli in sensory neurons. We found that STOML3 deficient mice have many mechanoreceptors and nociceptors which are essentially insensitive to mechanical stimulation. Interestingly, STOML3 deficient mice show only very minor symptoms of neuropathic pain and this may be due to the impairment of touch reception in these mice. We have developed novel high throughput assays for screening  small molecules that disrupt STOML3 function. For further validation and lead optimization of small molecules we employ a set of experimental paradigms. For example we can test whether candidate compounds block mechanosensitive currents in isolated sensory neurons using the whole-cell patch-clamp technique. We can further test if local application of our compounds to the skin will block mechanosensitivity at the receptive endings of single primary afferents in the skin using the in vitro skin-nerve technique. Eventually we will perform behavioral tests in order to determine if the application of novel, potentially analgesic compounds leads to a lack of hypersensitivity to touch evoked pain.