NAN SODIUM CHANNEL:NOVEL TARGET FOR PAIN DRUG DISCOVERY

Hyperexcitability of spinal sensory neurons contributes significantly to pain syndromes, e.g. after nerve injury and inflammation. A method for dampening hyperexcitability of these neurons is expected to ameliorate neuropathic pain, and the targeting of sensory neuron-specific molecules may yield pain relief with minimal side effects. Sodium channels generate the inward currents that underlie action potentials. Several sodium channels have now been identified in spinal sensory neurons (e.g. dorsal root ganglia, DRG neurons). Small diameter DRG neurons, the majority of which are nociceptive, express sodium currents that are sensitive to the neurotoxin tetrodotoxin (TTX-S) and others that are resistant (TTX-R). TTX-R currents are increased in experimental models of inflammation. Recently, a novel rat TTX-R Na+ channel that is preferentially expressed in high threshold nociceptive neurons of DRG and trigeminal ganglia was identified. Work supported by our Phase I SBIR permitted creation of several rat NaN/SNS2 clones which will be useful tools for developing cell-based assays. We also obtained the human NaN/SNS2 sequence. We propose to characterize rat and human NaN expression and current in transfected mammalian cells. This represents a critical step toward developing molecular targets in cell-based assays for high throughput screening for agents that modulate the activity of this sensory neuron-specific channel.