Voltage-sensitive sodium channels (VSSCs) are critical for the relay of information in all pain pathways, however, only now is their full role in specific pathways starting to be appreciated (Lai etal., 2004). In the search for much needed TTX-r channel blockers, we have identified μO-MrVIA and MrVIB as being ~ 10-fold selective inhibitors of the TTX-r VSSCs Importantly, i.t. MrVIB produced potent anti-allodynia in a rat model of neuropathic pain, with minimal side effects Once the specificity of this effect is established using Nav1.8 knockout mice (in collaboration with PI Wood), MrVIB will have confirmed the potential of Nav1.8 as a drug target. We have also developed a range of highly potent, neuronally selective μ-SIIIA analogues, including SIIIA#1 which is over 103 fold selective for neuronal TTX-s VSSCs. The SIIIA analogues we have designed are the first neuronally selective TTX-s VSSC inhibitors. Previously, we showed that μ-PIIIA was a subtype selective inhibitor of brain TTX-s VSSCs, with preferential affinity for persistent sodium current[RJL 15]. We will use μ- and μO-conotoxin to dissect for the first time the role of different VSSCs in pain pathways using cellular and synaptic analyses, combined with conventional and transfection approaches described above.