The noradrenaline transporter (NET) is the main pathway that removes released NA fromthe synapse. As such, it plays a key role in regulating the levels of NA, a major inhibitory transmitter released from descending inhibitory neurons in the spinal cord. We have recently found that intrathecal (i.t.) χ-MrIA,and an analogue Xen2174, are significantly more potent and efficacious than i.t. morphine in a chronic constriction injury model of neuropathic pain. We will use MrIA to investigate specifically the extent and nature role of the NET in regulating spinal NA effects. We have also identified two key residues on NET that determine MrIA affinity. Complementary binding interactions will be identified from studies of analogues of MrIA and mutants of NET. Novel peptides will be screened against a NET assay.