Lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalized amino acid which has shown activity in a wide range of animal models for pain and epilepsy. This activity is currently being evaluated in phase III clinical trials for epilepsy and diabetic neuropathic pain. Since lacosamide did not bind with significant affinity to any of more than 100 receptors, enzymes, transporters or ion channels tested, the aim of the current experiments was to identify the molecular mode of action. Employing proteomic affinity labeling techniques, putative binding partners of lacosamide were identified. Of special interest appeared collapsin-response mediator protein 2 (CRMP-2, also identified as DRP-2, TOAD-64, Ulip2), a protein involved in neuronal differentiation and control of axonal outgrowth. This was further studied in a radioligand binding experiment with CRMP-2 expressed in Xenopus oocytes. Binding of lacosamide to CRMP-2 was confirmed with an affinity of about 5 µM. In order to study the functional consequences of lacosamide's interaction with CRMP-2 a cellular assay was used in which the effects of CRMP-2 modulation have been characterized: Lacosamide (1-100 µM) inhibited the effects of neurotrophins (BDNF, NT-3) on axonal outgrowth of primary hippocampal cells without effects on basal growth. This is in line with published findings that inhibition of CRMP-2 by siRNA attenuated neurotrophin induced axonal outgrowth of cultured neurons. In summary, the results of these studies (see also corresponding abstract) suggest that lacosamide has a dual mode of action and that CRMP-2 is one of its molecular targets. Given the important role of neurotrophic factors in the pathophysiology of chronic pain, the interaction of lacosamide with CRMP-2 might potentially have disease modifying effects. This, however, remains to be proven.