Local anaesthetics (LA) inhibit the excitability of sensory neurons by blocking voltage-gated sodium channels. However, LAs also depolarize sensory neurons leading to a Ca2+-influx. Consistent with previous reports, we observed a concentration-dependent Ca2+-influx by lidocaine in dorsal root ganglion cells (EC50 3.4 ± 1.4 mM). Importantly, an increase of intracellular Ca2+ mediates release of the neuropeptide calcitonin gene-related peptide (CGRP) from a subpopulation of sensory neurons. We next explored the effect of lidocaine on CGRP release from isolated mouse sciatic nerves. Lidocaine evoked a major release of CGRP from nerves of wildtype mice (10 mM 2.8-fold and 30 mM 9.6-fold over baseline). Moreover, procain (30 mM) evoked a similar CGRP release (~6.7-fold over baseline). The capsaicin- receptor TRPV1 contributes to CGRP release from sensory neurons evoked by vanilloids, protons and heat. Therefore, involvement of TRPV1 in LA-evoked CGRP release was investigated. The TRPV1 antagonist capsazepine (10 mM) reduced the effect of 30 mM lidocaine by 77%. Moreover, less CGRP was released by lidocaine from sciatic nerves of TRPV1- null mice (4.6-fold over baseline). A LA-evoked release of CGRP from peripheral or central terminals of nociceptive afferents can induce "neurogenic inflammation" and spinal sensitization of nociceptive transmission, both sequelae of clinical relevance.