Upregulation of calcitonin gene related peptide (CGRP)-immunoreactive primary afferent nerve fibers accompanied by mastocytosis is characteristic for the S. mansoni-infected murine ileum. These mucosal mast cells (MMC) and CGRP-IR fibers, which originate from dorsal root (DRG) and nodose ganglia, are found in close apposition. We examined interactions between primary cultured MMC and CGRP-IR DRG neurons in vitro by confocal recording of [Ca²⁺]_i. The degranulatory EC₅₀ for the mast cell secretagogue C48/80 (10µg/ml) and the neuropeptides CGRP (2.10^-8 M) and Substance P (SP; 3.10^-8 M) were determined by measurement of extracellular release of the granule chymase, mouse mast cell protease-1 (mMCP-1). Application of C48/80 (10µg/ml), and CGRP and SP (both 10^-7M) to Fluo-4 loaded MMC induced after a lag time a transient rise in [Ca²⁺]_i, indicative of mast cell degranulation and/or secretion. The CGRP response could be completely blocked by pertussis toxin (2 µg/ml), indicating involvement of G_i proteins. Application of mucosal mast cell juice (MMC juice), obtained by C48/80 degranulation of MMC, to Fluo-4 loaded DRG neurons induced in all neurons a rise in [Ca²⁺]_i, indicative of activation. Degranulation of MMC by C48/80 in culture dishes containing Fluo-4 loaded DRG neurons also caused activation of the DRG neurons. In conclusion, these results demonstrate a bidirectional cross-talk between cultured MMC and CGRP-IR DRG neurons in vitro. This indicates that such a communication may be the functional relevance for the close apposition between MMC and CGRP-IR nerve fibers in vivo.