Activated mast cells contribute to a cycle of neuropeptide release in the skin of sickle mice. (1) Tryptase from mast cells activates protease activated receptor 2 (PAR2) on the peripheral nerve endings. (2) Activation of PAR2 sensitizes transient receptor potential vanilloid 1 (TRPV1). (3) Excited nociceptors stimulate the release of calcitonin gene-related peptide (CGRP) and substance P (SP) from the sensory nerve endings. (4) CGRP interacts with the type 1 CGRP receptor (CGRP-R) on arterioles to induce dilatation. (5) SP activates plasma extravasation via neurokinin 1 receptors (NK1R). (6) SP released from nerve endings and from mast cells also acts on the mast cells themselves, thus promoting a cycle of mast cell activation.