Activated mast cells contribute to a feed-forward cycle of neuropeptide release in the skin of sickle mice. (1) Tryptase from mast cells activates PAR2 on the peripheral nerve endings. (2) Activation of PAR2 sensitizes transient receptor potential vanilloid 1 (TRPV1). (3) Excited nociceptors stimulate the release of CGRP and SP from the sensory nerve endings. (4) CGRP interacts with the type 1 CGRP receptor on arterioles to induce dilatation. (5) Substance P activates plasma extravasation via neurokinin 1 (NK1) receptors. (6) SP released from nerve endings as well as from mast cells also acts on the mast cells themselves, thus promoting a vicious cycle of mast cell activation.