Figure. Factors influencing the release of substance P (SP) from sensory nerves. SP is released from large dense core vesicles (LDCVs) following (1) cleavage of protease-activated receptor-2 (PAR-2) by tryptase, (2) bradykinin binding to B2 receptors, (3) sensitization by cytokines induced by LPS, or (4) nitric oxide. Activation of the vanilloid receptor and sensitization of sensory nerves by prostaglandins are not shown. Exocytosed SP binds to the neurokinin-1 receptor (NK1-R) expressed on endothelial cells causing vaosodilation and edema formation, prominent features of neurogenic inflammation. SP also interacts with immune cells causing T-lymphocyte proliferation. NK-1 receptor expression on macrophages and monocytes is not shown. As a result of these interactions, SP is believed to act as an important mediator of crosstalk between the nervous and immune systems. SP, Substance P; NK1-R, neurokinin 1 receptor; LDCVs, large dense core vesicles (containing neuropeptdies); PAR-2, protease-activated receptor-2; B2, bradykinin receptor; TLR-4, Toll-like receptor-4; LPS, lipopolysaccharide; and LBP, lipopolysaccharide binding protein.