Fig. 1. Opioid-containing leukocytes: recruitment into the inflamed paw and peripheral opioid-mediated analgesia. Several steps influence the coordinated migration of opioid-containing leukocytes to a site of inflammation: (A ) the absolute number of opioid-containing leukocytes in the circulation and the content of opioid peptides per cell (i.e. , β-endorphin and Met-enkephalin;fig. 2), (B ) the expression of adhesion molecules on circulating leukocytes (i.e. , selectins [CD62L, L-selectin], integrins [CD18, β2integrin], and immunoglobulin superfamily [CD49d, VLA-4]; these molecules interact with adhesion molecules on the inflamed endothelium, leading to leukocyte rolling, sticking, and transmigration;fig. 3B), (C ) the ability of circulating opioid-containing leukocytes to migrate in direction to a stimulus (i.e. , chemotaxis by chemokines, e.g. , macrophage inflammatory protein-2;fig. 3C), and (D ) the expression of these chemokines in the inflamed paw (table 2). (E ) These factors determine the absolute number of opioid-containing leukocytes in the inflamed paw (fig. 5A). Intraplantarly injected corticotropin-releasing factor (CRF) induces the release of opioid peptides from leukocytes in the inflamed paw, leading to peripheral opioid-mediated analgesia.