We have shown that opioid receptors are present and upregulated on peripheral sensory nerves and that opioid peptides are expressed in immune cells within peripheral inflamed tissue (Nat Med. 9:1003-8, 2003). Environmental stimuli (stress) and releasing agents (corticotropin releasing factor, cytokines) can liberate these peptides to elicit local analgesia, while suppression of the immune system abolishes these effects (J Clin Invest. 100:142-8, 1997). These findings have led to the concept that opioid peptides can be secreted from immunocytes, occupy opioid receptors on sensory nerves and produce analgesia by inhibiting the excitability of these nerves and/or the release of proinflammatory neuropeptides. Our recent investigations have examined G-protein coupling in sensory neurons innervating injured tissue (Mol Pharmacol. 64:202-10, 2003; J Pharmacol Exp Ther. 308:712-8, 2004), subcellular pathways of opioid peptide processing and release in immune cells (Endocrinology. 145:1331-41, 2004) and adhesion molecules, chemokines and growth factors governing the migration of opioid containing immune cells to injured tissue (Nat Med. 4:1425-8, 1998; J Neurosci. 22:5588-96, 2002; Anesthesiology. 100:149-57, 2004; Pain. 108:67-75, 2004). Clinical studies have now shown that small doses of opioids (e.g. morphine) applied into arthritic joints can not only produce long lasting pain relief but also decrease synovial inflammation (Nat Med. 9:1003-8, 2003; Pain. 83:525-32., 1999).