Immunocyte-derived beta-endorphin can activate peripheral opioid receptors on sensory neurons to inhibit pain within inflamed tissue. This study examined mu-opioid receptors (MOR) on sensory nerves and beta-endorphin (END) in activated/memory CD4(+) cells (the predominant population homing to inflamed tissue). We found an upregulation of MOR in dorsal root ganglia, an increased axonal transport of MOR in the sciatic nerve and an accumulation of MOR in peripheral nerve terminals in Freund's adjuvant-induced hindpaw inflammation. A large number of CD4(+) cells containing beta-endorphin, but very few naive cells (CD45RC(+)), were observed in inflamed tissue, suggesting that this opioid is mainly present in activated/memory cells (CD4(+)/CD45RC(-)). Taken together, our results indicate an enhanced transport of both MOR and of the endogenous ligand beta-endorphin to injured tissue. This unique simultaneous upregulation of both receptors and ligands may serve to prevent excessive and/or chronic inflammatory pain.