Opioid peptide-expressing leukocytes - Identification, recruitment, and simultaneously increasing inhibition of inflammatory pain

Background: Inflammatory pain can be effectively controlled by an interacti on of opioid receptors on peripheral sensory nerve terminals with opioid pe ptides released from immune cells upon stressful stimulation. To define the source of opioid peptide production, we sought to identify and quantify po pulations of opioid-containing cells during the course of Freund's complete adjuvant-induced hind paw inflammation in the rat. In parallel, we examine d the development of stress-induced local analgesia in the paw. Methods: At 2, 6, and 96 h after Freund's complete adjuvant inoculation, ce lls were characterized by flow cytometry using a monoclonal pan-opioid anti body (3E7) and antibodies against cell surface antigens and by immunohistoc hemistry using a polyclonal antibody to beta -endorphin. After magnetic cel l sorting, the beta -endorphin content was quantified by radioimmunoassay. Pain responses before and after cold water swim stress were evaluated by pa w pressure thresholds. Results. In early inflammation, 66% of opioid peptide-producing (3E7(+)) le ukocytes were HIS48(+) granulocytes. In contrast, at Later stages (96 h), t he majority of 3E7(+) immune cells were ED1(+) monocytes or macrophages (73 %). During the 4 days after Freund's complete adjuvant inoculation, the num ber of 3E7+ cells increased 5.6-fold (P < 0.001, Kruskal-Wallis test) and t he beta -endorphin content in the paw multiplied 3.9-fold (P < 0.05, Kruska l-Wallis test). In parallel, cold water swim stress-induced analgesia incre ased by 160% (P < 0.01, analysis of variance). Conclusions. The degree of endogenous pain inhibition is proportional to th e number of opioid peptide-producing cells, and distinct leukocyte lineages contribute to this function at different stages of inflammation. These mec hanisms may be important for understanding pain in immunosuppressed states such as cancer, diabetes, or AIDS and for the design of novel therapeutic s trategies in inflammatory diseases.