Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages

In this study we investigated the capacity of morphine to modulate expressi on of cytokines in peritoneal macrophages. Mice were implanted subcutaneous ly with a 75-mg morphine slow-release pellet, and 48 h later resident perit oneal macrophages were harvested. Control groups received placebo pellets, naltrexone pellets, or morphine plus naltrexone pellets, Adherent cells wer e stimulated with lipopolysaccharide (LPS: 10 mug/mL) plus interferon-gamma (IFN-gamma: 100 units/mL) to induce cytokine production. After 24 h RNA wa s extracted for analysis of cytokine mRNA levels by reverse transcriptase-p olymerase chain reaction, or supernatants were collected after 48 h for det ermination of cytokine production by enzyme-linked immunosorbent assay (ELI SA), Morphine enhanced mRNA expression of interleukin (IL)-12 p40 and tumor necrosis factor alpha (TNF-alpha) compared with controls, whereas IL-10 le vels were unchanged by drug treatment. ELISA data showed that both (IL)-12 p40 and p70 were increased by morphine. The enhancement of IL-12 at both th e mRNA and protein levels was antagonized by naltrexone, indicating that th e modulation of this cytokine by morphine is via a classic opioid receptor. These results are particularly interesting in light of our previous observ ation that 48 h after morphine pellet implantation, the peritoneal cavity i s colonized with gram-negative and other enteric bacteria. The enhancement of IL-12 by morphine might be related to morphine-induced sepsis.