Inhibition of primary murine macrophage cytokine production in vitro following treatment with the kappa-opioid agonist U50,488H

Previous work in our laboratory has shown that both mu- and kappa-opioid agonists exhibit immunosuppressive activity for antibody responses in vitro. Our earlier work has suggested that both accessory cells and T cells may be altered following treatment with the kappa-opioid agonist U50,488H. We intend to further determine the identity of the immune cell population(s) which are affected by opioid treatment, and to determine the nature of the opioid receptor type expressed on these cells. In this study, non-elicited peritoneal macrophages were treated simultaneously with the kappa-agonist U50,488H and lipopolysaccharide (LPS), and the levels of the cytokines interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha were determined. The results show that U50,488H had a suppressive effect on the production of TNF-alpha and IL-1 at concentrations as low as 1 nM, while IL-6 was suppressed at concentrations as low as 10 nM. Additional experiments utilizing the opiate antagonist naloxone and the kappa-selective antagonist norbinaltorphimine (norBNI) were performed in order to further characterize the opioid receptor involved in the cytokine suppression produced by treatment with U50,488H. Results showed that naloxone was able to partially block U50,488H suppression while norBNI was able to completely reverse the suppression of IL-6 production. These results suggest that macrophage/monocyte function is significantly modulated following activation of the kappa-opioid receptor.