Morphine modulates monocyte-macrophage conversion phase: implications in obstructive nephropathy

Abstract: Monocyte migration and its activation into the macrophage phenotype play a role in the modulation of fibrosis at the site injury. We studied the effect of morphine on the monocyte macro-phage conversion phase (MMCP) and its implica-tions in renal fibrosis. The effect of morphine on an established “in vitro model of MMCP ” was studied. In addition, mice receiving normal saline or mor-phine underwent unilateral ureteral obstruction (UUO) or sham operations for variable time periods followed by evaluation for interstitial macrophage accumulation and fibrosis. Morphine-receiving mice not only showed diminished renal interstitial accumu-lation of macrophages but also demonstrated attenu-ated fibrosis in the obstructed kidneys. As there was no difference in the tubular cell expression of che-moattractants in normal saline or morphine-receiv-ing mice, it appears that morphine inhibited intersti-tial macrophage accumulation despite chemoattrac-tion. In in vitro studies, morphine inhibited phorbol 12-myristate 13-acetate (PMA)-induced MMCP. However, opiate receptor antagonists attenuated this effect of morphine. It is interesting that PMA as well as morphine stimulated superoxide production by monocytes. Superoxide dismutase not only inhibited PMA-mediated MMCP but also attenuated the inhib-itory effect of morphine. PMA not only enhanced adhesion of monocytes to a filter but also promoted their migration. These findings suggest that the PMA-induced macrophage phenotype conversion may be accelerating their migration, whereas morphine may be preventing the migration of monocytes by inhibit-ing MMCP. Our in vitro findings provide insight into the mechanism involved in morphine-induced modu-lation of renal fibrosis in a mouse UUO model. J