IMMUNOMODULATORY EFFECTS OF IN-VITRO EXPOSURE TO MORPHINE AND ITS METABOLITES

Both in vivo and in vitro exposure to morphine have been reported to p roduce a number of immunomodulatory effects in both laboratory animals and humans. The current study was performed to assess the direct in v itro effect of exposure to morphine or morphine metabolites on immune response parameters. Murine B6C3F1 splenic lymphocytes or peritoneal m acrophages were cultured in vitro at concentrations of 0.0001-100 mu m ol/l morphine sulfate, morphine-3-glucuronide, morphine-6-glucuronide, or normorphine. B cell proliferation was significantly suppressed fol lowing exposure to all drugs. Production of interleukin (IL)-2, IL-4, and IL-6 was affected only moderately by all drugs except morphine-6-g lucuronide, which produced a marked suppression at 100 mu mol/l. Both basal and augmented natural killer (NK) cell function were unaffected by any drug except morphine-6-glucuronide, which enhanced NK cell acti vity at concentrations between 0.0001 and 1.0 mu mol/l. In contrast, b oth morphine-3-glucuronide and morphine-6-glucuronide significantly in hibited cytotoxic T lymphocyte induction at concentrations between 0.0 001 and 100 mu mol/l, whereas morphine and normorphine were inactive i n this assay. In summary, in the absence of direct cellular cytotoxici ty, a differential immunomodulation was observed following in vitro ex posure to morphine and its metabolites.