Dose Range-Finding Report on the Immunological Evaluation of Morphine Sulfate (CAS No. 64-31-3) in Female B6C3F1 Mice
Report Date: December 1992
The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.
Morphine sulfate represents the prototype opiate antagonist which binds to the opiate receptor and produces biological effects on several systems of the body. Its actions as an analgesic and tolerance to this effect is well documented. Other systems of the body affected include the autonomic nervous system, cardiovascular and pulmonary systems, hepatobiliary system and the immune system.
Morphine sulfate was nominated for investigation by the National Institute of Drug Abuse based on several diverse studies that indicated that it is immunosuppressive.
The purpose of this range-finding study was to determine the doses and the exposure schedule for use in the protocol study. A time course study was performed using slow release 75 mg morphine pellets. The IgM AFC response to sRBC and MLR were used as the indicators of immunosuppression. A request was made to the National Institute of Drug Abuse for 3 pellet dose levels of morphine. As a part of the range-finding investigation, a dose-response study was performed which measured morphine levels and corticosterone levels as well as the IgM spleen antibody-forming cell response. The pellet sizes used were 8, 25, and 75 mg pellets.
The peak time for immunosuppression occurred when the antigen was administered 24 hours after implant. In these same studies, complete tolerance to the morphine action occurred by day 5 after implantation. Morphine levels reaching 1610 ng/ml were obtained within 24 hours of pellet implant. The studies showed that 24 hours after implant with 8 mg pellets morphine levels were 904 ng/ml while mice implanted with 25 and 75 mg dose pellets had mean blood levels of 1299 and 1610 ng/ml. The bioavailability of morphine in these pellets was not linear and the release on corticosterone was very similar for all three pellet sizes.