Mechanism of hematocrit increase induced by the combined administration of morphine and Adriamycin: Role of histamine release

The mechanism by which morphine interacts with Adriamycin to increase hematocrit has been investigated in mice. Treatment with Adriamycin (12.8 mg/kg, iv) or morphine (20 mg/kg, sc) resulted in slight increases in hematocrit 30 min postdose, while animals given sc morphine 30 min prior to iv Adriamycin exhibited significant increases in hematocrit as early as 1 min post-Adriamycin. The hematocrit increase reached maximal levels 12 min post-Adriamycin and returned to basal values 4 hr postdose. Splenectomizing animals prior to morphine and Adriamycin treatment had no effect on the drug-induced hematocrit increase. This indicates that red cell release from splenic contracture is not the mechanism for the hematocrit increase. Measurement of plasma histamine levels following drug treatment demonstrated a marked and rapid rise in plasma histamine levels reaching maximal values 1 min post-Adriamycin. Adriamycin alone triggered this release; however, morphine pretreatment resulted in a higher maximum and more prolonged elevation of plasma histamine levels. Treatment with pyrilamine (3.1-50 mg/kg, ip) prior to morphine and Adriamycin administration partially reversed drug-induced hematocrit increase and protected against resultant lethality. Cimetidine (50-200 mg/kg, ip) treatment was not effective. The temporal relationship between hematocrit and histamine increases suggests a cause/effect relationship between released histamine and hematocrit elevation. Protection by pyrilamine and not cimetidine further supports this cause/effect relationship and indicates the effects is mediated via histamine type 1 receptors.