Insight into the mechanism by which metoclopramide improves immune functions after trauma-hemorrhage

Although studies have shownthat prolactin (Prl) and metoclopramide (Mcp) administration restoresthe depressed cell-mediated immune functions after hemorrhage, theunderlying mechanism responsible for the immunostimulatory effects ofMcp remains unknown. We hypothesized that Mcp improves immune responsesby upregulating the secretion of Prl. To test this hypothesis, maleC3H/HeN mice were subjected to sham operation or laparotomy (i.e., softtissue trauma) and hemorrhagic shock (Hem; 35 ± 5 mmHg for 90 min) and then resuscitated. Plasma Prl levels were determined 30 minafter Mcp (1 µg/g body wt sc at end of Hem) or vehicle (Veh)treatment in sham and Hem mice. The results indicate that plasma Prllevels increased significantly in Mcp-treated mice (sham-Veh 249.9 ± 5.3, Hem-Veh 229.9 ± 7.6, Hem-Mcp 596.9 ± 73.1 ng/ml,one-way ANOVA, P < 0.05 vs. Veh). To determine whetherMcp produces its salutary effects directly or indirectly via increasedPrl secretion, splenocyte proliferation and splenocyte interleukin(IL)-2 and IL-3 release from untreated sham or Hem mice were determinedin the presence of increasing concentrations of mouse Prl or Mcp. Theaddition of Mcp had no effect on splenocyte immune functions in vitro.However, the addition of Prl restored the hemorrhage-induced depressedsplenocyte proliferation as well as splenocyte IL-2 and IL-3 release invitro in a dose-dependent manner. Thus the beneficial effects of Mcp onimmune functions after Hem appear to be mediated by Prl. Because Mcpincreases plasma levels of the immunoenhancing hormone Prl, this agentshould be considered a useful adjunct for the treatment ofimmunodepression in trauma victims.