Central versus peripheral mediation of naloxone's perfusion effects in endotoxic rats

Opioid receptor antagonists can act centrally and peripherally. It is uncle ar if these 2 pathways differentially mediate the perfusion-associated effe cts of opioid antagonism during endotoxemia. Male, Sprague-Dawley rats (340 -390 g) were surgically prepared with left ventricular, tail artery, and ju gular vein catheters 24 h before experiments were begun. Conscious, unrestr ained rats were challenged with Escherichia coli lipopolysaccharide (LPS; 2 mg/kg/hr over 30 min) infusion. Measurements of regional blood flows were made using radioactive microspheres prior to (baseline), and at 60 and 120 min after LPS infusion. Saline (1 mL/kg bolus + 0.5 mL/kg/h infusion), nalo xone (Nlx; 4 mg/kg bolus + 2 mg/kg/h infusion), or naloxone methyl bromide (Nlx-mb; 4.64 mg/kg, bolus + 2.32 mg/kg/h infusion) were administered 40 mi n after LPS infusion was begun. Nlx-mb does not cross the blood-brain barri er, and was thus used to differentiate central from peripherally mediated r esponses. At the end of each experiment, blood samples were collected for d etermination of ET-1 and nitric oxide metabolites (NOX = NO3 + NO2) using e nzyme-linked immunosorbent assay (ELISA) and Griess reaction methods, respe ctively. Endotoxemia produced a significant decrease in cardiac output and an increase in systemic vascular resistance. Treatment with Nlx or Nlx-mb s ignificantly attenuated the endotoxin-induced elevation in systemic vascula r resistance and the decrease in cardiac output at 60 min after induction o f endotoxemia compared with their respective baseline values. Nlx and Nlx-m b also attenuated the endotoxin-induced increases in hepatic portal and ske letal vascular resistances. These observations suggested that the ameliorat ive effect of Nlx on endotoxemia-induced regional vascular resistance alter ations was mediated via peripheral opioid receptor mechanisms. However, alt hough Nlx attenuated the endotoxin-induced decreases in the blood flow to t he stomach and pancreas, Nlx-mb attenuated the endotoxin-induced decreases in the blood flow to the small intestine and cecum, in addition to the panc reas and, to some extent, the stomach. As such, separate central and periph erally mediated actions of opioid receptor antagonism were indicated. Nlx a lso resulted in an increase in the plasma levels of ET-1 only, whereas Nlx- mb increased the plasma levels of ET-1 and NOX. These observations suggest that separate central and peripheral effects of opioids during endotoxemia play a role in the associated circulatory alterations, and may differential ly affect the release and/or synthesis of vasoactive mediators that might b e related to their varied hepatosplanchnic vascular response during endotox emia.