Endogenous opioids regulate the expression of inducible nitric oxide synthase by splenocytes

In the present study, we tested the hypothesis that lipopolysaccharide (LPS )-induced expression of nitric oxide synthase (iNOS) by splenocytes is modu lated through the activation of endogenous opioids in the central nervous s ystem. The initial studies determined the parameters of LPS-induced express ion of iNOS by splenocytes. Rats were injected with LPS at doses of 0, 1, 1 0, 100, and 1000 mu g/kg, and measures of both iNOS mRNA and protein showed a dose-dependent increase in expression. In a time course study, rats rece ived 100 mu g/kg LPS and were killed at 0, 2, 4, 8, and 16 h postinjection. Both iNOS mRNA and protein expression was detectable at the 2-h time point , with peak expression occurring at 8 h. To evaluate the involvement of end ogenous opioids, the opioid receptor antagonist naltrexone was administered at 0, 0.1, 1, or 10 mg/kg s.c. in combination with LPS (100 mu g/kg), with a second injection of naltrexone at the same dose 4 h after the injection of LPS. Naltrexone induced a pronounced dose-dependent reduction in iNOS mR NA and protein expression by splenocytes. The modulation of iNOS expression occurs via central opioid receptors as intracerebroventricular administrat ion but not peripheral administration of N-methylnaltrexone, the quaternary form of naltrexone that does not readily cross the blood-brain barrier, re duced the expression of iNOS. For all of the manipulations, nitrite/nitrate levels in the plasma showed effects similar to those for iNOS mRNA and pro tein. Collectively, these findings indicate that central opioid receptors a re involved in the in vivo regulation of splenic nitric oxide production.