Dt. Lysle et T. How, Endogenous opioids regulate the expression of inducible nitric oxide synthase by splenocytes, J PHARM EXP, 288(2), 1999, pp. 502-508
Citations number
41
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.