nitric oxide and histone deacetylases modulate cocaine-induced mu-opioid receptor levels in pc12 cells一氧化氮和组蛋白去乙酰酶抑制剂调节cocaine-induced mu-opioid pc12细胞受体的水平.pdfVIP

Winick-Ng et al. BMC Pharmacology and Toxicology 2012, 13:11 /2050-6511/13/11 RESEARCH ARTICLE Open Access Nitric oxide and histone deacetylases modulate cocaine-induced mu-opioid receptor levels in PC12 cells 1 2 1* Warren Winick-Ng , Francesco Leri and Bettina E Kalisch Abstract Background: Cocaine exposure has been reported to alter central μ-opioid receptor (MOR) expression in vivo. The present study employed an in vitro cellular model to explore possible mechanisms that may be involved in this action of cocaine. Methods: To assess the effects of cocaine on MOR levels, two treatment regimens were tested in PC12 cells: single continuous or multiple intermittent. MOR protein levels were assessed by western blot analysis and quantitative PCR was used to determine relative MOR mRNA expression levels. To evaluate the role of nitric oxide (NO) and histone acetylation in cocaine-induced MOR expression, cells were pre-treated with the NO synthase inhibitor Nω-nitro-L-arginine methylester (L-NAME) or the non-selective histone acetyltransferase inhibitor curcumin. Results: Both cocaine treatment regimens significantly increased MOR protein levels and protein stability, but only multiple intermittent treatments increased MOR mRNA levels as well as c-fos mRNA levels and activator protein 1 binding activity. Both regimens increased NO production, and pre-treatment with L-NAME prevented cocaine-induced increases in MOR protein and mRNA levels. Single and multiple cocaine treatment regimens inhibited histone deacetylase activity, and pre-treatment with curcumin prevented cocaine-induced up-regulation of MOR protein expression. Conclusions: In the PC12 cell model, both NO and histone deacetylase activity regulate cocaine-induced MOR expression at