Morphine enhances purine nucleotide catabolism in vivo and in vitro

Abstract

Aim: To investigate the effect and mechanism of morphine on purine nucleotide catabolism. Methods: The rat model of morphine dependence and withdrawal and rat C6 glioma cells in culture were used. Concentrations of uric acid in the plasma were measured by the uricase-rap method, adenosine deaminase (ADA) and xanthine oxidase (XO) in the plasma and tissues were measured by the ADA and XO test kit. RT-PCR and RT-PCR-Southern blotting were used to examine the relative amount of ADA and XO gene transcripts in tissues and C6 cells. Results: (i) the concentration of plasma uric acid in the morphine-administered group was significantly higher (P<0.05) than the control group; (ii) during morphine administration and withdrawal periods, the ADA and XO concentrations in the plasma increased significantly (P<0.05); (iii) the amount of ADA and XO in the parietal lobe, liver, small intestine, and skeletal muscles of the morphine-administered groups increased, while the level of ADA and XO in those tissues of the withdrawal groups decreased; (iv) the transcripts of the ADA and XO genes in the parietal lobe, liver, small intestine, and skeletal muscles were higher in the morphineadministered group. The expression of the ADA and XO genes in those tissues returned to the control level during morphine withdrawal, with the exception of the skeletal muscles; and (v) the upregulation of the expression of the ADA and XO genes induced by morphine treatment could be reversed by naloxone. Conclusion:The effects of morphine on purine nucleotide metabolism might be an important, new biochemical pharmacological mechanism of morphine action.

Effects of purine nucleotide administration on purine nucleotide metabolism in brains of heroin-dependent rats

“…Significant increases in UA concentration in plasma were observed in the rats following both morphine and heroin administration. The enzymatic activities of ADA and XO were found to be enhanced significantly in the brain and other organs of rats administered heroin, and morphine was shown to increase ADA and XO gene expression in the rat brain cortex (Liu et al, 2007;Yang et al, 2006).…”

“…However, in some organs, including the brain, purine nucleotide synthesis relies exclusively on salvage pathways. Previously, our research showed that gene expression levels of HGPRT, AK, and APRT, essential enzymes in the purine nucleotide salvage pathway, are down-regulated by heroin both in vivo and in vitro (Li et al, 2011;Liu et al, 2007). HGPRT catalyzes the salvage of the purine bases hypoxanthine and guanine to produce nucleotides (Balasubramaniam, Duley, Christodoulou, 2014).…”

“…Significant increases in UA concentration in plasma were observed in the rats following both morphine and heroin administration. The enzymatic activities of ADA and XO were found to be enhanced significantly in the brain and other organs of rats administered heroin, and morphine was shown to increase ADA and XO gene expression in the rat brain cortex (Liu et al, 2007;Yang et al, 2006).Our experiments using rat C6 glioma cells also revealed that the gene expression of HGPRT and AK, two key enzymes in the purine nucleotide salvage pathway, are down-regulated by morphine, indicating that morphine inhibits purine nucleotide anabolism (Liu, Hong, Zhao, 2003). To further clarify the effects of heroin on purine nucleotide metabolism in vivo, we measured the absolute content of purine nucleotides in rat brain cortices by HPLC, and found that the levels of AMP and GTP are significantly reduced in rats administered heroin, resulting in a purine nucleotide deficiency (Li et al, 2011).…”

“…Rats were administered morphine (ip) over a period of 7 days in doses of 20,30,45,55,65,85, and 95 mg/kg, respectively, to induce morphine addiction (Liu et al, 2007). Rats also received heroin (ip) over a period of 9 days in doses of 3, 3.45, 4.35, 5.7, 7.5, 9.75, 18.68, 17.16, and 21.12 mg/kg, respectively, to induce heroin addiction (Yang et al, 2006).…”

“…Imbalances in purine nucleotide levels lead to a variety of human diseases (Burhans, Weinberger, 2007;El-Hattab, Scaglia, 2013;Kimura et al, 2003). Studies have shown that morphine and heroin can enhance the oxidation of xanthine and hypoxanthine in the lobus temporalis, lobus frontalis, and lobus parietalis of rats (Liu et al, 2007;Yang et al, 2006). Uric acid (UA) is the final oxidation product of purine metabolism in humans and higher primates, and changes in UA levels may reflect the catabolism of purine nucleotides (Liang, Clark, 2004).…”